chinese medicine 2 (1)

CHINESE MEDICINE AND BIOMODULATION IN CANCER PATIENTS

CURRENT ONCOLOGY—VOLUME 15, NUMBER 28

INTEGRATIVE THERAPIES FOR ONCOLOGY

Copyright © 2008 Multimed Inc.

Chinese medicine andbiomodulation in cancerpatients—Part twoS.M. Sagar MD* and R.K. Wong MD*

ABSTRACT

Traditional Chinese Medicine (TCM) is a whole sys-tem containing therapeutic interventions that individu-ally induce biomodulation at the physiologic, chemi-cal, and molecular levels. The theory of TCM proposesa synergy between specific interventions selected aspart of a care plan based on TCM diagnostic theory.Combining TCM with the modern practice of oncologyseems, in conjunction with biomedical interventions(surgery, radiotherapy, chemotherapy, and pharmaceu-ticals), to have potential advantages through the synergyof biomodulation. Biomodulation approaches arebroadly categorized as modification of tumour responseand reduction of adverse effects; modulation of immu-nity; prevention of cancer progression; and enhance-ment of symptom control. Although the database ofpreclinical studies is rapidly expanding, good-qualityclinical trials are notably scarce.

Laboratory studies suggest that some herbs increasethe effectiveness of conventional chemotherapy with-out increasing toxicity. A healthy immune system isnecessary for control of malignant disease, and theimmune suppression associated with cancer contrib-utes to its progression. Many Chinese herbs containglycoproteins and polysaccharides (among them, con-stituents of Coriolus versicolor, Ganoderma lucidum,Grifola frondosa, Astragalus membranaceus, Panaxginseng, and various other medicinal mushrooms) thatcan modulate metastatic potential and the innate im-mune system. Phytochemicals such as specific poly-saccharides have been shown to boost the innate im-mune system, especially through interaction with Toll-like receptors in mucosa-associated lymphoid tissue.This intervention can potentially improve the effective-ness of new anticancer vaccines. An increase in virus-associated cancers presents a major public health prob-lem that requires novel therapeutic strategies. A numberof herbal therapies have both antiviral activity and theability to promote immunity, possibly inhibiting the ini-tiation and promotion of virus-associated cancers.

The mechanisms learned from basic science shouldbe applied to clinical trials both of specific interventionsand of whole-system care plans that safely combine

the TCM approach with the conventional biomedicalmodel. In Western medicine, the combination of TCMherbs with drug therapies is controversial, given lackof knowledge concerning whether a drug is favourablyenhanced or whether adverse effects occur. Using ini-tial data from the preclinical studies, future clinicalresearch needs to evaluate the combinations, some ofwhich are showing favourable synergy.

KEY WORDS

Chinese medicine, herbs, acupuncture, supportive care,immunity, research

1. INTRODUCTION

Biomodulation is the reactive or associative adjustmentof the biochemical or cellular status of an organism.Most modulation events describe an interaction inwhich a molecule (modulating entity) alters the abilityof an enzyme to catalyze a specific reaction. In thecontext of cancer, biomodulation includes the use of asubstance to augment the host’s antitumour response,including immunotherapy. It encompasses the regula-tion of innate electrophysiologic, chemical, and mo-lecular pathways through relatively low-intensity physi-cal and chemical interventions. In contrast to conven-tional biomedicine—for example, pharmaceuticals—therapies such as herbs or their extracts are a mixtureof chemicals administered at relatively low doses overa prolonged period of time. Acupuncture produces low-level electrochemical changes in the soft-tissue fas-cia. In TCM, the practice model includes the use of adiagnostic philosophy derived from cumulative clini-cal observation to target individual imbalances.

In Western medicine, the combination of TCM herbswith drug therapies is controversial, because of a lackof knowledge concerning whether the drug is favour-ably enhanced or whether adverse effects occur. Usinginitial data from preclinical studies, future clinical re-search has to evaluate the combinations, some of whichare showing favourable synergy. Both parts of this arti-cle deal with examples of biomodulation and the resultsof combining TCM with biomedicine. Part one discussed

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9CURRENT ONCOLOGY—VOLUME 15, NUMBER 2

the broad principles of TCM; part two discusses the po-tential clinical applications of TCM in oncology.

2. ROLES OF TCM IN BIOMODULATION

The goals of cancer treatment should be to increasesurvival (when possible) and to improve quality of lifefor patients. Traditional Chinese Medicine is able tosupport patients being treated with conventional West-ern medicine (surgery, radiotherapy, and chemotherapy)through four approaches:

1. Modification of tumour response and reduction ofadverse effects

2. Modulation of immunity3. Prevention of cancer progression4. Enhancement of symptom control

Very often, TCM therapy works through more thanone approach synergistically.

2.1 Modification of Tumour Response and Reduc-tion of Adverse Effects

2.1.1 Tumour PhysiologyEvidence increasingly suggests that TCM can favour-ably modify the tumour response to conventional West-ern cancer treatment. There is a correspondence be-tween the TCM theory of cancer and recent medicalresearch findings. In TCM, the malignant tumour isviewed as being associated with stagnation of qi (en-ergy) and blood. Qi may be viewed as a model forintracellular and intercellular information and poten-tial energy transfer. That definition would correlate withthe known abnormalities of signal transduction, cellcontact, and electrophysiology of cancer cells 1–3.

Increased fluid content and a stagnant blood sup-ply have been demonstrated in malignant tumours 4–6.The microcirculation within a tumour is very abnor-mal, and there are regions within the tumour wherethe blood flow is sluggish. In TCM, stagnation of bloodis classically associated with tumours. The impairedblood circulation leads to areas of poor oxygenation inthe tumour. Cancer cells that survive in an environ-ment of low oxygen tension are also found to be moreresistant to radiotherapy and to some types of chemo-therapy 7,8. Interestingly, the use of anticoagulants suchas heparin and coumadin (warfarin) as adjunctive treat-ment with chemotherapy has been shown in laboratorystudies in animals to prevent the development of blood-borne metastases and in clinical studies to improve thesurvival of cancer patients 9,10. Destagnation or de-toxification herbs are used to move the blood and qiwithin a malignant tumour. Many of these herbs areproving to be anti-angiogenic agents 11.

Herbs from TCM have been extensively investigatedin the laboratory and are known to have multiple phar-macologic effects 11–17. Specifying the botanical partsfrom which the herbal agent is prepared is important,

because the active pharmacologic agents depend ontheir source: “Radix” (Rx) denotes the root; “Cortex”(Cx), the bark or rind; and “Rhizome” (Rh), the rhi-zome. Many examples of anticancer therapeutic multi-plicity are available:

• Rx Ginseng has antitumour activity and inhibitsplatelet aggregation and chemotherapy-inducedimmunosuppression.

• Glycyrrhizic acid has antitumour activity, acts asan anti-inflammatory by increasing serum corti-sol, and also increases natural killer (NK) cell ac-tivity against cancer cells.

• Rx Astragalus membranaceus is a powerful stimu-lator of the immune system, has anti-tumour ac-tivity, and inhibits platelet aggregation.

• Rx Angelica sinensis stimulates the immune sys-tem, has antitumour activity, inhibits platelet ag-gregation, and inhibits vascular permeability.

• Rh Atractylodis macrocephala has antitumour ac-tivity and acts as an anti-thrombotic and fibrino-lytic agent.

• Ginkgo biloba has multiple effects, including inhibi-tion of platelet activation factor; stimulation of theimmune system, fibrinolysis, and anti-thrombosis;scavenging of free radicals; and dilation of blood ves-sels to increase perfusion.

As more is learned about the interactive roles ofbone marrow, hematopoietic system, and angiogen-esis in the progression of cancer, the foregoing ef-fects of herbs on the hemostatic coagulation systemare interesting 11.

The possible usefulness of destagnation herbs wasdemonstrated in a randomized controlled clinical trial(RCT) evaluating the combined-modality treatment ofa Chinese herbal destagnation formula and radiotherapyin patients with nasopharyngeal carcinoma 18. In thattrial, 90 patients who received combined herbal andradiation treatment were compared with 98 patientswho were randomized to receive radiation treatmentalone. The ingredients of the herbal formula includedRx Astragalus membranaceus, Rx Paeoniae rubrae,Rx Ligustici chuanxiong, Rx Angelica sinensis, Semenpersica, Flos Carthami tinctorii, Rx et Caulis jixueteng,Rx puerariae, Pericarpium citri reticulatae, and RxCodonopsitis pilosulae. As compared with the grouptreated with radiation alone, the combined-treatmentgroup showed a statistically significant increase in lo-cal tumour control and overall 5-year survival. The rateof local recurrence in the intervention group was halvedfrom 29% in those receiving radiation alone to 14% inthe group receiving destagnation herbs as well. The5-year disease-free survival was increased from 37%in the control group to 53% in the group receiving des-tagnation herbs.

It is postulated that the tested herbal destagnationformula may have improved tumour microcirculation andincreased tumour blood flow, leading to an improvement



in the oxygen tension inside the tumour. Improved oxy-gen tension increases the radiosensitivity of the tumour.In other words, the destagnation formula acted as aradiation sensitizer.

In animal experiments, Ginkgo biloba was alsoshown to increase perfusion and radiosensitivity 19,20.Chinese herbs such as Salviae miltiorrhizae, whichinhibits tumour edema caused by free radicals, mayalso increase tumour perfusion, oxygenation, and re-sponse to radiotherapy 21,22. Other herbs may directlysensitize neoplastic cells to radiotherapy 23.

Some herbs may protect normal tissues from ra-diotherapy. For example, Panax ginseng and Panaxquinquefolium water extract (Rh2 ginsenoside) exer-cise radioprotection through mechanisms involving anti-oxidative and immunomodulating properties 24. Thesubtle balance between anticancer effects and protec-tion of normal tissue—termed “therapeutic gain”—isnot currently understood.

The TCM herbs contain a variety of chemicals thatmay act synergistically to inhibit tumour cell division,to increase tumour cell death (apoptosis), to increasethe proportion of immune cells within the tumour, andto increase blood flow through the tumour. Thesechanges are associated with a change in the balance ofcytokines and other communicating peptides releasedby the immune cells, resulting in a reduction in theproliferation of tumour cells and an increase in tumourcell death, and in the minimization of many side ef-fects for normal tissues. This synergy appears to besecondary to induction of apoptosis, anti-angiogenesis,antagonism of the viral genome, and induction of animmune response.

Some herbs can reverse multi-drug resistance 25.Extracts of multiple Chinese herbs traditionally usedfor anticancer therapy (for example, Anemarrhenaasphodeloides, Artemisia argyi, Commiphora myrrha,Duchesnea indica, Gleditsia sinensis, Ligustrum luci-dum, Rheum palmatum, Rubia cordifolia, Salviachinensis, Scutellaria barbata, Uncaria rhynchophylla,and Vaccaria segetalis) demonstrate growth-inhibitoryactivity against various cancer cell lines, but limitedinhibitory activity against normal cell proliferation 17.Huanglian (Coptidis rhizoma) induces cell-growth ar-rest and apoptosis by upregulation of interferon-β andtumour necrosis factor α (TNFα) in human breast can-cer cells 26.

Recent meta-analyses confirmed the utility of Chi-nese herbs both to enhance control of particular cancers(particularly viral-induced cancers such as hepatocellu-lar carcinoma and nasopharyngeal cancers) and to re-duce side effects of chemotherapy 27,28. Laboratory stud-ies suggest that some herbs increase the effectiveness ofconventional chemotherapy. For example, red ginsengacidic polysaccharide increases the cytotoxicity ofpaclitaxel 29, and Phellinus linteus enhances the cytotox-icity of doxorubicin 30. A meta-analysis of Astragalus-based Chinese herbs and platinum-based chemotherapy

for advanced non-small-cell lung cancer indicates a prom-ising therapeutic gain 31.

Occasionally, herbs alone are associated with tu-mour regression. For example, a 51-year-old womanwith pathology-proven squamous cell carcinoma of thelung attained complete regression with the use of a com-bination of herbs as sole treatment (Herba Hedyotis dif-fusae, Rx Ophiopogonis, Herba Taraxaci, Rx Notoginseng,Pseudobulbus cremastrae seu pleiones, Rx Panacis quin-quefolii, Herba Houttuyniae, Bulbus Fritillariae thunber-gii, Rh Pinelliae preparata) 32. This anecdotal report isunusual, but deserves further exploration.

More clinical trials are required to further evaluatethe promising role for herbs in potentially improvingtherapeutic gain.

2.1.2 Hormone EffectsPhytoestrogens that possess either estrogenic or anti-estrogenic activity are found in some botanical supple-ments. Controversy has arisen concerning these substan-ces for patients with hormone-responsive cancers whocould theoretically deteriorate as a result of hormone-enhanced cancer progression. Angelica sinensis (dongquai), Glycyrrhiza glabra (liquorice), and the variousginsengs are cited in this category. However, in vitroand in vivo models of estrogenic activity have producedconflicting data. Clinically, the substances appear to serveas chemopreventive agents while also being capable ofpromoting growth in some estrogen receptor–positivecell lines. In addition, they may exert their estrogenicinfluence through either or both of receptor-dependent andreceptor-independent mechanisms 33–35. Other studiesdemonstrate inhibition of breast cancer cell models,particularly by ginseng and its extracts 36–41. Piersenreviewed the conflicting data in detail 42.

Test-tube assays have limitations. They ignore is-sues related to metabolism and cannot address bio-availability. Phytoestrogens usually demonstrate higheractivity in vitro than in vivo. In animals, route of ad-ministration and interspecies variability in metabolismproduce unreliable results for the human situation. Hu-man studies are confounded by the composition of gutflora, intestinal transit time, the redox potential of thecolon, and genetic differences in metabolism. In addi-tion, herbs are not single-entity drugs. Each is a com-plex mixture of hundreds of compounds that may exerttheir biologic activity alone or in synergy with othercompounds, with multiple targets of action 43. Even if aphytoestrogen compound is present, other compoundsmay counteract its effect.

In vitro studies of Angelica sinensis show weakagonist activity on MCF-7 breast cancer cells 44, buthuman studies do not support an estrogenic mechanismof action. Indeed, although the proposed main utility ofAngelica sinensis is to treat symptoms of menopause,a double-blind RCT showed no significant reduction inthe relief of such symptoms, in endometrial thickness,or in vaginal maturation index 45.

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The evidence for proestrogenic activity of theginsengs against breast cancer is extremely weak andderives from two in vitro studies on MCF-7 cells 33,35.A study of 20(S)-protopanaxadiol, a major gastro-intestinal metabolite of the ginsenosides, suggests that itinhibits estrogen-stimulated gene expression in MCF-7estrogen receptor (ER)–positive breast cancer cells,inhibits xenograft growth, and enhances the cytotox-icity of tamoxifen in an ER-independent fashion 39.The Rh2 ginsenoside extract hypersensitizes multi-drug-resistant breast cancer cells to paclitaxel 37. Thetumoricidal effect of cisplatin on MCF-7 cells is notattenuated by American ginseng (Panax quinquefoliusL.) 41. Water-extracted compounds of Panax quin-quefolius L. inhibit MCF-7 cell proliferation by inhibit-ing mitogen-activated protein kinase 40. A combina-tion herbal formula of ginseng and Carthami tinctoriiinhibits a breast cancer cell line through apoptosis 38.

Laboratory and epidemiologic data indicate thatwhole ginseng has anti-proliferative activity 37,46,47,and a clinical study reported improvement in qualityof life without increase in cancer recurrence 48. Anabstract from the Mao Clinic (Rochester) presentedat the 2007 American Society of Clinical Oncologymeeting reported a phase II RCT of North Americanginseng (Panax quinquefolium) for cancer patientssuffering from fatigue, demonstrating an up to 40%reduction in fatigue in patients on the highest doselevel. The cohort included breast cancer patients, andno adverse effects were reported 49. The safety aspectsof ginseng in patients with hormone-responsive can-cers are important because of emerging clinical evi-dence for the anti-fatigue and immunogenic propertiesof this herb.

The PC-SPES herbal combination has partial estro-genic activity associated with activity against pros-tate cancer. One study correlated laboratory activitywith clinical response 50. On the basis of those find-ings, a U.S. National Cancer Institute (NCI) RCT wasinitiated. Unfortunately, the clinical trial was termi-nated when a batch of PC-SPES was found to be con-taminated with the hormone diethylstilbestrol and otherpharmacologic agents. It is not certain whether thecontamination was accidental or the result of deliber-ate adulteration 51. However, there is evidence that thecombination was more effective than diethylstilbes-trol alone 52.

Soybeans contain genistein, which is an isoflavonewith multiple anticancer effects demonstrated in thelaboratory 15. These include the induction of tumourcell death through the process of apoptosis, inhibitionof cancer cell proliferation by a decrease in the avail-ability of sex hormones, inhibition of angiogenesis, in-hibition of tyrosine kinase (involved in intracellular sig-nalling from the membrane to the nucleus), and inhibi-tion of platelet aggregation 53–55. Some epidemiologystudies suggest that populations with a high soy or tofucontent in their diet may have a reduced risk of breastcancer 56–58; other studies have not been able to con-

firm this link 59. Animal studies suggest that exposureto soy during early life may alter differentiation of breastcells in a way that protects them against later assaultby carcinogenic agents 60. That finding would implythat soy protects against breast cancer only if regularlyingested before menarche. Some reports suggest thatphytoestrogens contained within soy may reduce thesymptoms of hot flashes associated with chemotherapy-induced menopause 61; however, most RCTs do not sup-port that hypothesis 62,63. Practitioners should be cau-tious in treating patients with ER-positive breast can-cer, especially those on estrogen antagonist therapy.The use of soy isoflavones to promote health in breastcancer survivors remains controversial because of scantscientific data 64,65.

Limited evidence suggests that acupuncture di-rectly influences hormone levels. There is weak evi-dence that it modulates hormones such as melatonin 66

and corticotrophin-releasing factor 67. Its effect is likelyto occur via the central nervous system and the pinealand pituitary glands. A nonrandomized human studyreported that acupuncture induced melatonin and wasassociated with improved sleep 66.

2.2 Modulation of Immunity

2.2.1 HerbsAnother strategy that TCM uses in cancer therapy isto strengthen the whole body–mind system by enhanc-ing and harmonizing the energy balance between allthe organs. This approach may be viewed as correct-ing an imbalance in the body–mind communicationnetwork—an intervention that is reflected in an enhan-cement in immunity. This “Fu Zheng treatment” ismediated by the specific group of TCM herbs calledFu Zheng herbs 68–78. There is some limited evidencethat improvement in the immunologic function of can-cer patients is associated with an improvement in theirsurvival. In China, Fu Zheng herbs have been reportedto increase survival when combined with radiotherapyfor patients with nasopharyngeal cancer 79 and whencombined with chemotherapy for patients with stom-ach and liver cancer 1,80, but the clinical evidence isweak because of a lack of RCTs.

Fu Zheng herbs, including Rx ginseng, Ganoderma,Rx Astragalus membranaceus, Rx Angelica sinensis,Cordyceps sinensis, and Fructus Lycii, have beenshown to enhance the body’s defence mechanisms.Clinical studies, including two randomized trials, havefound that cell counts of NK cells and OKT4 (immune-enhancing) lymphocytes were increased with the useof Fu Zheng herbs 68–78. These immunocytes are knownto attack cancer cells. In a study of gastric cancer pa-tients, increased survival was found in the combined-treatment group (receiving both Fu Zheng herbs andchemotherapy) as compared with the chemotherapy-alone group.

Many of the Fu Zheng herbs are associated withan increase in cytokines, such as interferon and



interleukin (IL) 81–83. Chinese studies also suggestthat healing of normal tissues may be enhanced. Anti-inflammatory constituents may diminish radiation-in-duced ulcers and chemotherapy-induced stomatitis 84,85.These studies still need to be verified in the West, usingacceptable standards and quality assurance.

Recently, the concept of immune enhancementgained new ground with the discovery that cytotoxictherapies and cancer both suppress immunity, and thatlow immune levels may increase the probability ofrelapse. In addition, an intact innate immune systemis necessary for activity of the new cancer vaccines.The interaction of host immunity with the natural his-tory of cancer is suggested by Burnet’s immune sur-veillance theory, by the fact that immunodeficiencydiseases are associated with an increased risk of can-cer, and by the fact that immune-enhancing therapiesin malignant melanoma and renal cell carcinoma haveproduced antitumour responses. There is evidence thatthe healthy immune system is necessary for the con-trol of malignant disease and that the immune sup-pression associated with cancer contributes to diseaseprogression.

Natural immune mediators are implicated in re-sistance against tumour development 86. Adaptive im-munity is often suppressed in tumour-bearing hosts, andspecially designed agents are required to boost thisdefence 87. Hormonal manipulation of the host can re-sult in the elevation of immune defences against can-cer. Such manipulation strengthens both the adaptiveand natural immune defences of the host, both of whichplay significant roles. Cytokines and hormones boostnatural defence mechanisms during febrile reactions,which are now known as the acute-phase response.Hormonal stimulation of immune mechanisms, cou-pled with other immunostimulants, may be employedto good advantage for the combination immunotherapyof cancer.

Many Chinese herbs contain glycoproteins andpolysaccharides that can modulate metastatic potentialand the innate immune system. Metastasis of malig-nant tumours may be a specific receptor-mediated proc-ess in which organ-specific lectins play a role in theadhesion of disseminated tumour cells. Glycoprotein-mediated membrane identity is part of the human leu-cocyte antigen histocompatibility system. The abnormalcarbohydrate group on the tumour cell could have formedduring malignant transformation. The metastatic tumourcell, with its membrane-associated glycoprotein (oftenidentical with the tumour marker) is recognized byorgan-specific lectins as belonging to the organ, and isthereby captured. In vitro experiments show thatgalactoglycoconjugates can inhibit the adhesion of tu-mour cells to hepatocytes 88.

Immune suppression in cancer contributes to pro-gression and relapse 86,89–97. Multiple strategies foridentifying candidate tumour antigens currently exist,and more is now understood about activation and regu-lation of immunity against cancer. Vaccines can target

tumour-specific antigens, but adjuvants are required toboost the innate immune response, especially in patientswho already have depressed immunity from tumour-derived signalling molecules and the effects of cyto-toxic therapies 98–100.

Phytochemicals such as specific polysaccharideshave been shown to boost the innate immune sys-tem, especially through interaction with Toll-like re-ceptors (TLRs) in mucosa-associated lymphoid tis-sue (MALT) 101–103. The TLRs evolved to interact withpolysaccharides found in the walls of bacteria; theyare an essential part of developing and maintaining acompetent immune system 104. Polysaccharide extractsand complexes from Chinese medicinal herbs andmushrooms may have a potential role in enhancing in-nate immunity. Clinical trials have provided some evi-dence that they can improve survival 105. The polysac-charide complexes and extracts include constituentsof Coriolus versicolor (whose extract is called Krestin,PSK, or PSP) 106–118, Ganoderma lucidum 119–121,Grifola frondosa (maitake MD-fraction) 122–127, Astra-galus membranaceus 128, Panax ginseng 129–132, andvarious other medicinal mushrooms 133–135.

Molecular mechanisms for the immunobiologicfunctions may act through various receptors on mac-rophages, monocytes, and NK cells, which activate sec-retion of nuclear factor κB and antitumour cytokines.Interactions may include complement receptor type 3,CD14, mannose, and beta-glucan receptors. There isevidence that polysaccharides derived from Astragalusmembranaceus, Acanthopanax senticosus and koreanum,Ganoderma lucidum, and Platycodon grandiflorum 136,137

interact with TLRs (especially TLR4).Regulatory T cells (Tregs) and myeloid suppres-

sor cells inhibit the anticancer activity of NK and T-helper cells and are partly responsible for tumour pro-gression, resistance to chemotherapy, and ineffectiveantitumour vaccines. Enhancement of innate immu-nity seems to improve anticancer therapies. Tregs arecharacterized by CD25 and FoxP3 expression. Theirnormal role is to control the adaptive immune responsethrough cell contact–dependent mechanisms. The in-terplay between Tregs and antigen-responsive T cellsis modulated by dendritic cells (DCs): whereas imma-ture myeloid precursors of DCs suppress T-cell activa-tion and induce Treg development, mature monocytes(macrophages) override Treg-mediated suppression.Mature DC macrophages can be activated through theTLR pattern-recognition receptors found on monocytesin the gastrointestinal tract. They then secrete IL-6,which renders T-helper and NK cells refractory to thesuppressive effect of Tregs 138.

Other studies have shown that elimination of Tregscan significantly improve the outcome of cancer im-munotherapy in preclinical models. For example,Sutmuller et al. 139 showed that therapeutic whole-cell vaccination against melanoma was significantlymore effective upon depletion of CD4+CD25+ Tregswith an anti-CD25 monoclonal antibody. Unfortunately,

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they also showed that Treg depletion with anti-CD25antibody carries an inherent risk of depleting tumour-specific effector CD4+ (and possibly CD8+) T cells, thusnegatively affecting treatment efficacy. Myeloid sup-pressor cells may have additional properties that cancompromise anticancer therapies, such as promotionof angiogenesis 140. Specific cytokines also play a rolein immune suppression. The cytokines IL-13 and IL-4suppress NK T cell immunosurveillance 141.

Tregs that suppress immune responses may limitthe efficiency of cancer immunotherapy. Recent find-ings indicate that TLRs directly regulate the suppres-sive activity of Tregs. Linking TLR signalling to thefunctional control of Tregs may offer new opportuni-ties to improve the outcome of cancer immunotherapyby co-administration of certain TLR ligands 142. Stimu-lation by TLR blocks the generation of DCs from pro-genitor cells and diverts them to mature macrophagemonocytes. That effect is achieved by inhibition ofgranulocyte–macrophage colony–stimulating factor sig-nalling through the induction of SOCS1.

Microbial ligands are able to skew the dichotomyof macrophage versus DC differentiation from com-mon progenitors. In uninflamed tissues, granulocyte–macrophage colony–stimulating factor induces the gen-eration of immature DCs, preparing the host to senseinfectious danger. However, during infectious inflam-mation, TLR stimulation drives incoming monocytesto behave more like macrophages than to differentiateinto DCs. That mechanism could be of help for the di-rect antimicrobial defence, which is more effectivelymediated by macrophage-like cells with a high capac-ity to phagocytise. Pre-existing resident DCs are suffi-cient to perform the task of antigen sampling and trans-duction of information to the adaptive immune system.Thus, TLR stimulation would guide the innate immunesystem to assure a sufficient supply of phagocytic cellsin inflamed tissues 143.

Garay 144 reviewed the potential benefits of TLRagonists when added to chemotherapy TLR2/4 agoniststo induce well-controlled TNFα secretion at plasmalevels known to make neoangiogenic tumour vesselspermeable to the passage of cytotoxic drugs. Moreo-ver, TLR2/4 agonists induce expression of induciblenitric oxide synthase, and nitric oxide is able to indu-ce apoptosis of chemotherapy-resistant tumour cell clo-nes. Finally, TLR2/4 stimulation activates dendritic celltraffic, macrophage production, and cytotoxic T-cellresponses.

Breast cancer patients have increased levels ofTregs 145. Vaccine peptides need to be combined withstrong adjuvants, such as TLR agonists. A peptide vac-cination strategy that incorporates a TLR agonist couldprevent the occurrence of spontaneous breast tumours.Transgenic mice that carry the activated rat epidermalgrowth factor receptor HER2/neu oncogene were vacci-nated with a synthetic peptide from the rat HER2/neugene product in combination with a TLR agonist adjuvant.The results show that, to obtain tumour antigen–specific

T-lymphocyte responses and antitumour effects, thefunction of CD4/CD25 Tregs had to be blocked withanti-CD25 antibody therapy. Mice that were vaccinatedusing this approach remained tumour-free or wereable to control spontaneous tumour growth; they alsoexhibited long-lasting T-lymphocyte responses. Theresults suggest that similar strategies should be fol-lowed for conducting clinical studies in patients 146.

The polysaccharide beta-glucans stimulate leu-kocyte anti-infective activity and enhance (murine)hematopoietic activity. In a study of human bone mar-row mononuclear cells, PGG-glucan acted on commit-ted myeloid progenitors to enhance activity by directaction independent of IL-3 147. Beta-glucans and poly-saccharides are potent stimulators of TLR. Some spe-cific polysaccharides have already been shown to boostthe innate immune system through interaction withTLRs in MALT 101–103.

Polysaccharide extracts and complexes from Chi-nese medicinal herbs and mushrooms seem to have apotential role for enhancing innate immunity. There issome evidence from clinical trials that they can im-prove survival 105. Polysaccharide extracts from Panaxginseng can increase immunity and enhance chemo-therapy 129–131. There is evidence of interaction withTLRs, especially TLR4 136,137,148.

Maitake D-Fraction, a polysaccharide extractedfrom maitake mushrooms (Grifola frondosa), has beenreported to exhibit an antitumour effect through acti-vation of immunocompetent cells, including macro-phages and T cells, with modulation of the balancebetween T-helper 1 and 2 cells. It can lower the dos-age of mitomycin chemotherapy that is effective intumour-bearing mice by increasing the proliferation,differentiation, and activation of immunocompetentcells 123.

Further evidence of the potential usefulness ofpolysaccharides in stimulating an enhanced immuneresponse comes from a study of orally administeredbeta-glucans (from maitake mushrooms) that demon-strated an enhancement of the antitumour effects ofmonoclonal antibody–targeted therapies 149. A meta-analysis of another immune-enhancing botanical, As-tragalus, reported an enhancement of the efficacy ofplatinum-based chemotherapy for lung cancer 31 andPSK (Coriolus versicolor) for the enhancement oftegafur for colorectal cancer 108.

Immunosuppression in cancer patients can reducethe efficacy of anticancer vaccines and increase com-plications from opportunistic infections. Polysac-charides (mainly beta-D-glucans alone or linked to pro-teins) from the cell walls of various traditional Chi-nese medicinal mushrooms and plants show antitu-mour and anti-infective activities through activationof monocytes, macrophages, and NK cells. A futureresearch strategy should authenticate the source ofthese polysaccharide extracts and screen them for in-teraction with TLRs in the gastrointestinal tract ofanimals. Oral agents that boost cell-mediated



immunity through MALT may be subsequently evalu-ated in human phase I studies for dose–response(cytokine and immune cell assays) and safety.

Optimized, authenticated polysaccharides may playa role in enhancing the potency of anticancer vaccinesand other therapeutic modalities. These non-cytokinemolecules appear to signal primarily through the TLRs,which are expressed by dendritic cells. In MALT, theseagonists can induce a host of pro-inflammatorycytokines such as TNFα, IL-12, and IL-6, as well asCD4+ and CD8+ T cells.

Combining radiation therapy and TLR agonists mayreduce the amount of radiation therapy required toeradicate tumours, with the TLR agonists thus actingas immunosensitizers 150,151. Evidence of the poten-tial usefulness of polysaccharides in stimulating anenhanced immune response is strengthened by the studyof orally administered beta-glucans (from maitakemushroom) that showed enhancement of the antitumoureffects of targeted monoclonal antibodies 149. Ganopoly(a Ganoderma lucidum polysaccharide extract) modu-lated immune function in advanced-stage cancer pa-tients. Treatment for 12 weeks resulted in a significantincrease in the mean plasma concentrations of IL-2,IL-6, and interferon-γ, and a decrease in IL-1 and TNFα.Activity of NK cells increased, but no significant changewas observed in the levels of CD4+ or CD8+, or in theCD4+/CD8+ ratio 122.

Lymphoproliferative neoplasms, such as lympho-mas and leukemias, may be particularly sensitive tochanges in cytokine balance. The Memorial Sloan–Kettering Cancer Center in New York has commencedan NCI-sponsored phase I study of beta-glucan andrituximab in pediatric patients with relapsed or pro-gressive CD20-positive lymphoma or leukemia 152.

The evidence indicates that a healthy immune sys-tem is necessary for the control of malignant diseaseand that the immune suppression associated with can-cer contributes to disease progression. Tumours havedeveloped strategies to successfully evade the hostimmune system, and various molecular and cellularmechanisms responsible for tumour evasion have beenidentified. Some of these mechanisms target immuneantitumour effector cells. Dysfunction and apoptosisof those cells in the tumour-bearing host creates animmune imbalance that cannot be corrected by tar-geted immunotherapies alone. Reversal of existingimmune dysfunction and normalization of lymphocytehomeostasis in patients with cancer needs to be a partof future cancer immunotherapy 86. Therapeutic strat-egies are being designed to correct the immune im-balance, to deliver adequate in vivo stimulation, totransfer effector T cells capable of in vivo expansion,and to provide protection for the immune effector cellsrepopulating the host. Survival of these cells and long-term immune “memory” development in patients withmalignancy are necessary for improving the clinicalbenefits of cancer immunotherapies. Polysaccharidesderived from Chinese herbs and mushrooms are

emerging agents that seem to enhance cytotoxic drugs,radiotherapy, surgery, and the newer targeted thera-pies and vaccines 31,105,153. Rigorous authenticationand quality control of these phytoceuticals are neces-sary before clinical studies begin 43.

2.2.2 AcupunctureMultiple animal and clinical studies have also suggestedthat acupuncture has a positive immune-modulatingeffect in cancer patients 154–162. In those studies,acupuncture has been shown to increase T-lymphocyteproliferation and NK cell activity, to activate the com-plement system and heat-stable mitogenic humoralfactor, and to increase OKT4 cell counts. Inhibition ofthe growth of transplanted mammary cancer has alsobeen shown in mice with the use of acupuncture. Themain acupoints that were used in these studies werethose that support blood formation and spleen function.These points include LI4, LI11, St36, Sp6, Sp10, P6,UB20, GB39, and GV14. An increased level of allcomponents (red blood cells, white blood cells, andplatelets) was found.

Lu et al. recently reported an exploratory meta-analysis of the clinical trials 163. The trials from theChinese journals suffered from low quality and biases.An analysis of a small set of seven trials did not findstatistical significance in publication bias. The hetero-geneity was explained by the varying treatment char-acteristics. The frequency of the acupuncture was oncedaily, with a median of 16 sessions. Use of acupunc-ture was associated with an increase in leukocytesduring chemotherapy, with a weighted mean differenceof 1221 cells/μL (95% confidence interval: 636 to 1807;p < 0.0001).

2.3 Prevention of Cancer Progression

In China, a high incidence of chronic viral infectionsresults in cancers. Cancer sites include liver, stomach,esophagus, and nasopharynx. In addition, cervix can-cer has increased to become the second most commoncancer in women. The cause of the relatively higherincidence of virus-associated cancers as compared withthe West is unclear. Factors include spread of infec-tion, genetic predisposition, poor diet, and smoking. Aninadequate response from the immune system to eradi-cate chronic viral infections and cancer cells is a com-mon determinant. The total number of new cases ofcancer was expected to increase by almost 15% by2005. The increase in virus-associated cancers presentsa major public health problem that requires more datadirected at developing novel therapeutic strategies basedupon local evidence-based remedies.

Hepatocellular carcinoma (HCC) is ranked secondin cancer mortality in China, and the disease is nowalso increasing in frequency in men in many other coun-tries. Hepatitis B (HBV) and C (HCV) viruses remainthe major causative factors, and the hepatitis G virusand other transfusion-transmitted viruses cannot be

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excluded 164. Infection with HBV is nearly ubiquitousin HCC patients in China. The tight association of HBVwith HCC strongly suggests the dominant role of HBVinfection in causing the cancer. Almost 12% of HCCpatients have co-infection with HBV and HCV 165. Ameta-analysis concluded that HBV and HCV infectionsare important independent risk factors for HCC, andthat dual infection with HBV and HCV is associated witha higher risk for HCC than is either infection alone,suggesting a synergism between the two 166.

Nasopharyngeal cancer is associated with Epstein–Barr virus infection 167,168. It may also be associatedwith some cases of Hodgkin lymphoma 169 and gastriccancer 170. Its highest incidence is in the SouthernChinese population, with familial aggregation. Theannual detection rate is 433 per 100,000 for men and499 per 100,000 for women in high-risk families, ascompared with an average overall annual incidence inHong Kong of 24 per 100,000 for men and 10 per100,000 for women 171.

The incidence of cervix cancer is increasing. Thecombination of human papilloma virus (HPV) infec-tion and cigarette-smoking is synergistic for the in-duction of cervix and anal cancers. In the West, thesubtype HPV16 is the most common cause; in China,other types of HPV viruses (for example, HPV18 and59) are more commonly associated with the disease.The HPV16 E7 variant protein may induce a host hu-moral immune response, but not a special cellularimmune response 172. The association is strengthenedin smokers. Inducing an appropriate cell-mediatedimmune response may be key to eradicating the virusand its potential to induce and promote cancer. TheHPV16 virus is also a major factor in the developmentof esophageal cancer in China, but not yet in the West173,174. In addition, the West and China are both ex-periencing an increase in HPV-associated head andneck cancers 175,176. Another major concern is a risein breast cancer in women. Although a high-fat diet,less exercise, and reduced parity are contributing fac-tors, infection with the HPV33 virus appears to play arole in China 177.

Most evidence for successful herbal treatmentof cancers comes from case reports or case seriesthat may be biased by selection or spontaneous re-mission 178; however, a meta-analysis of existingRCTs provided promising evidence that combiningChinese herbal medicine with chemotherapy may ben-efit patients with HCC 28. A major weakness of the datais that high-quality, rigorously controlled trials are lack-ing. Reasonable epidemiologic evidence suggests thatPanax ginseng is a non-organ-specific cancer preven-tive, with a dose–response relationship 179. Ginsengextracts and synthetic derivatives should be examinedfor their preventive effect on various types of humancancers. A case–control study of green tea consump-tion and lung cancer in a population of women living inShanghai showed an association with reduced risk innon-smoking women 180.

Some Chinese herbs increase immunity. AlthoughAstragalus, Ligusticum, and Schizandrae have a longhistory of medicinal use within the TCM system, theWest has only recently begun to understand theirpharmacologic possibilities and clinical applications.Astragalus has demonstrated a wide range of immu-nopotentiating effects, and it has proven efficacious asan adjunct cancer therapy. Ligusticum and its activecomponents have been investigated for enhancementof the immune system, treatment of ischemic disor-ders, and use as an anti-inflammatory. Clinically, thehepatoprotective and antioxidant actions of Schizandraehave proven beneficial in the treatment of chronic vi-ral hepatitis 181. More data are required to determinethe clinical effects of Chinese herbs on immunity andto prevent cancer progression 182.

The prevalence of AIDS is increasing rapidly 183,and research into the effectiveness of Chinese herbson immunity may also help people with that syndrome.The syndrome is a result of infection with HIV, whichsubsequently leads to significant suppression of immunefunction. The search for effective therapies to treat AIDSis of paramount importance. Several chemical anti-HIV agents have been developed; however, besides highcost, adverse effects and limitations are associated withthe use of chemotherapy for the treatment of HIV in-fection. Thus, herbal medicines have frequently beenused as an alternative medical therapy by HIV-positiveindividuals and AIDS patients in China. For example,Scutellaria baicalensis georgi and its identified com-ponents (that is, baicalein and baicalin) have beenshown to inhibit infectivity and replication of HIV 184.Some preliminary evidence of efficacy has recentlybeen published 185.

Data from controlled clinical trials suggest thatmedicinal mushrooms may be beneficial as adjunc-tive anticancer therapies 120,186. A RCT in colorectalcancer patients receiving curative resection comparedadjuvant chemotherapy alone to chemotherapy plus anextract (PSK) from the fungus Coriolus versicolor. Bothdisease-free and overall survival were significantlyhigher in the group that received the PSK 117. Medici-nal mushrooms contain a class of polysaccharidesknown as beta-glucans that promote antitumour im-munity. They may act synergistically with some ofthe new therapeutic antibodies and chemotherapyagents and may protect normal marrow 149,187.Maitake mushroom and Ganoderma lucidum are bothChinese medicinal mushrooms that are showing pre-liminary evidence that they can suppress viral infec-tions and inhibit cancer progression through modula-tion of the immune system 124,188–190.

In TCM, appropriate nutrition according to specificconstitutional and disease patterns is also emphasized.Green tea (Camellia sinensis) and Panax ginseng aretwo dietary supplements that have been extensivelyinvestigated in both laboratory and epidemiologic stud-ies. Both reduce the risk of cancer induction, and theymay prevent cancer recurrence 191–193. Green tea



contains isoflavones and a powerful antioxidant calledepigallocatechin 194. The latter may potentiate the de-struction of cancer cells by promoting apoptosis andinhibiting angiogenesis 195,196. Panax ginseng mayinduce the differentiation of neoplastic cells into nor-mal tissue 197. Both epigallocatechin and ginseng re-store normal intercellular communication through thegap junctions 3. Both dietary supplements work throughnovel mechanisms of signalling.

The isoflavones and phytoestrogens in soy appearto reduce the incidence of prostate cancer and mayplay a role in prevention and as adjunctive therapy toreduce the risk of recurrence 198–202. Cell culture andanimal xenograft studies show that treatment with soyis associated with inhibition of prostate-specific anti-gen, deactivation of nuclear factor κB (a nuclear tran-scription factor), induction of apoptosis (programmedcell death), and inhibition of angiogenesis 203–206.

Future goals for cancer prevention in China includepublic education to reduce the risk of infection, massimmunization, antiviral drugs, and chemotherapy. Theseare extremely expensive programs, and more educa-tion and research are required before their implemen-tation. However, many Chinese currently have accessto traditional herbal remedies within the culture of TCM.Some of the herbs and their derivatives seem to beeffective treatments. An opportunity exists to develop,refine, and evaluate the effectiveness of Chinese herbalmedicine to prevent the development of cancers sec-ondary to virus infections.

The idea of using Chinese herbs to prevent cancerprogression is already being tested in the West. A TCMherb combination may reduce the risk of lung cancerin ex-smokers. An NCI-sponsored study being conductedthrough the BC Cancer Agency, led by Dr. StephenLam, is recruiting participants 45–74 years of age whoare ex-smokers to evaluate the efficacy of a herbalcombination called “anti-cancer preventive healthagent” (ACAPHA) 207. This compound contains Sophoratonkinensis, Polygonum bistorta, Prunella vulgaris,Sonchus brachyotus, Dictamnus dasycarpus, andDioscorea bulbifera. In Chinese studies, ACAPHA re-duced the risk of esophageal cancer by 50%, by re-versing severe esophageal dysplasia. In addition, a pi-lot study of 20 former heavy smokers with bronchialdysplasia treated with ACAPHA showed that, after 6months, 50% had complete regression of dysplasia, ascompared with only 13% of subjects in the placebogroup. Panax quinquefolium (American ginseng) ap-pears to reduce death and increase quality of life insurvivors of breast cancer, suggesting that somebotanicals may prevent recurrence 208.

2.4 Symptom Control

Cancer patients experience multiple symptoms relatedeither to the cancer itself or to late treatment side ef-fects. Even if the cancer is cured, the survivor maystill be suffering from the late treatment side effects,

which have an adverse effect on quality of life and areoften not effectively managed with conventional West-ern medicine. Chinese medicine plays a useful role insupportive care for these symptomatic cancer patients.Symptoms that can be effectively managed includegeneral constitutional symptoms such as fatigue, de-pression, and pain, and specific symptoms such asgastrointestinal side effects and myelosuppression.

Cancer patients receiving chemotherapy usuallydevelop myelosuppression (with risk of infection andbleeding) and gastrointestinal side effects (nausea,vomiting, and diarrhea). They easily become fatiguedand develop a reduced appetite. In TCM terms, thechemotherapeutic agents are causing Spleen and Kid-ney deficiency, leading to a general decrease in qi andblood. Note that “Spleen” and “Kidney” refer to com-munication systems (resembling the acupuncture me-ridian system) rather than actual organs. Radiotherapyand chemotherapy act as “heat toxins” that damageyin and qi. “Heart fire” is expressed as stomatitis; “de-ficient Spleen qi” is manifest as diarrhea. Chemo-therapy drugs “disturb Spleen and Stomach qi,” ex-pressed physically as damage to the lining of the stom-ach and intestines 51.

The conventional oncologist will often find thatthe language of a TCM practitioner seems quite unu-sual and metaphoric, but that language is consistentwithin the TCM system of diagnosis and treatment.The physical expressions are only part of the distur-bance in the body–mind network, and they will inevi-tably be accompanied by emotional disorders (suchas depression, anxiety, insomnia) and constitutionalchange (such as fatigue or hyper-excitability and poorconcentration). After an evaluation and diagnosis ofthe disturbance in the body–mind network, appropri-ate combinations of herbs, acupuncture, nutrition, andQigong may be utilized.

2.4.1 HerbsGastrointestinal Toxicity, Depressed Immunity, andFatigue: Chinese medicine treats the combination ofgastrointestinal symptoms, depressed immunity, andfatigue as a single syndrome. Spleen and Stomach qiare supported by appropriate formulas containing Rxginseng, Poria, and Rh Atractylodis macrocephala 51.Ginger root has been shown in many clinical studiesto have antiemetic activity 209–213. It appears par-ticularly to help nausea that may be intransigent tostandard antiemetics. Ginger syrup was shown in aRCT to be effective 214. Caution should be used inpatients on anticoagulants or those with low plateletlevels, because the syrup has anticoagulant effects athigher doses.

Depleted yin leads to dry and sore mouth, thirst,constipation, and scanty dark urine. The harmoniousrelationship between Kidney and Heart is disturbed,leading to insomnia, restlessness, disorientation, pal-pitations, and low back pain. This combination ofsymptoms is traditionally alleviated with combinations

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of Rh Anemarrhenae, Cx Phellodendron, and RxRehmanniae.

Vitexina (Vigna radiata) is a flavonoid herb withradioprotective effects that may be useful for reducingsome side effects of radiotherapy. It treats the heat(yin)–deficiency side effects of anticancer treatment,such as fatigue, restlessness, insomnia, and constipa-tion. This “empty heat” syndrome is characterizedthrough tongue diagnosis, which reveals a red, denuded,and cracked tongue. Because the tongue is the mostdensely innervated organ in the body, it may reflect theimbalance between yin and yang via the autonomicnervous system, which in turn may influence blood flowand epithelial cell turnover through the local release ofneuropeptides and cytokines. A RCT of breast cancerpatients receiving radiotherapy showed that vitexinaprevented the “empty heat” syndrome, reduced weightloss, and protected against a reduction in peripherallymphocytes and platelets 215.

According to Chinese medicine, the weakening ofqi is associated with depressed immunity and suscep-tibility to infection and cancer progression. Medicinalmushrooms such as Ganoderma, Cordyceps sinensis,and Shitake strengthen the qi, which is associated withan improved immune profile and antitumour activity.Another herb with potent immune-stimulating proper-ties is Rx Astragalus membranaceus. In Western ter-minology, these patients are fatigued and have de-pressed immunity that renders them more susceptibleto infection. High-quality clinical studies are rare, butthe Mao Clinic (Rochester) recently reported a prom-ising phase II RCT of ginseng (Panax quinquefolia L.)for fatigue in cancer patients. They reported a dose–response and demonstrated a 40% reduction in fatiguefor patients taking the highest dose level as comparedwith those taking placebo 49.

At least five RCTs have shown that Chinese herbaltreatment can decrease the degree of myelosuppres-sion, reduce gastrointestinal side effects, and increaseappetite 39,68–71,73-78,80,216. Importantly, such treat-ment can also increase the probability of completionof scheduled chemotherapy. One randomized trialrecruited 669 patients with late-stage gastric cancer 74.One group of patients was treated with herbs that sup-port Spleen and Kidney function (“jian pi yi shen pre-scription”) twice daily for 4–6 weeks with concurrentchemotherapy; another group was treated with thesame type of chemotherapy alone. The combined-treatment group showed significantly higher leukocyteand platelet counts with fewer general and gastroin-testinal side effects. The percentage of patients com-pleting the scheduled chemotherapy was 95% in thecombined-treatment group as compared with 74% inthe chemotherapy-alone group (a statistically signifi-cant result at the 0.01 level). Unfortunately, the qual-ity and verification of the data from these studies,which were reported from China, are not at a highenough standard that a definitive meta-analysis canbe undertaken at this stage.

A more recent high-quality study was reported fromHong Kong 217. This double-blind placebo-controlledRCT used Chinese herbal medicine for the reduction ofchemotherapy-induced toxicity from adjuvant therapyfor breast or colon cancer. The herbal combination wasindividualized by the TCM practitioner and thenrandomized against placebo. The investigators couldnot show a reduction in hematologic toxicity, but theyreported a significant impact on control of nausea.

The role of Chinese herbs in combination with con-ventional Western pharmaceuticals for symptom con-trol is currently unclear. Laboratory data suggest thatherbs can be effective modifiers of biochemical path-ways, immunostimulants, and signal transductionmodulators. But detrimental interactions and idiosyn-cratic toxicity are certainly a potential possibility.

A Cochrane systematic review of Chinese medi-cinal herbs for chemotherapy side effects in colorectalcancer patients found some merit in the concoctiontermed “huangqi compounds” (containing Astragal-us) 27. Four relevant trials were reviewed, all of lowquality. None of the studies reported common toxic-ity criteria. There appeared to be a significant reduc-tion in the number of patients who experienced nau-sea and vomiting, a decrease in the rate of leucope-nia, and an increase in T-lymphocyte subsets. Althoughno adverse effects were reported, these are rarelydocumented in Chinese studies. Another Cochranesystematic review of Chinese medicinal herbs usedto treat the side effects of chemotherapy in breastcancer patients provided limited evidence, althoughbenefits in bone marrow improvement and quality oflife were suggested 218. Future studies using more rig-orous methodology and quality assurance are required.

Chemotherapy and Radiotherapy-Induced CognitiveDysfunction: Chinese herbal therapies may have a rolein improving cognitive function. Because conventionalpharmaceutical interventions have produced verylimited improvement, opportunities are opening toinvestigate some natural health products from theChinese pharmacopoeia.

Many patients complain about changes in cogni-tive function during and after chemotherapy. This phe-nomenon has been particularly studied in breast can-cer patients 219,220. Despite the fact that neurocognitivedeficits limit productivity and independence forpatients, these problems are underreported by patientsand underdiagnosed by health care professionals. Atleast 18% of cancer patients who received standard-dose chemotherapy manifested cognitive deficits onpost-treatment neuropsychological testing, and thateffect may be sustained 2 years after treatment 221.The patients typically complain of a “foggy brain.”The impairments have an impact on tests that requiresustained attention and speed of information process-ing. Fatigue and depression are associated disorders.Whether the initial cause of dysfunction is attribut-able to loss of neuronal integrity or is secondary to a



metabolic pathology is as yet unknown. There maybe a genetic component, such as the e4 allele of Apo-lipoprotein 222.

Because “chemo-brain” is mainly a subjectivephenomenon, it is important to develop techniques toobjectively measure neurophysiologic or anatomicchanges 223–226. Cytokines such as IL-1 and interferonsmay play a role, according to some animal experiments.Chemotherapy may damage the endothelium of bloodvessels, resulting in thromboses and micro-infarcts inthe central nervous system. Currently, the changes thatoccur in cerebral tissue after anticancer treatments arepoorly understood, and no proven interventions areavailable.

Radiotherapy treatment of the brain can also impaircognitive function. Long-term survivors experience ma-jor cognitive dysfunction that influences their rehabili-tation and quality of life. Radiotherapy can damage thebrain, eventually resulting in demyelination that mayappear only months later and lead to the development ofcognitive impairment. These deficits manifest as anyor all of impaired memory; diminished attention; low-ered concentration; or functional, behavioural, and psy-chiatric deficits; and similarities to Alzheimer diseaseare seen 226-229. Receptors for N-methyl-D-aspartate(NMDA) are overactivated, leading to neuronal damageand learning impairment 230.

Interventions that could ameliorate such disabili-ties would be of great benefit to these patients and theircaregivers. Ginkgo biloba, from the ginkgo tree, has along history of use in TCM. Effects of Ginkgo bilobaextracts have been postulated to include improvementof memory, increased blood circulation, and benefi-cial effects to patients with Alzheimer disease. Themost unique components of the extracts are the ter-pene trilactones—that is, ginkgolides and bilobalide.These structurally complex molecules have been at-tractive targets for total synthesis. Terpene trilactonesare believed to be partly responsible for the neuro-modulatory properties of Ginkgo biloba extracts, andseveral biologic effects of the terpene trilactones havebeen discovered in recent years, making them attrac-tive pharmacologic tools that could provide insight intothe effects of Ginkgo biloba extracts.

Ginkgolides A, B, C, J, K, L, and M and bilobalideare rare terpene trilactones that have been isolatedfrom leaves and root bark of the Chinese Ginkgo bilobatree. The compounds were found to be potent and se-lective antagonists of platelet-activating factor, res-ponsible for their effect of increasing bleeding time.The mean absolute bioavailability for ginkgolides Aand B and bilobalide are 80%, 88%, and 79% respec-tively. Much of the given dose is excreted unchangedin urine. Radioactive isotope studies show cerebralavailability, particularly in the hippocampus, striatum,and hypothalamus 231-233.

Lipid peroxidation and brain edema are importantfactors that produce tissue damage in head injury. Aninvestigation of the effect of mexiletine and Gingko

biloba extract (EGb 761) on head trauma in rats showedthe usefulness of mexiletine and its combination withEGb 761 as a cerebroprotective agent 234. In vivo studieshave indicated that systemically administered bilobalide,a sesquiterpene trilactone constituent of Ginkgo bilobaleaf extracts, can reduce cerebral edema produced bytriethyltin, decrease cortical infarct volume in certainstroke models, and reduce cerebral ischemia. In vitroand ex vivo studies indicate that bilobalide has multiplemechanisms of action that may be associated withneuroprotection, including its preservation of mitochon-drial ATP synthesis, its inhibition of apoptotic damageinduced by staurosporine or by serum-free medium, itssuppression of hypoxia-induced membrane deteriorationin the brain, and its action in increasing the expressionof the mitochondrial DNA-encoded COX III subunit ofcytochrome C oxidase and the ND1 subunit of NADHdehydrogenase. Because multiple modes of action mayapply to bilobalide, it could be useful in developingtherapy for disorders involving cerebral ischemia andneurodegeneration 235–237.

Standardized ginkgo leaf extracts such as Egb76,120–720 mg daily, have been used in clinical trialsfor dementia, memory, and circulatory disorders. Acommon dose is 80 mg or 240 mg (divided into 2 or3 doses) daily of 50:1 standardized leaf extract bymouth 238. Ginkgo biloba increases vascular perfusionand improves cognitive function 239. It may also pro-tect damaged neurones by maintaining the balance ofinhibitory and excitatory amino acids and inhibiting theeffect of glutamate on the NMDA receptor 240–242.Some RCTs and a Cochrane review concluded that itsuse is promising 243,244; however, other RCTs have notconfirmed its effectiveness 245. That ineffectivenessmay be a function of inadequate dose or purity of thepreparation.

When compared with cholinesterase inhibitors,Ginkgo biloba is better tolerated with similar effica-cy 246. An abstract from Wake Forest University de-scribed a phase II (non-controlled) study in brain-irradiated patients and concluded that Ginkgo bilobacan improve cognitive dysfunction 247. A dose of 40 mg3 times daily was administered for 30 weeks. Of 34patients entered into the study, 18 completed the 30weeks of treatment; 16 patients went off-study be-cause of tumour progression, treatment toxicity, orchoice to discontinue treatment. Brain quality of lifeas measured by the Functional Assessment of Can-cer Therapy–Brain Subscale was significantly im-proved at 12, 24, and 30 weeks as compared to base-line. Mood improved on the Profile of Mood Statesscale, confusion and fatigue were reduced, and cog-nitive testing showed improved attention and execu-tive function. A RCT to compare donepezil with Ginkgobiloba (Egb761) is currently being initiated at WakeForest University 248.

Hasegawa 249 reviewed the metabolism of indi-vidual ginsenosides. Ingested ginsenosides are me-tabolized in the large intestine through deglycosylation

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by colonic bacteria followed by fatty acid esterifica-tion. The resulting metabolites enter the circulation,where they exert their pharmacologic effects. The gin-senosides can inhibit NMDA receptor–mediated sig-nals 250–254. A combination of ginseng and Ginkgobiloba was shown to improve cognitive function in nor-mal volunteers 255. Laboratory studies suggest thatinhibition of the neurotoxic effects of NMDA receptoroveractivity by ginseng derivatives may delay or re-verse neurocognitive dysfunction, but as yet, no con-trolled clinical studies have addressed that hypoth-esis. However, one type of ginseng (Panax quinque-folium) has demonstrated encouraging therapeuticeffects in a clinical trial involving memory deficien-cy 256. Ginseng derivatives and Ginkgo biloba bothinhibit the overstimulation of the NMDA receptor byglutamate, which is implicated in neurodegenerativedisorders. Ginsenosides may also increase cerebralacetylcholine levels. Although it is not yet known whe-ther radiotherapy specifically interacts with the NMDAreceptor or acetylcholine levels, the clinical and patho-logic process appears similar to primary and vasculardementia alike 257. Animal and early clinical evidencesuggests that Ginkgo biloba and ginseng derivativescould have a neuroprotective effect, reducing cogni-tive impairment.

2.4.2 AcupunctureEmesis: Acupuncture treatment at acupoint P6 has beenshown to increase the antiemetic effect of drugs forperioperative and chemotherapy-induced nausea andvomiting 258,259. Innovative single-blind RCTs havesince confirmed these results 260–262 and led to a con-sensus statement from the U.S. National Institutes ofHealth that “acupuncture is a proven effective treat-ment modality for nausea and vomiting” 263. A three-arm RCT comparing conventional modern antiemetics(such as the 5-hydroxytryptamine 3 receptor antago-nists), electroacupuncture, and the combination ofantiemetic drugs and acupuncture clearly demonstratedthat the combination arm was the most effective forpreventing nausea and vomiting 264.

Stimulation of P6 may be carried out more conven-iently with a small transcutaneous nerve stimulation(TENS) device, such as the ReliefBand (NeurowaveMedical, Chicago, IL, U.S.A.). However, a recent RCTcould not confirm the efficacy of TENS in the control ofchemotherapy-induced nausea in women with breastcancer 265, despite promising results in patients withmotion sickness. Those results may be attributable tothe focus on nausea rather than vomiting, to physiologictolerance, or to maximal control having already beenreached by the application of pharmaceutical antiemeticsin these patients such that the device provided no ad-vantage over medication alone. A meta-analysis of acu-puncture-point stimulation for chemotherapy-inducednausea or vomiting shows a benefit over and above drugtherapy 266; however, the studies did not all use optimaldrug therapy, and the pharmaceutical approach may need

to be optimized before acupuncture is used in refractorycases. According to the meta-analysis, self-administeredacupressure also appears to have a protective effectagainst acute nausea.

Pain: Pain is a common symptom of cancer. The causesof the pain can be the cancer itself or its treatment.Acupuncture, along with other interventions, has beenshown to be effective in managing pain and othersymptoms in cancer patients 267. In a retrospective studyfrom the Royal Marsden Hospital in London, England,183 cancer patients with malignant pain, iatrogenic pain,and radiation-induced chronic ulcers were treated withacupuncture 268–270. An improvement was seen in 82%of the patients, but effectiveness lasted for more than3 days in only half of the patients. Iatrogenic pain (forexample, pain resulting from radiation fibrosis or skinulceration) and pain caused by secondary muscle spasmresponded better than did malignant pain. Furthermore,increased blood flow, with improved healing of skinulcers, was demonstrated after treatment with acu-puncture. A RCT using ear acupuncture showed aprofound effect on cancer pain 271, and we obtainedencouraging results from a small pilot study of acu-puncture for chemotherapy-induced neuropathic pain 272.A systematic review could not demonstrate the effec-tiveness of acupuncture as an adjunctive analgesicmethod for cancer patients 273; however, it includedonly one RCT 271, and all the other studies were generallyof poor scientific quality. The intensity of stimulation,especially electrostimulation, may be important 274.

We suggest that acupuncture is a useful treatmentmodality that may best be combined with other treat-ments to improve pain control, resulting in reduceddoses of pharmaceutical analgesics. The reduction inmedication use has the benefit of reducing the inci-dence and degree of drug-induced side effects. Forsome patients, a TENS device has the advantage of easyself-administration or administration by staff afterminimal training.

Acupuncture-like TENS (AL-TENS) devices havebeen developed to apply low-frequency (4 Hz, for in-stance), high-intensity stimulation that mimics acupunc-ture treatment 275. The goal is to recruit the high-thresh-old type III afferent nerve fibres that are potent releasersof endorphins. Recent meta-analyses (including aCochrane systematic review) have shown that AL-TENSis more effective than placebo and improves functionmore than standard TENS in the treatment of chronicpain 276–279. The AL-TENS devices are very simplemachines that patients can learn to operate with lessthan 60 minutes of training. An acupoint prescriptionmay then be given to the patient, who can administerthe appropriate treatments with AL-TENS at home. TheCodetron (EHM Rehabilitation Technologies, Toronto,ON, Canada) is a sophisticated AL-TENS device thathas the advantage of reducing tolerance to its analgesiceffect by electronically rotating through a series of ran-dom electrical stimulation patterns and acupoint locations.



Xerostomia: Radiation-induced xerostomia is one of thedistressing late side effects seen in patients who receiveradiation treatment involving the parotid glands. Thecondition leads to loss of taste and difficulty in speakingand swallowing for the patients. Recently, acupuncturetreatment has been found to increase blood flow to theparotid glands and may stimulate tissue regeneration inglands damaged by radiotherapy 280–282.

A RCT involving 38 patients with radiation xeros-tomia was reported from the Karolinska Institute inSweden 283. Subjects were randomized to either deepacupuncture treatment or superficial acupuncture treat-ment. The superficial group was used as the control,despite previous evidence that superficial acupuncturetreatment can have a certain degree of effectivenessand should not be used as a control in acupuncture treat-ment trials. In the Swedish study, more than 50% of thepatients in both groups were found to have experienceda greater than a 20% increase in saliva flow rate. In thedeep acupuncture group, 68% of patients demonstratedan increase in salivary flow rate. Changes in the controlgroup were smaller and appeared after a longer latencyphase. Moreover, patients in the treatment group reportedless dryness, less hoarseness, and improved taste.

In another study, 70 patients with xerostomia at-tributable either to Sjögren syndrome or to irradiationwere treated with acupuncture 284. A statistically sig-nificant increase in unstimulated and stimulated sali-vary flow rates was found in all patients immediatelyafter acupuncture treatment, and for up to 6 monthsof follow-up. After a review at 3 years, patients whochose to be treated with additional acupuncture demon-strated a consistently higher median salivary flow rateas compared with patients not choosing to have addi-tional acupuncture.

Despite some limitations in design, both of the fore-going studies provided evidence suggesting that acu-puncture can be effective in treating radiation-inducedxerostomia, with minimal side effects. In a prospec-tive single-cohort visual-analogue-assessed study ofacupuncture in palliative care patients with xerosto-mia, highly significant alleviation of subjective xeros-tomia was observed 285. Other studies are confirmingthe clinical use of acupuncture for relief of radiation-induced xerostomia 286.

At the Juravinski Cancer Centre in Ontario, Cana-da, a combined phase I and II study of AL-TENS in thetreatment of radiation-induced xerostomia was carriedout 287. The 45 participating patients were randomizedinto three treatment groups that received Codetron AL-TENS stimulation to one of three different sets of acu-puncture points:

• Group A: CV24, St36, Sp6, LI4• Group B: CV24, St36, Sp6, P6• Group C: CV24, St5, St6, Sp6, P6

The goal of the study was to determine the opti-mum pattern of stimulation (based on TCM theory) to

feed into the design of a placebo-controlled study. TheAL-TENS treatment was administered twice weekly fora total of 12 weeks. Unstimulated and stimulated sali-vary flow rates before, during, and after treatmentwere measured, and the patients’ quality of life wassurveyed at a 1-year follow-up. Improvement in xeros-tomia symptoms was noted, with mean score increasesof 86 (p < 0.0005) and 77 (p < 0.0001) on the visualanalogue scale at 3 and 6 months respectively aftertreatment completion. For all patients, the increasein mean basal and citric acid–primed whole salivaproduction at 3 and 6 months after treatment comple-tion was also statistically significant (p < 0.001 andp < 0.0001 respectively). No statistically significantchange in the quality-of-life evaluation as comparedwith baseline was observed.

Those results suggest that Codetron treatment im-proves saliva production and related symptoms in pa-tients suffering from radiation-induced xerostomia.Treatment effects are sustained at least 6 months aftercompletion of treatment. A recent study using func-tional magnetic resonance imaging showed activationof the insula region of the brain, the location associ-ated with gustatory function 288.

Anxiety, Depression, Cognitive Impairment, and Fatigue:Suppression of anxiety by acupuncture is associatedwith an increase in the pain threshold 289. Acupuncturecan also play a role in the treatment of fatigue andmalignant cachexia through the modulation of cytokinesand hormones 290–295.

Treatment of depression is an important interven-tion in the management of the body–mind network incancer patients. Conventionally, clinical depressionis treated with oral medication such as amitriptylineor the newer serotonin reuptake inhibitor drugs. Stud-ies indicate that acupuncture treatment may be anequally effective alternative modality to drug treat-ment in patients suffering from mild depression. Inone study, the side effects profile associated with acu-puncture treatment was shown to be better than thatassociated with amitriptyline 296. In a single-blindplacebo-controlled study of the antidepressant mian-serin, supplementary acupuncture improved the courseof depression more than did pharmacologic treatmentwith the drug alone 297.

A Cochrane review concluded that the evidence isinsufficient to determine the efficacy of acupunctureas compared with medication or with wait list controlor sham acupuncture in the management of depression298; however, because pharmaceutical antidepressantsare not usually effective until 2 weeks after the start oftherapy, their combination with acupuncture may pro-duce more rapid results with reduced side effects.

The role of acupuncture for cognitive impairmentcaused by chemotherapy or radiotherapy is unclear. Anintriguing study in rats showed improvement in cognitiveimpairment caused by multiple infarcts 299. A recent re-view concluded that some limited evidence supports the

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use of acupuncture in effectively managing a range ofpsychoneurologic problems, some of which are similarto those experienced by patients with chemotherapy-as-sociated cognitive dysfunction 300. A phase II study ofacupuncture for post-chemotherapy fatigue (average of 2years) showed a mean improvement of 30% on the BriefFatigue Inventory 301. That finding met the researchgroup’s pre-specified criterion of clinical importance andhas prompted initiation of a sham acupuncture RCT.

Miscellaneous Symptoms: Other symptoms that maybe helped with acupuncture include constipation, tris-mus (post-radiotherapy contracture of the massetermuscle) 302, radiotherapy-associated proctitis 303,hiccups 304, persistent yawning 305, chemotherapy-induced peripheral neuropathy 272, and dysphagiasecondary to an esophageal neoplasm 306. Althoughobservational studies by Filshie et al. 307 showed thatacupuncture may improve cancer-associated dyspnea,that group’s findings were not supported by a later RCTusing semi-permanent acupuncture studs 308.

Acupuncture can reduce the hot flushes associatedwith anticancer hormone therapy. Three prospective un-controlled cohort studies have been completed, one inmen who had undergone castration for prostate cancer,and two in women who were taking tamoxifen for breastcancer. All demonstrated a reduction in vasomotor symp-toms 309–311. Prolonged stimulation using semi-perma-nent studs or needles, especially at SP6 appears to beassociated with more long-term relief of symptoms 270.

3. CONCLUSIONS

Emerging scientific evidence suggests that TCM canplay an important role in the supportive care of can-cer patients. Enough preliminary evidence is avail-able to encourage good-quality clinical trials evaluat-ing the efficacy of integrating TCM into Western can-cer care 312–316. Currently, the evidence for the utilityof TCM in cancer care is promising, but prospectiveRCTs for specific clinical scenarios are necessary toobtain reliable and generalizable data.

Appropriate stratification and individualizationaccording to TCM diagnostic criteria is possible withinthe context of a RCT 317. We believe that an evidence-based approach can be integrated into an individual-ized therapeutic plan and that a major role still existsfor individual belief systems and psycho-spiritual ex-perience. Assessment and measurement of coping strat-egies, maintenance of function, quality of life, andpatient satisfaction are important. We are hopeful thatfuture integration of various models of health such asTCM may lead to further improvements in survival andquality of life for cancer patients.

4. ACKNOWLEDGMENTS

We thank Christina M. Garchinski for administrativeassistance.

5. REFERENCES

1. Coffey DS. Self-organization, complexity and chaos: the newbiology for medicine. Nature Med 1998;4:882–5.

2. Cuzick J, Holland R, Barth V, et al . Electropotential measure-ments as a new diagnostic modality for breast cancer. Lancet1998;352:359–63.

3. Kang K, Kang B, Lee B, et al. Preventive effect of epicatechinand ginsenoside Rb2 on the inhibition of gap junctional intercel-lular communication by TP and H2O2. Cancer Lett 2000;152:97–106.

4. Sagar SM, Klassen GA, Barclay KD, Aldrich JE. Tumour bloodflow: measurement and manipulation for therapeutic gain. Can-cer Treat Rev 1993;19:299–349.

5. Milosevic MF, Fyles AW, Wong R, et al. Interstitial fluid pres-sure in cervical carcinoma: within tumor heterogeneity, andrelation to oxygen tension. Cancer 1998;82:2418–26.

6. Baxter LT, Jain RK. Transport of fluid and macromolecules intumors. I. Role of interstitial pressure and convection. MicrovascRes 1989;37:77–104.

7. Brizel DM, Sibley GS, Prosnitz LR, Scher RL, DewhirstMW. Tumor hypoxia adversely affects the prognosis of car-cinoma of the head and neck. Int J Radiat Oncol Biol Phys1997;38:285–9.

8. Fyles AW, Milosevic M, Wong R, et al. Oxygenation predictsradiation response and survival in patients with cervix cancer.Radiother Oncol 1998;48:149–56.

9. Lebeau B, Chastang C, Brechot JM, et al. Subcutaneous heparintreatment increases survival in small cell lung cancer. “PetitesCellules” Group. Cancer 1994;74:38–45.

10. Hejna M, Raderer M, Zielinski CC. Inhibition of metastasesby anticoagulants. J Natl Cancer Inst 1999;91:22–36.

11. Yance DR, Sagar SM. Targeting angiogenesis with integrativecancer therapies. Integr Cancer Ther 2006;5:9–29.

12. Wang JZ, Tsumura H, Shimura K, Ito H. Antitumor activity ofpolysaccharide from a Chinese medicinal herb, Acanthopanaxgiraldii Harms. Cancer Lett 1992;65:79–84.

13. Tode T, Kikuchi Y, Kita T, Hirata J, Imaizumi E, Nagata I.Inhibitory effects by oral administration of ginsenoside Rh2 onthe growth of human ovarian cancer cells in nude mice. J Can-cer Res Clin Oncol 1993;120:24–6.

14. Lau BH, Ruckle HC, Botolazzo T, Lui PD. Chinese medicinalherbs inhibit growth of murine renal cell carcinoma. CancerBiother 1994;9:153–61.

15. Boik J. Cancer and Natural Medicine: A Textbook of BasicScience and Clinical Research. Rev ed. Princeton, MN: OregonMedical Press; 1996.

16. Boik J. Emerging trends in cancer research: development of amechanism-based approach. Protocol J Botanic Med 1996;2:5–10.

17. Shoemaker M, Hamilton B, Dairkee SH, Cohen I, CampbellMJ. In vitro anticancer activity of twelve Chinese medicinalherbs. Phytother Res 2005;19:649–51.

18. Xu GZ, Cai WM, Qin DX, et al. Chinese herb “destagnation”series I: combination of radiation with destagnation in the treat-ment of nasopharyngeal carcinoma (NPC): a prospectiverandomized trial on 188 cases. Int J Radiat Oncol Biol Phys1989;16:297–300.

19. Kleijnen J, Knipschild P. Ginkgo biloba. Lancet 1992;340:1136–9.



20. Ha SW, Yi CJ, Cho CK, Cho MJ, Shin KH, Park CI. Enhance-ment of radiation effect by Ginkgo biloba in C3H mouse fibro-sarcoma. Radiother Oncol 1996;41:163–7.

21. Sagar SM, Singh G, Hodson DI, Whitton AC. Nitric oxide andanti-cancer therapy. Cancer Treat Rev 1995;21:159–81.

22. Kuang P, Tao Y, Tian Y. Radix Salviae miltiorrhizae treatmentresults in decreased lipid peroxidation in reperfusion injury. JTradit Chin Med 1996;16:138–42.

23. Sun H, Duan S, Yu G. Free radical mechanism in enhancement ofradiosensitization by SRSBR. J Tradit Chin Med 1994;14:51–5.

24. Lee TK, Johnke RM, Allison RR, O’Brien KF, Dobbs LJJr. Radioprotective potential of ginseng. Mutagenesis2005;20: 237–43.

25. Zhou RF, Liu PX. Study progress in reversing multidrug resist-ance to breast cancer with Chinese herbs [Chinese]. ZhongguoZhong Yao Za Zhi 2005;30:1797–800.

26. Kang JX, Liu J, Wang J, He C, Li FP. The extract of huanglian,a medicinal herb, induces cell growth arrest and apoptosis byupregulation of interferon-β and TNF-α in human breast can-cer cells. Carcinogenesis 2005;26:1934–9.

27. Taixiang W, Munro AJ, Guanjian L. Chinese medical herbs forchemotherapy side effects in colorectal cancer patients. Coch-rane Database Syst Rev 2005;(1):14651858.CD004540.pub2.

28. Shu X, McCulloch M, Xiao H, Broffman M, Gao J. Chineseherbal medicine and chemotherapy in the treatment of hepato-cellular carcinoma: a meta-analysis of randomized controlledtrials. Integr Cancer Ther 2005;4:219–29.

29. Shin HJ, Kim YS, Kwak YS, Song YB, Kim YS, Park JD.Enhancement of antitumor effects of paclitaxel (Taxol) in com-bination with red ginseng acidic polysaccharide (RGAP). PlantaMed 2004;70:1033–8.

30. Collins L, Zhu T, Guo J, Xiao ZJ, Chen CY. Phellinus linteussensitises apoptosis induced by doxorubicin in prostate can-cer. Br J Cancer 2006;95:282–8.

31. McCulloch M, See C, Shu XJ, et al. Astragalus-based Chineseherbs and platinum-based chemotherapy for advanced non-small-cell lung cancer: meta-analysis of randomized trials. JClin Oncol 2006;24:419–30.

32. Liang HL, Xue CC, Li CG. Regression of squamous cell carci-noma of the lung by Chinese herbal medicine: a case with an 8-year follow-up. Lung Cancer 2004;43:355–60.

33. Lee YJ, Jin YR, Lim WC, et al. Ginsenoside-Rb1 acts as a weakphytoestrogen in MCF-7 human breast cancer cells. Arch PharmRes 2003;26:58–63.

34. Amato P, Christophe S, Mellon PL. Estrogenic activity of herbscommonly used as remedies for menopausal symptoms. Meno-pause 2002;9:145–50.

35. Chang CJ, Chiu JH, Tseng LM, et al. Modulation of HER2expression by ferulic acid on human breast cancer MCF7 cells.Eur J Clin Invest 2006;36:588–96.

36. Campbell MJ, Hamilton B, Shoemaker M, Tagliaferri M, Cohen I,Tripathy D. Antiproliferative activity of Chinese medicinal herbson breast cancer cells in vitro. Anticancer Res 2002;22:3843–52.

37. Jia WW, Bu X, Philips D, et al. Rh2, a compound extractedfrom ginseng, hypersensitizes multidrug-resistant tumor cellsto chemotherapy. Can J Physiol Pharmacol 2004;82:431–7.

38. Loo WT, Cheung MN, Chow LW. The inhibitory effect of aherbal formula comprising ginseng and Carthamus tinctoriuson breast cancer. Life Sci 2004;76:191–200.

39. Yu Y, Zhou Q, Hang Y, Bu X, Jia W. Antiestrogenic effect of20S-protopanaxadiol and its synergy with tamoxifen on breastcancer cells. Cancer 2007;109:2374–82.

40. King ML, Murphy LL. American ginseng (Panax quinquefoliusL.) extract alters mitogen-activated protein kinase cell signalingand inhibits proliferation of MCF-7 cells. J Exp Ther Oncol2007;6:147–55.

41. Aung HH, Mehendale SR, Wang CZ, Xie JT, McEntee E, YuanCS. Cisplatin’s tumoricidal effect on human breast carcinomaMCF-7 cells was not attenuated by American ginseng. CancerChemother Pharmacol 2007;59:369–74.

42. Piersen CE. Phytoestrogens in botanical dietary supplements:implications for cancer. Integrat Cancer Ther 2003;2:120–38.

43. Sagar SM. Future directions for research on Silybum marianumfor cancer patients. Integr Cancer Ther 2007;6:166–73.

44. Lau CB, Ho TC, Chan TW, Kim SC. Use of dong quai (Angelicasinensis) to treat peri-or postmenopausal symptoms in womenwith breast cancer: is it appropriate? Menopause 2005;12:734–40.

45. Hirata JD, Swiersz LM, Zell B, Small R, Ettinger B. Does dongquai have estrogenic effects in postmenopausal women? A dou-ble-blind, placebo-controlled trial. Fertil Steril 1997;68:981–6.

46. Duda RB, Zhong Y, Navas V, Li MZ, Toy BR, Alavarez JG.American ginseng and breast cancer therapeutic agentssynergistically inhibit MCF-7 breast cancer cell growth. J SurgOncol 1999;72:230–9.

47. King ML, Adler SR, Murphy LL. Extraction-dependent ef-fects of American ginseng (Panax quinquefolium) on humanbreast cancer cell proliferation and estrogen receptor activa-tion. Integr Cancer Ther 2006;5:236–43.

48. Cui Y, Shu XO, Gao YT, Cai H, Tao MH, Zheng W. Associa-tion of ginseng use with survival and quality of life amongbreast cancer patients. Am J Epidemiol 2006;163:645–53.

49. Barton DL, Soori GS, Bauer B, et al. A pilot, multi-dose, pla-cebo-controlled evaluation of American ginseng (Panaxquinquefolius) to improve cancer-related fatigue: NCCTG trialN03CA [abstract 9001]. J Clin Oncol 2007;25:18S.

50. DiPaola RS, Zhang H, Lambert GH, et al. Clinical and biologicactivity of an estrogenic herbal combination (PC-SPES) in pros-tate cancer. N Engl J Med 1998;339:785–91.

51. Guns ES, Goldenberg SL, Brown PN. Mass spectral analysisof PC-SPES confirms the presence of diethylstilbestrol. Can JUrol 2002;9:1684–8.

52. Oh WK, Kantoff PW, Weinberg V, et al. Prospective, multicenterrandomized phase II trial of the herbal supplement: PC-SPES, anddiethylstilbestrol in patients with androgen-independent pros-tate cancer. J Clin Oncol 2004;22:3705–12.

53. Kim H, Peterson TG, Barnes S. Mechanisms of action of thesoy isoflavone genistein: emerging role for its effects via trans-forming growth factor beta signaling pathways. Am J Clin Nutr1998;68:1418S–25S.

54. Li Y, Bhuiyan M, Sarkar FH. Induction of apoptosis and inhi-bition of c-erbB-2 in MDA-MB-435 cells by genistein. Int JOncol 1999;15:525–33.

55. Li Y, Upadhyay S, Bhuiyan M, Sarkar FH. Induction ofapoptosis in breast cancer cells MDA-MB-231 by genistein.Oncogene 1999;18:3166–72.

56. Wu AH, Ziegler RG, Horn–Ross PL, et al. Tofu and risk ofbreast cancer in Asian–Americans. Cancer Epidemiol BiomarkersPrev 1996;5:901–6.

SAGAR AND WONG


57. Witte JS, Ursin G, Siemiatycki J, Thompson WD, Paganini–HillA, Haile RW. Diet and premenopausal bilateral breast cancer: acase–control study. Breast Cancer Res Treat 1997;42:243–51.

58. Lu LJ, Cree M, Josyula S, Nagamani M, Grady JJ, AndersonKE. Increased urinary excretion of 2-hydroxyestrone but not16α-hydroxyestrone in premenopausal women during a soyadiet containing isoflavones. Cancer Res 2000;60:1299–305.

59. Key TJ, Sharp GB, Appleby PN, et al. Soya foods and breastcancer risk: a prospective study in Hiroshima and Nagasaki,Japan. Br J Cancer 1999;81:1248–56.

60. Hsieh CY, Santell RC, Haslam SZ, Helferich WG. Estrogeniceffects of genistein on the growth of estrogen receptor-positivehuman breast cancer (MCF-7) cells in vitro and in vivo. CancerRes 1998;58:3833–8.

61. Scambia G, Mango D, Signorile PG, et al. Clinical effects of astandardized soy extract in postmenopausal women: a pilotstudy. Menopause 2000;7:105–11.

62. Quella SK, Loprinzi CL, Barton DL, et al. Evaluation of soyphytoestrogens for the treatment of hot flashes in breast can-cer survivors: A North Central Cancer Treatment Group Trial.J Clin Oncol 2000;18:1068–74.

63. MacGregor CA, Canney PA, Patterson G, McDonald R, PaulJ. A randomised double-blind controlled trial of oral soy sup-plements versus placebo for treatment of menopausal symp-toms in patients with early breast cancer. Eur J Cancer2005;41:708–14.

64. Hu SA. Risks and benefits of soy isoflavones for breast cancersurvivors. Oncol Nurs Forum 2004;31:249–63.

65. Messina M, McCaskill–Stevens W, Lampe JW. Addressing thesoy and breast cancer relationship: review, commentary, andworkshop proceedings. J Natl Cancer Inst 2006;98:1275–84.

66. Spence DW, Kayumov L, et al. Acupuncture increases noctur-nal melatonin secretion and reduces insomnia and anxiety: apreliminary report. J Neuropsychiatry Clin Neurosci 2004;16:19–28.

67. Stener–Victorin E, Lundeberg T, Waldenstrom U, Bileviciute–Ljungar I, Janson PO. Effects of electro-acupuncture on corti-cotropin-releasing factor in rats with experimentally-inducedpolycystic ovaries. Neuropeptides 2001;35:227–31.

68. Ning CH, Wang GM, Zhao TY, Yu GQ, Duan FW. Therapeu-tical effects of jian pi yi shen prescription on the toxicity reac-tions of postoperative chemotherapy in patients with advancedgastric carcinoma. J Tradit Chin Med 1988;8:113–16.

69. Chen JZ. Clinical effect of chemotherapy combined with Chi-nese herbs and western drugs on leukocytes of gastric cancerpatients [Chinese]. Zhong Xi Yi Jie He Za Zhi 1990;10:717–19.

70. Yu RC, Guan CF, Zhang JH. Immune function of cancer pa-tients with spleen-deficiency syndrome [Chinese]. Zhong Xi YiJie He Za Zhi 1990;10:535–7,516.

71. Hou J, Liu S, Ma Z, et al. Effects of Gynostemma pentaphyllummakino on the immunological function of cancer patients. JTradit Chin Med 1991;11:47–52.

72. Rao XQ, Yu RC, Zhang JH. Sheng xue tang on immunologicalfunctions of cancer patients with spleen-deficiency syndrome[Chinese]. Zhong Xi Yi Jie He Za Zhi 1991;11:218–19.

73. Li NQ. Clinical and experimental study on shen-qi injectionwith chemotherapy in the treatment of malignant tumor ofdigestive tract [Chinese]. Zhongguo Zhong Xi Yi Jie He Za Zhi1992;12:588–92.

74. Yu G, Ren D, Sun G, Zhang D. Clinical and experimental stud-ies of JPYS in reducing side-effects of chemotherapy in late-stage gastric cancer. J Tradit Chin Med 1993;13:31–7.

75. Cao GW, Yang WG, Du P. Observation of the effects of LAK/IL-2 therapy combining with Lycium barbarum polysaccharidesin the treatment of 75 cancer patients [Chinese]. ZhonghuaZhong Liu Za Zhi 1994;16:428–31.

76. Cheng JH. Clinical study on prevention and treatment to chemo-therapy caused nephrotoxicity with jian-pi yi-qi li-shui decoc-tion [Chinese]. Zhongguo Zhong Xi Yi Jie He Za Zhi1994;14:331–3.

77. Horie Y, Kato K, Kameoka S, Hamano K. Bu ji (hozai) fortreatment of postoperative gastric cancer patients. Am J ChinMed 1994;22:309–19.

78. Lin SY, Liu LM, Wu LC. Effects of Shenmai injection on im-mune function in stomach cancer patients after chemotherapy[Chinese]. Zhongguo Zhong Xi Yi Jie He Za Zhi 1995;15:451–3.

79. Pan MJ, Li YH, Chen LF. Long-term curative effect of 150cases of nasopharyngeal cancer treated with fu zheng sheng jindecoction and radiotherapy [Chinese]. Zhong Xi Yi Jie He ZaZhi 1985;5:83–5.

80. Wang GT. Treatment of operated late gastric carcinoma withprescription of strengthening the patient’s resistance and dis-pelling the invading evil in combination with chemotherapy:follow-up study of 158 patients and experimental study inanimals [Chinese]. Zhong Xi Yi Jie He Za Zhi 1990;10:712–16.

81. Kawakita T, Nakai S, Kumazawa Y, Miura O, Yumioka E,Nomoto K. Induction of interferon after administration of tra-ditional Chinese medicine, xiao-chai-hu-tang (shosaiko-to). IntJ Immunopharmacol 1990;12:515–21.

82. Jin R, Wan LL, Mitsuishi T, et al. Effect of shi-ka-ron andChinese herbs on cytokine production of macrophage inimmunocompromised mice. Am J Chin Med 1994;22:255–66.

83. Feng PF, Liu LM, Shen YY. Effect of shenmai injection on sIL-2R, NK and LAK cells in patients with advanced carcinoma.Zhongguo Zhong Xi Yi Jie He Za Zhi 1995;15:87–9.

84. Zhu H, Zhang J. Treatment of stomatological complications in31 cases of acute leukemia with Chinese herbal drugs. J TraditChin Med 1993;13:253–6.

85. Zhu BF. Observation on 17 patients with radio-ulcer with com-bined traditional Chinese medicine and Western medicinetherapy [Chinese]. Zhongguo Zhong Xi Yi Jie He Za Zhi1994;14:89–91,68–9.

86. Whiteside LT. Immune suppression in cancer: effects on im-mune cells, mechanisms and future therapeutic intervention.Semin Cancer Biol 2006;16:3–15.

87. Berczi I, Chow DA, Baral E, Nagy E. Neuroimmunoregulationand cancer [review]. Int J Oncol 1998;13:1049–60.

88. Beuth J, Ko HL, Schirrmacher V, Uhlenbruck G, Pulverer G.Inhibition of liver tumor cell colonization in two animal tumormodels by lectin blocking with D-galactose or arabinogalactan.Clin Exp Metastasis 1988;6:115–20.

89. Kebudi R, Ayan I, Darendeliler E, et al. Immunologic status inchildren with brain tumors and the effect of therapy. JNeurooncol 1995;24:219–27.

90. Vuckovic–Dekic LJ, Susnjar S, Stanojevic–Bakic N, Rajner L,Frim O. The protective activity of Thymex L againstradiotherapeutically-induced cellular immunodepression in lungcancer patients. Neoplasma 1992;39:171–6.



91. Maier H, Daniel V, Heimlich F, Frank C, Opelz G. Cellularimmune defect caused by postoperative irradiation in patientswith squamous epithelial carcinomas of the upper aerodigestivetract [German]. HNO 1995;43:364–70.

92. Miyazaki K, Mizutani H, Katabuchi H, Fukuma K, Fujisaki S,Okamura H. Activated (HLA-DR+) T-lymphocyte subsets incervical carcinoma and effects of radiotherapy and immuno-therapy with sizofiran on cell-mediated immunity and sur-vival. Gynecol Oncol 1995;56:412–20.

93. Baniyash M. Chronic inflammation, immunosuppression and can-cer: new insights and outlook. Semin Cancer Biol 2006;16:80–8.

94. Sasada T, Kimura M, Yoshida Y, Kanai M, Takabayashi A.CD4+CD25+ regulatory T cells in patients with gastrointestinalmalignancies: possible involvement of regulatory T cells in dis-ease progression. Cancer 2003;98:1089–99.

95. Wichmann MW, Meyer G, Adam M, et al. Detrimental immu-nologic effects of preoperative chemoradiotherapy in advancedrectal cancer. Dis Colon Rectum 2003;46:875–87.

96. Bang S, Kim HS, Choo YS, Park SW, Chung JB, Song SY.Differences in immune cells engaged in cell-mediated immunityafter chemotherapy for far advanced pancreatic cancer. Pan-creas 2006;32:29–36.

97. Koukourakis MI, Ktenidou–Kartali S, Bourikas G, Kartalis G,Tsatalas C. Amifostine protects lymphocytes during radio-therapy and stimulates expansion of the CD95/Fas and CD31expressing T-cells, in breast cancer patients. Cancer ImmunolImmunother 2003;52:127–31.

98. Stevenson FK. Update on cancer vaccines. Curr Opin Oncol2005;17:573–7.

99. Minev BR. Melanoma vaccines. Semin Oncol 2002;29:479–93.100. Hoffmann TK, Bier H, Whiteside TL. Targeting the immune

system: novel therapeutic approaches in squamous cell carci-noma of the head and neck. Cancer Immunol Immunother2004;53:1055–67.

101. Tsan MF. Toll-like receptors, inflammation and cancer. SeminCancer Biol 2006;16:32–7.

102. Sen G, Khan AQ, Chen Q, Snapper CM. In vivo humoral im-mune responses to the isolated pneumococcal polysaccharidesare dependent on the presence of associated TLR ligands. JImmunol 2005;175:3084–91.

103. Rezaei N. Therapeutic targeting of pattern-recognitionreceptors. Int Immunopharmacol 2006;6:863–9.

104. Heine H, Ulmer AJ. Recognition of bacterial products by Toll-like receptors. Chem Immunol Allergy 2005;86:99–119.

105. Chang R. Bioactive polysaccharides from traditional Chinesemedicine herbs as anticancer adjuvants. J Altern ComplementMed 2002;8:559–65.

106. Zeng F, Hon CC, Sit WH, et al. Molecular characterization ofCoriolus versicolor PSP-induced apoptosis in human prom-yelotic leukemic HL-60 cells using cDNA microarray. Int J Oncol2005;27:513–23.

107. Ito K, Nakazato H, Koike A, et al., for the Study Group ofImmunochemotherapy with PSK for Colon Cancer. Long-termeffect of 5-fluorouracil enhanced by intermittent administra-tion of polysaccharide K after curative resection of colon can-cer. A randomized controlled trial for 7-year follow-up. Int JColorectal Dis 2004;19:157–64.

108. Ohwada S, Ikeya T, Yokomori T, et al. Adjuvant immuno-chemotherapy with oral tegafur/uracil plus PSK in patients with

stage II or III colorectal cancer: a randomised controlled study.Br J Cancer 2004;90:1003–10.

109. Koda K, Miyazaki M, Sarashina H, et al. A randomized con-trolled trial of postoperative adjuvant immunochemotherapyfor colorectal cancer with oral medicines. Int J Oncol2003;23:165–72.

110. Tsang KW, Lam CL, Yan C, et al. Coriolus versicolor polysac-charide peptide slows progression of advanced non-small celllung cancer. Respir Med 2003;97:618–24.

111. Kanazawa M, Mori Y, Yoshihara K, et al. Effect of PSK on thematuration of dendritic cells derived from human peripheralblood monocytes. Immunol Lett 2004;91:229–38.

112. Wong CK, Tse PS, Wong EL, Leung PC, Fung KP, Lam CW.Immunomodulatory effects of yun zhi and danshen capsules inhealthy subjects: a randomized, double-blind, placebo-control-led, crossover study. Int Immunopharmacol 2004;4:201–11.

113. Wong CK, Bao YX, Wong EL, Leung PC, Fung KP, Lam CW.Immunomodulatory activities of yunzhi and danshen in post-treatment breast cancer patients. Am J Chin Med 2005;33:381–95.

114. Munemoto Y, Iida Y, Abe J, et al. Significance of postoperativeadjuvant immunochemotherapy after curative resection ofcolorectal cancers: association between host or tumor factorsand survival. Int J Oncol 2002;20:403–11.

115. Hayakawa K, Mitsuhashi N, Saito Y, et al. Effect of Krestin asadjuvant treatment following radical radiotherapy in non-smallcell lung cancer patients. Cancer Detect Prev 1997; 21:71–7.

116. Ogoshi K, Satou H, Isono K, Mitomi T, Endoh M, Sugita M.Immunotherapy for esophageal cancer. A randomized trial incombination with radiotherapy and radiochemotherapy. Co-operative Study Group for Esophageal Cancer in Japan. Am JClin Oncol 1995;18:216–22.

117. Mitomi T, Tsuchiya S, Iijima N, et al. Randomized, controlledstudy on adjuvant immunochemotherapy with PSK in curativelyresected colorectal cancer. The Cooperative Study Group ofSurgical Adjuvant Immunochemotherapy for Cancer of Colonand Rectum (Kanagawa). Dis Colon Rectum 1992;35:123–30.

118. Nakazato H, Hoike A, Saji S, et al. Efficacy of immuno-chemotherapy as adjuvant treatment after curative resection ofgastric cancer; Study Group of Immunochemotherapy withPSK for Gastric Cancer. Lancet 1994;343:1122–6.

119. Shao BM, Dai H, Xu W, Lin ZB, Gao XM. Immune receptorsfor polysaccharides from Ganoderma lucidum. BiochemBiophys Res Commun 2004;323:133–141.

120. Lin ZB. Cellular and molecular mechanisms of immuno-modulation by Ganoderma lucidum. J Pharmacol Sci 2005;99:144–53.

121. Kuo MC, Weng CY, Ha CL, Wu MJ. Ganoderma lucidummycelia enhance innate immunity by activating NF-κB. J Ethno-pharmacol 2006;103:217–22.

122. Gao Y, Zhou S, Jiang W, Huang M, Dai X. Effects of ganopoly(a Ganoderma lucidum polysaccharide extract) on the immunefunctions in advanced-stage cancer patients. Immunol Invest2003;32:201–15.

123. Kodama N, Asakawa A, Inui A, Masuda Y, Nanba H. Enhance-ment of cytotoxicity of NK cells by D-Fraction, a polysaccha-ride from Grifola frondosa. Oncol Rep 2005;13:497–502.

124. Kodama N, Komuta K, Nanba H. Effect of maitake (Grifolafrondosa) D-Fraction on the activation of NK cells in cancerpatients. J Med Food 2003;6:371–7.

SAGAR AND WONG


125. Kodama N, Murata Y, Asakawa A, et al. Maitake D-Fractionenhances antitumor effects and reduces immunosuppression bymitomycin-C in tumor-bearing mice. Nutrition 2005;21:624–9.

126. Kodama N, Komuta K, Nanba H. Can maitake MD-Fractionaid cancer patients? Altern Med Rev 2002;7:236–9.

127. Inoue A, Kodama N, Nanba H. Effect of maitake (Grifolafrondosa) D-Fraction on the control of the T lymph node Th-1/Th-2 proportion. Biol Pharm Bull 2002;25:536–40.

128. Shao BM, Xu W, Dai H, Tu P, Li Z, Gao XM. A study on theimmune receptors for polysaccharides from the roots of Astra-galus membranaceus, a Chinese medicinal herb. BiochemBiophys Res Commun 2004;320:1103–11.

129. Shin HJ, Kim YS, Kwak YS, Song YB, Kim YS, Park JD.Enhancement of antitumor effects of paclitaxel (Taxol) in com-bination with red ginseng acidic polysaccharide (RGAP). PlantaMed 2004;70:1033–8.

130. Shin JY, Song JY, Yun YS, Yang HO, Rhee DK, Pyo S.Immunostimulating effects of acidic polysaccharides extract ofPanax ginseng on macrophage function. ImmunopharmacolImmunotoxicol 2002;24:469–82.

131. Han SK, Song JY, Yun YS, Yi SY. Ginsan improved Th1 im-mune response inhibited by gamma radiation. Arch Pharm Res2005;28:343–50.

132. Lim TS, Na K, Choi EM, Chung JY, Hwang JK. Immuno-modulating activities of polysaccharides isolated from Panaxginseng. J Med Food 2004;7:1–6.

133. Ooi VE, Liu F. Immunomodulation and anti-cancer activity ofpolysaccharide–protein complexes. Curr Med Chem 2000;7:715–29.

134. Zaidman BZ, Yassin M, Mahajna J, Wasser SP. Medicinalmushroom modulators of molecular targets as cancer therapeu-tics. Appl Microbiol Biotechnol 2005;67:453–68.

135. Lindequist U, Niedermeyer TH, Julich WD. The pharmaco-logical potential of mushrooms. Evid Based Complement AlternatMed 2005;2:285–99.

136. Han SB, Yoon YD, Ahn HJ, et al. Toll-like receptor–mediatedactivation of B cells and macrophages by polysaccharide iso-lated from cell culture of Acanthopanax senticosus. Int Immuno-pharmacol 2003;3:1301–12.

137. Schepetkin IA, Quinn MT. Botanical polysaccharides: macro-phage immunomodulation and therapeutic potential. IntImmunopharmacol 2006;6:317–33.

138. Kabelitz D, Wesch D, Oberg HH. Regulation of regulatory Tcells: role of dendritic cells and Toll-like receptors. Crit RevImmunol 2006;26:291–306.

139. Sutmuller RP, van Duivenvoorde LM, van Elsas A, et al.Synergism of cytotoxic T lymphocyte–associated antigen 4blockade and depletion of CD25+ regulatory T cells in antitumortherapy reveals alternative pathways for suppression ofautoreactive cytotoxic T lymphocyte responses. J Exp Med2001;194:823–32.

140. Yang L, DeBusk LM, Fukuda K, et al. Expansion of myeloidimmune suppressor Gr+CD11b+ cells in tumor-bearing host di-rectly promotes tumor angiogenesis. Cancer Cell 2004;6:409–21.

141. Terabe M, Park JM, Berzofsky JA. Role of IL-13 in regulationof anti-tumor immunity and tumor growth. Cancer ImmunolImmunother 2004;53:79–85.

142. Wang RF. Regulatory T cells and Toll-like receptors in cancertherapy. Cancer Res 2006;66:4987–90.

143. Bartz H, Avalos NM, Baetz A, Heeg K, Dalpke AH. Involve-ment of suppressors of cytokine signaling in Toll-like receptor–mediated block of dendritic cell differentiation. Blood2006;108:4102–8.

144. Garay RP, Viens P, Bauer J, et al. Cancer relapse under chemo-therapy: why TLR2/4 receptor agonists can help. Eur J Phar-macol 2007;563:1–17.

145. Liyanage UK, Moore TT, Joo HG, et al. Prevalence of regula-tory T cells is increased in peripheral blood and tumor micro-environment of patients with pancreas or breast adenocarci-noma. J Immunol 2002;169:2756–61.

146. Nava–Parada P, Forni G, Knutson KL, Pease LR, Celis E. Pep-tide vaccine given with a Toll-like receptor agonist is effectivefor the treatment and prevention of spontaneous breast tumors.Cancer Res 2007;67:1326–34.

147. Turnbull JL, Patchen ML, Scadden DT. The polysaccharide,PGG-glucan, enhances human myelopoiesis by direct action in-dependent of and additive to early-acting cytokines. ActaHaematol 1999;102:66–71.

148. Ahn JY, Choi IS, Shim JY, et al. The immunomodulator ginsaninduces resistance to experimental sepsis by inhibiting Toll-like receptor–mediated inflammatory signals. Eur J Immunol2006;36:37–45.

149. Cheung NK, Modak S, Vickers A, Knuckles B. Orally admin-istered beta-glucans enhance anti-tumor effects of monoclonalantibodies. Cancer Immunol Immunother 2002;51:557–64.

150. Koski GK, Czerniecki BJ. Combining innate immunity withradiation therapy for cancer treatment. Clin Cancer Res2005;11:7–11.

151. Demaria S, Bhardwaj N, McBride WH, Formenti SC. Combin-ing radiotherapy and immunotherapy: a revived partnership.Int J Radiat Oncol Biol Phys 2005;63:655–66.

152. United States, National Institutes of Health, ClinicalTrials.gov.Beta-Glucan and rituximab in treating young patients with re-lapsed or progressive lymphoma or leukemia, or lymphoproli-ferative disorder related to donor stem cell transplantation [Webpage]. Bethesda: National Institutes of Health; 2006. [Avail-able at: www.clinicaltrials.gov/ct/gui/show/NCT00087009; citedJuly 2007]

153. Chan WL, Lam DT, Law HK, et al. Ganoderma lucidum myc-elium and spore extracts as natural adjuvants for immuno-therapy. J Altern Complement Med 2005;11:1047–57.

154. Bianchi M, Jotti E, Sacerdote P, Panerai AE. Traditional acu-puncture increases the content of beta-endorphin in immunecells and influences mitogen induced proliferation. Am J ChinMed 1991;19:101–4.

155. Yuan J, Zhou R. Effect of acupuncture on T-lymphocyte andits subsets from the peripheral blood of patients with malig-nant neoplasm [Chinese]. Zhen Ci Yan Jiu 1993;18:174–7.

156. Wu B, Zhou RX, Zhou MS. Effect of acupuncture oninterleukin-2 level and NK cell immunoactivity of peripheralblood of malignant tumor patients [Chinese]. Zhongguo ZhongXi Yi Jie He Za Zhi 1994;14:537–9.

157. Wu B, Zhou RX, Zhou MS. Effect of acupuncture onimmunomodulation in patients with malignant tumors [Chi-nese]. Zhongguo Zhong Xi Yi Jie He Za Zhi 1996;16:139–41.

158. Yang J, Zhao R, Yuan J, et al. The experimental study ofprevention and treatment of the side-effects of chemotherapywith acupuncture (comparison among the effect of acupuncture



at different acupoints) [Chinese]. Zhen Ci Yan Jiu 1994;19:75–8.

159. Liu LJ, Guo CJ, Jiao XM. Effect of acupuncture on immuno-logic function and histopathology of transplanted mammarycancer in mice. Zhongguo Zhong Xi Yi Jie He Za Zhi1995;15:615–17.

160. Sato T, Yu Y, Guo SY, Kasahara T, Hisamitsu T. Acupuncturestimulation enhances splenic natural killer cell cytotoxicity inrats. Jpn J Physiol 1996;46:131–6.

161. Petti F, Bangrazi A, Liguori A, Reale G, Ippoliti F. Effects ofacupuncture on immune response related to opioid-like pep-tides. J Tradit Chin Med 1998;18:55–63.

162. Zhou JQ, Li ZH, Jin PL. A clinical study on acupuncturefor prevention and treatment of toxic side-effects duringradiotherapy and chemotherapy. J Tradit Chin Med 1999;19:16–21.

163. Lu W, Hu D, Dean–Clower E, et al. Acupuncture for chemotherapy-induced leukopenia: exploratory meta-analysis of random-ized controlled trials. J Soc Integrat Oncol 2007;5:1–10.

164. Tang ZY. Hepatocellular carcinoma. J Gastroenterol Hepatol2000;15(suppl):G1–7.

165. Gao JD, Shao YF, Xu Y, et al. Tight association of hepatocellu-lar carcinoma with HBV infection in North China. HepatobiliaryPancreat Dis Int 2005;4:46–9.

166. Shi J, Zhu L, Liu S, Xie WF. A meta-analysis of case-controlstudies on the combined effect of hepatitis B and C virus infec-tions in causing hepatocellular carcinoma in China. Br J Cancer2005;92:607–12.

167. Cheng WM, Chan KH, Chen HL, et al. Assessing the risk ofnasopharyngeal carcinoma on the basis of EBV antibody spec-trum. Int J Cancer 2002;97:489–92.

168. Zong Y, Liu K, Zhong B, Chen G, Wu W. Epstein–Barr virusinfection of sinonasal lymphoepithelial carcinoma in Guang-zhou. Chin Med J 2001;114:132–6.

169. Jarett RF. Risk factors for Hodgkin’s lymphoma by EBV statusand significance of detection of EBV genomes in serum of pa-tients with EBV-associated Hodgkin’s lymphoma. Leuk Lym-phoma 2003;44(suppl 3):S27–32.

170. Lo YM, Chan WY, Ng EK, et al. Circulating Epstein–Barr virusDNA in the serum of patients with gastric carcinoma. Clin Can-cer Res 2001;7:1856–9.

171. Ng WT, Yau TK, Yung RW, et al. Screening for family membersof patients with nasopharyngeal carcinoma. Int J Cancer2005;113:998–1001.

172. Li H, Zhao M, Qiu X, Ding X, Tan Y, Wu X. Characterizationof a new type HPV16 E7 variant isolated from cervical cancerhighest incidence area in Hubei province of China. Eksp Onkol2004;26:48–54.

173. Chang F, Syrjänen S, Shen Q, et al. Evaluation of HPV, CMV, HSV

and EBV in esophageal squamous cell carcinomas from a high-incidence area of China. Anticancer Res 2000;20:3935–40.

174. Li T, Lu ZM, Chen KN, et al. Human papillomavirus type 16is an important infectious factor in the high incidence ofesophageal cancer in Anyang area of China. Carcinogenesis2001;22:929–34.

175. Mellin H, Friesland S, Lewensohn R, Dalianis T, Munck–Wikland E. Human papillomavirus (HPV) DNA in tonsillar can-cer: clinical correlates, risk of relapse, and survival. Int J Can-cer 2000;89:300–4.

176. Almadori G, Galli J, Cadoni G, Bussu F, Maurizi M. Humanpapillomavirus infection and cyclin D1 gene amplification inlaryngeal squamous cell carcinoma: biologic function and clini-cal significance. Head Neck 2002;24:597–604.

177. Yu Y, Morimoto T, Sasa M, et al. Human papillomavirus type33 DNA in breast cancer in Chinese. Breast Cancer 2000; 7:33–6.

178. Cheng HM, Tsai MC. Regression of hepatocellular carcinomaspontaneous or herbal medicine related? Am J Chin Med 2004;32:579–85.

179. Yun TK, Choi SY, Yun HY. Epidemiological study on cancerprevention by ginseng: are all kinds of cancers preventable byginseng? J Korean Med Sci 2001;16(suppl):S19–27.

180. Zhong L, Goldberg MS, Gao YT, Hanley JA, Parent ME, Jin F.A population-based case–control study of lung cancer and greentea consumption among women living in Shanghai, China. Epi-demiology 2001;12:695–700.

181. Sinclair S. Chinese herbs: a clinical review of Astragalus,Ligusticum, and Schizandrae. Altern Med Rev 1998;3:338–44.

182. Block KI, Mead MN. Immune system effects of echinacea,ginseng, and astragalus: a review. Integr Cancer Ther 2003;2:247–67.

183. Qian ZH, Vermund SH, Wang N. Risk of HIV/AIDS in China:subpopulations of special importance. Sex Transm Infect2005;81:442–7. [Erratum in: Sex Transm Infect 2006;82:93]

184. Wu JA, Attele AS, Zhang L, Yuan CS. Anti-HIV activity ofmedicinal herbs: usage and potential development. Am J ChinMed 2001;29:69–81.

185. Tani M, Nagase M, Nishiyama T, Yamamoto T, Matusa R.The effects of long-term herbal treatment for pediatric AIDS. AmJ Chin Med 2002;30:51–64.

186. Matsui Y, Uhara J, Satoi S, et al. Improved prognosis of post-operative hepatocellular carcinoma patients when treated withfunctional foods: a prospective cohort study. J Hepatol 2002;37:78–86.

187. Lin H, She YH, Cassileth BR, Sirotnak F, Cunningham RundlesS. Maitake β-glucan MD-Fraction enhances bone marrowcolony formation and reduces doxorubicin toxicity in vitro. IntImmunopharmacol 2004;4:91–9.

188. Fullerton SA, Samadi AA, Torterelis DG, et al. Inductionof apoptosis in human prostatic cancer cells with beta-glucan (Maitaki mushroom polysaccharide). Molec Urol2000;4:7–13.

189. Jiang J, Slivova V, Harvey K, Valachovicova T, Sliva D.Ganoderma lucidum suppresses growth of breast cancer cellsthrough the inhibition of Akt/NF-κB signaling. Nutr Cancer2004;49:209–16.

190. Sliva D. Ganoderma lucidum (Reishi) in cancer treatment. IntegrCancer Ther 2003;2:358–64.

191. Yang CS, Wang ZY. Tea and cancer. J Natl Cancer Inst1993;85:1038–49.

192. Kaegi E. Unconventional therapies for cancer: 2. Green tea. TheTask Force on Alternative Therapies of the Canadian BreastCancer Research Initiative. CMAJ 1998;158:1033–5.

193. Yun TK, Choi SY. Non–organ specific cancer prevention ofginseng: a prospective study in Korea. Int J Epidemiol1998;27:359–64.

194. McKenna DJ, Hughes K, Jones K. Green tea monograph. AlternTher Health Med 2000;6:61–8,70–2,74 passim.

SAGAR AND WONG


195. Cao Y, Cao R. Angiogenesis inhibited by drinking tea. Nature1999;398:381.

196. Fujiki H, Suganuma M, Okabe S, et al. Mechanistic findings ofgreen tea as cancer preventive for humans. Proc Soc Exp BiolMed 1999;220:225–8.

197. Lee YN, Lee HY, Chung HY, et al. In vitro induction of differ-entiation by ginsenosides in F9 teratocarcinoma cells. Eur JCancer 1996;32A:1420–8.

198. Jacobsen BK, Knutsen SF, Fraser GE. Does high soy milkintake reduce prostate cancer incidence? The Adventist HealthStudy (United States). Cancer Causes Control 1998;9:553–7.

199. Kamat AM, Lamm DL. Chemoprevention of urological cancer.J Urol 1999;161:1748–60.

200. Moyad MA. Soy, disease prevention, and prostate cancer.Semin Urol Oncol 1999;17:97–102.

201. Stephens FO. The rising incidence of breast cancer in womenand prostate cancer in men. Dietary influences: a possible pre-ventive role for nature’s sex hormone modifiers—the phyto-estrogens (review). Oncol Rep 1999;6:865–70.

202. Adlercreutz H, Mazur W, Bartels P, et al. Phytoestrogens andprostate disease. J Nutr 2000;130:658S–9S.

203. Aronson WJ, Tymchuk CN, Elashoff RM, et al. Decreased growthof human prostate LNCaP tumors in SCID mice fed a low-fat, soyprotein diet with isoflavones. Nutr Cancer 1999;35:130–6.

204. Davis JN, Kucuk O, Sarkar FH. Genistein inhibits NF-κ B acti-vation in prostate cancer cells. Nutr Cancer 1999;35:167–74.

205. Zhou JR, Gugger ET, Tanaka T, Guo Y, Blackburn GL, ClintonSK. Soybean phytochemicals inhibit the growth of transplant-able human prostate carcinoma and tumor angiogenesis in mice.J Nutr 1999;129:1628–35.

206. Davis JN, Muqim N, Bhuiyan M, Kucuk O, Pienta KJ, SarkarFH. Inhibition of prostate specific antigen by genistein in pros-tate cancer cells. Int J Oncol 2000;16:1091–7.

207. United States, National Institutes of Health, National CancerInstitute. Notes. CAM scientist tests lung cancer herb. NCI Can-cer Bull 2006;3(7):7. [Available online at: www.cancer.gov/NCICancerBulletin/NCI_Cancer_Bulletin_021406.pdf; cited Oc-tober 28, 2007]

208. Cui Y, Shu XO, Gao YT, Cai H, Tao MH, Zheng W. Associa-tion of ginseng use with survival and quality of life amongbreast cancer patients. Am J Epidemiol 2006;163:645–53.

209. Mowrey DB, Clayson DE. Motion sickness, ginger, and psy-chophysics. Lancet 1982;1:655–7.

210. Grøntved A, Brask T, Kambskard J, Hentzer E. Ginger rootagainst seasickness. A controlled trial on the open sea. ActaOtolaryngol 1988;105:45–9.

211. Grøntved A, Hentzer E. Vertigo-reducing effects of ginger root.A controlled clinical study. ORL J Otorhinolaryngol Relat Spec1986;48:282–6.

212. Bone ME, Wilkinson DJ, Young JR, McNeil J, Charlton S.Ginger root—a new antiemetic. The effect of ginger root onpostoperative nausea and vomiting after major gynaecologicalsurgery. Anaesthesia 1990;45:669–71.

213. Fischer–Rasmussen W, Kjaer SK, Dahl C, Asping U. Gingertreatment of hyperemesis gravidarum. Eur J Obstet GynecolReprod Biol 1991;38:19–24.

214. Keating A, Chez RA. Ginger syrup as an antiemetic in earlypregnancy. Altern Ther Health Med 2002;8:89–91.

215. Hien TV, Huong NB, Hung PM, Duc NB. Radioprotectiveeffects of vitexina for breast cancer patients undergoing radio-therapy with cobalt-60. Integrat Cancer Ther 2002;1:38–43.

216. Ling HY, Wang NZ, Zhu HZ. Preliminary study of traditionalChinese medicine–Western medicine treatment of patients withprimary liver carcinoma [Chinese]. Zhong Xi Yi Jie He Za Zhi1989;9:348–9.

217. Mok TS, Yeo W, Johnson PJ, et al. A double-blind placebo-controlled randomized study of Chinese herbal medicine ascomplementary therapy for reduction of chemotherapy-inducedtoxicity. Ann Oncol 2007;18:768–74.

218. Zhang M, Liu X, Li J, He L, Tripathy D. Chinese medicinalherbs to treat the side-effects of chemotherapy in breast cancerpatients. Cochrane Database Syst Rev 2007;(2):14651858.CD004921.pub2.

219. Brezden CB, Phillips KA, Abdolell M, Bunston T, TannockIF. Cognitive function in breast cancer patients receivingadjuvant chemotherapy. J Clin Oncol 2000;18:2695–701.

220. Schagen SB, van Dam FS, Muller MJ, Boogerd W, LindeboomJ, Bruning PF. Cognitive deficits after postoperative adjuvantchemotherapy for breast carcinoma. Cancer 1999;85:640–50.

221. Meyers CA, Abbruzzese JL. Cognitive functioning in cancerpatients: effect of previous treatment. Neurology 1992;42:434–6.

222. Ahles TA, Saykin AJ, Noll WW, et al. The relationship of APOE

genotype to neuropsychological performance in long-term can-cer survivors treated with standard dose chemotherapy.Psychooncology 2003;12:612–19.

223. Tannock IF, Ahles TA, Ganz PA, Van Dam FS. Cognitive im-pairment associated with chemotherapy for cancer: report of aworkshop. J Clin Oncol 2004;22:2233–9.

224. Fan HG, Houédé–Tchen N, Yi QL, et al. Fatigue, menopausalsymptoms, and cognitive function in women after adjuvantchemotherapy for breast cancer: 1- and 2-year follow-up of aprospective controlled study. J Clin Oncol 2005;23:8025–32.

225. Wefel JS, Lenzi R, Theriault R, Buzdar AU, Cruickshank S,Meyers CA. “Chemobrain” in breast carcinoma? A prologue.Cancer 2004;101:466–75.

226. Wefel JS, Kayl AE, Meyers CA. Neuropsychological dys-function associated with cancer and cancer therapies: a con-ceptual review of an emerging target. Br J Cancer 2004;90:1691–6.

227. Taphoorn MJB, Schiphorst AK, Snoek FJ, et al. Cognitivefunctions and quality of life in patients with low-grade glio-mas: the impact of radiotherapy. Ann Neurol 1994;36:48–54.

228. Taphoorn MJ, Klein M. Cognitive deficits in adult patientswith brain tumours. Lancet Neurol 2004;3:159–68.

229. Taylor BV, Buckner JC, Cascino TL, et al. Effects of radiationand chemotherapy on cognitive function in patients with high-grade glioma. J Clin Oncol 1998;16:2195–201.

230. Danysz W, Parsons CG. The NMDA receptor antagonistmemantine as a symptomatological and neuroprotective treat-ment for Alzheimer’s disease: preclinical evidence. Int J GeriatrPsychiatry 2003;18:S23–32.

231. van Beek TA. Ginkgolides and bilobalide: their physical, chro-matographic and spectroscopic properties. Bioorg Med Chem2005;13:5001–12.

232. Strømgaard K, Nakanishi K. Chemistry and biology of terpenetrilactones from Ginkgo biloba. Angew Chem Int Ed Engl2004;43:1640–58.



233. Biber A. Pharmacokinetics of Ginkgo biloba extracts. Pharma-copsychiatry 2003;36(suppl 1):S32–7.

234. Menku A, Koc RK, Tayfur V, Saraymen R, Narin F, AkdemirH. Effects of mexiletine, Ginkgo biloba extract (EGb 761), andtheir combination on experimental head injury. Neurosurg Rev2003;26:288–91.

235. Defeudis FV. Bilobalide and neuroprotection. Pharmacol Res2002;46:565–8.

236. DeFeudis FV, Papadopoulos V, Drieu K. Ginkgo biloba ex-tracts and cancer: a research area in its infancy. Fundam ClinPharmacol 2003;17:405–17.

237. Ahlemeyer B, Krieglstein J. Pharmacological studies support-ing the therapeutic use of Ginkgo biloba extract for Alzheim-er’s disease. Pharmacopsychiatry 2003;36(suppl 1):S8–14.

238. Bressler R. Herb–drug interactions: interactions betweenGinkgo biloba and prescription medications. Geriatrics2005;60:30–3.

239. Santos RF, Galduroz JC, Barbieri A, Castiglioni ML, Ytaya LY,Bueno OF. Cognitive performance, SPECT, and blood viscosityin elderly non-demented people using Ginkgo biloba.Pharmacopsychiatry 2003;36:127–33.

240. Hu B, Sun S, Mei G, Chen L, Tong E. Protective effects ofGinkgo biloba extract on rats during cerebral ischemia/reperfusion. Chin Med J (Engl) 2002;115:1316–20.

241. Wang YS, Xu L, Ma K, Wang S, Wang JJ. Protective effects ofGinkgo biloba extract 761 against glutamate-induced neuro-toxicity in cultured retinal neuron. Chin Med J (Engl) 2005;118:948–52.

242. Ivic L, Sands TT, Fishkin N, Nakanishi K, Kriegstein AR,Strømgaard K. Terpene trilactones from Ginkgo biloba are an-tagonists of cortical glycine and GABA

A receptors. J Biol Chem

2003;278:49279–85.243. Kanowski S, Hoerr R. Ginkgo biloba extract EGb 761 in de-

mentia: intent-to-treat analyses of a 24-week, multi-center,double-blind, placebo-controlled, randomized trial.Pharmacopsychiatry 2003;36:297–303.

244. Birks J, Grimley Evans J. Ginkgo biloba for cognitive impair-ment and dementia. Cochrane Database Syst Rev 2002;(4):14651858.CD003120.pub2.

245. van Dongen M, van Rossum E, Kessels A, Sielhorst H,Knipschild P. Ginkgo for elderly people with dementia andage-associated memory impairment: a randomized clinical trial.J Clin Epidemiol 2003;56:367–76.

246. Kurz A, Van Baelen B. Ginkgo biloba compared with cholineste-rase inhibitors in the treatment of dementia: a review based onmeta-analyses by the Cochrane collaboration. Dement GeriatrCogn Disord 2004;18:217–26.

247. Shaw EG. A phase II study of Ginkgo biloba in irradiated braintumor patients: effects on quality of life and cognitive function[abstract 61]. In: Society for Integrative Oncology (SIO). Onlineprogram planner for the 2nd International Conference; Novem-ber 10–12, 2005; San Diego, CA [Web tool]. Mt. Royal, NJ:SIO; n.d. [Available by key word search at: www.abstractsonline.com/viewer/?mkey=%7B52C9E2CA%2D010B%2D4149%2D9D7C%2DD25107EF113A%7D; cited October28, 2007]

248. Shaw EG. Phase II studies of donepezil and Ginkgo biloba inirradiated brain tumor patients. Research base protocol CCCWFU

97100. Winston–Salem, NC: Comprehensive Cancer Center,Wake Forest University; 2000. [Available online at: www1.wfubmc.edu/NR/rdonlyres/4A8DC232-84E1-4401-B673-C6C1617A9BD2/0/97100Am4protocol.pdf; cited July 3,2007]

249. Hasegawa H. Proof of the mysterious efficacy of ginseng: basicand clinical trials: metabolic activation of ginsenoside:deglycosylation by intestinal bacteria and esterification withfatty acid. J Pharmacol Sci 2004;95:153–7.

250. Kim S, Ahn K, Oh TH, Nah SY, Rhim H. Inhibitory effect ofginsenosides on NMDA receptor-mediated signals in rat hip-pocampal neurons. Biochem Biophys Res Commun 2002;296:247–54.

251. Kim S, Rhim H. Ginsenosides inhibit NMDA receptor–mediatedepileptic discharges in cultured hippocampal neurons. ArchPharm Res 2004;27:524–30.

252. Kim S, Kim T, Ahn K, Park WK, Nah SY, Rhim H. GinsenosideRg3 antagonizes NMDA receptors through a glycine modulatorysite in rat cultured hippocampal neurons. Biochem Biophys ResCommun 2004;323:416–24.

253. Radad K, Gille G, Moldzio R, Saito H, Rausch WD. Ginse-nosides Rb1 and Rg1 effects on mesencephalic dopaminergiccells stressed with glutamate. Brain Res 2004;1021:41–53.

254. Bao HY, Zhang J, Yeo SJ, et al. Memory enhancing andneuroprotective effects of selected ginsenosides. Arch PharmRes 2005;28:335–42.

255. Kennedy DO, Scholey AB, Wesnes KA. Differential, dosedependent changes in cognitive performance following acuteadministration of a Ginkgo biloba/Panax ginseng combi-nation to healthy young volunteers. Nutr Neurosci2001;4:399–412.

256. Johnson A, Jiang N, Stuba E. Whole ginseng effects on humanresponse to demands for performance. In: Proceedings of the3rd International Ginseng Symposium; September 8–10, 1980;Seoul, Korea. Seoul: Korea Ginseng and Tobacco Research In-stitute; 1980: 244.

257. Moretti R, Torre P, Antonello RM, et al. Neuropsychologicalevaluation of late-onset post-radiotherapy encephalopathy: acomparison with vascular dementia. J Neurol Sci 2005;229–230:195–200.

258. Dundee JW, Chestnutt WN, Ghaly RG, Lynas AG. TraditionalChinese acupuncture: a potentially useful antiemetic? Br MedJ (Clin Res Ed) 1986;293:583–4.

259. Dundee JW, Ghaly RG, Fitzpatrick KT, Abram WP, LynchGA. Acupuncture prophylaxis of cancer chemotherapy–inducedsickness. J R Soc Med 1989;82:268–71.

260. al-Sadi M, Newman B, Julious SA. Acupuncture in the preven-tion of postoperative nausea and vomiting. Anaesthesia1997;52:658–61.

261. Schlager A, Offer T, Baldissera I. Laser stimulation of acupunc-ture point P6 reduces postoperative vomiting in children un-dergoing strabismus surgery. Br J Anaesth 1998;81:529–32.

262. Lee A, Done ML. The use of nonpharmacologic techniques toprevent postoperative nausea and vomiting: a meta-analysis.Anesth Analg 1999;88:1362–9.

263. NIH Consensus Development Panel on Acupuncture. NIH con-sensus conference. Acupuncture. JAMA 1998;280:1518–24.

264. Shen J, Wenger N, Glaspy J, et al. Electroacupuncture for con-trol of myeloablative chemotherapy–induced emesis: arandomized controlled trial. JAMA 2000;284:2755–61.

SAGAR AND WONG


265. Roscoe JA, Matteson SE, Morrow GR, et al. Acustimulationwrist bands are not effective for the control of chemotherapy-induced nausea in women with breast cancer. J Pain SymptomManage 2005;29:376–84.

266. Ezzo J, Vickers A, Richardson MA, et al. Acupuncture-pointstimulation for chemotherapy-induced nausea and vomiting. JClin Oncol 2005;23:7188–98.

267. Thompson JW, Filshie J. Transcutaneous electrical nerve stimu-lation (TENS) and acupuncture. In: Doyle D, Hanks GWC,MacDonald N, eds. Oxford Textbook of Palliative Medicine.2nd ed. Oxford, U.K.: Oxford University Press; 1998: 421–37.

268. Filshie J, Redman D. Acupuncture and malignant pain prob-lems. Eur J Surg Oncol 1985;11:389–94.

269. Filshie J. Acupuncture for malignant pain. Acupunct Med1984;2:12–14.

270. Filshie J, Bolton T, Browne D, Ashley S. Acupuncture and selfacupuncture for long-term treatment of vasomotor symptomsin cancer patients—audit and treatment algorithm. AcupunctMed 2005;23:171–80.

271. Alimi D, Rubino C, Pichard–Leandri E, Fermand–Brule S,Dubreuil–Lemaire ML, Hill C. Analgesic effect of auricularacupuncture for cancer pain: a randomized, blinded, controlledtrial. J Clin Oncol 2003;21:4120–6.

272. Wong R, Sagar S. Acupuncture treatment for chemotherapy-induced peripheral neuropathy—a case series. Acupunct Med2006;24:87–91.

273. Lee H, Schmidt K, Ernst E. Acupuncture for the relief of cancer-related pain: a systematic review. Eur J Pain 2005;9:437–44.

274. Barlas P, Ting SL, Chesterton LS, Jones PW, Sim J. Effects ofintensity of electroacupuncture upon experimental pain inhealthy human volunteers: a randomized, double-blind, pla-cebo-controlled study. Pain 2006;122:81–9.

275. Pomeranz B, Niznik G. Codetron: a new electrotherapy deviceovercomes the habituation problems of conventional TENS de-vices. Am J Electromed 1987;2:22–6.

276. Patel M, Gutzwiller F, Paccaud F, Marazzi A. A meta-analysisof acupuncture for chronic pain. Int J Epidemiol 1989;18:900–6.

277. Gadsby JG, Flowerdew MW. Review: transcutaneous electri-cal nerve stimulation reduces pain and improves range of move-ment in chronic low-back pain. Evid Based Med 1997;2:107.

278. Ernst E, White AR. Acupuncture for back pain: a meta-analy-sis of randomized controlled trials. Arch Intern Med1998;158:2235–41.

279. Ghoname EA, Craig WF, White PF, et al. Percutaneous electri-cal nerve stimulation for low back pain: a randomized crosso-ver study. JAMA 1999;281:818–23.

280. Blom M, Dawidson I, Angmar–Månsson B. The effect of acu-puncture on salivary flow rates in patients with xerostomia.Oral Surg Oral Med Oral Pathol 1992;73:293–8.

281. Blom M, Lundeberg T, Dawidson I, Angmar–Månsson B. Ef-fects on local blood flux of acupuncture stimulation used totreat xerostomia in patients suffering from Sjögren’s syndrome.J Oral Rehabil 1993;20:541–8.

282. Talal N, Quinn JH, Daniels TE. The clinical effects of elec-trostimulation on salivary function of Sjögrens syndrome pa-tients: a placebo controlled study. Rheumatol Int 1992;12: 43–5.

283. Blom M, Dawidson I, Fernberg JO, Johnson G, Angmar–Månsson B. Acupuncture treatment of patients with radiation-

induced xerostomia. Eur J Cancer B Oral Oncol 1996;32B:182–90.

284. Blom M, Lundeberg T. Long-term follow-up of patients treatedwith acupuncture for xerostomia and the influence of addi-tional treatment. Oral Dis 2000;6:15–24.

285. Rydholm M, Strang P. Acupuncture for patients in hospital-based home care suffering from xerostomia. J Palliat Care1999;15:20–3.

286. Johnstone PA, Peng YP, May BC, Inouye WS, Niemtzow RC.Acupuncture for pilocarpine-resistant xerostomia followingradiotherapy for head and neck malignancies. Int J Radiat OncolBiol Phys 2001;50:353–7.

287. Wong RK, Jones GW, Sagar SM, Babjak AF, Whelan T. A phaseI/II study in the use of acupuncture-like transcutaneous nervestimulation in the treatment of radiation-induced xerostomia inhead-and-neck cancer patients treated with radical radiotherapy.Int J Radiat Oncol Biol Phys 2003; 57:472–80.

288. Deng G, Hou BL, Holodny AI, Vickers AJ, Cassileth BR.Randomized controlled trial of functional magnetic resonanceimaging (fMRI) changes associated with acupuncture at a pointused to treat xerostomia versus sham acupuncture or gustatorystimulation [abstract]. In: Society for Integrative Oncology(SIO). Abstracts of the 3rd International Conference; Novem-ber 9–11, 2006; Boston, MA. Mt. Royal, NJ: SIO; 2006.[Available online at: www.integrativeonc.org/images/2006%20Conference %20Abstracts%20&%20Posters.pdf;cited October 28, 2007]

289. Widerstrom–Noga E, Dyrehag LE, Borglum–Jensen L, AslundPG, Wenneberg B, Andersson SA. Pain threshold responses totwo different modes of sensory stimulation in patients withorofacial muscular pain: psychological considerations. J OrofacPain 1998;12:27–34.

290. Lissoni P, Paolorossi F, Tancini G, et al. Is there a role formelatonin in the treatment of neoplastic cachexia? Eur J Can-cer 1996;32A:1340–3.

291. Campbell SS, Murphy PJ. Extraocular circadian phototrans-duction in humans. Science 1998;279:396–9.

292. Glaus A. Fatigue and cachexia in cancer patients. Support CareCancer 1998;6:77–8.

293. Stone P, Richards M, Hardy J. Fatigue in patients with cancer.Eur J Cancer 1998;34:1670–6.

294. Bonta IL. Acupuncture beyond the endorphin concept? MedHypotheses 2002;58:221–4.

295. Han JS. Acupuncture and endorphins. Neurosci Lett2004;361:258–61.

296. Han JS. Electroacupuncture: an alternative to antidepressantsfor treating affective diseases. Int J Neurosci 1986;29:79–92.

297. Roschke J, Wolf C, Muller MJ, et al. The benefit from wholebody acupuncture in major depression. J Affect Disord2000;57:73–81.

298. Smith CA, Hay PPJ. Acupuncture for depression. CochraneDatabase Syst Rev 2005;(2):14651858.CD004046.pub2.

299. Yu J, Liu C, Zhang X, Han J. Acupuncture improved cognitiveimpairment caused by multi-infarct dementia in rats. PhysiolBehav 2005;86:434–41.

300. Johnston MF, Yang C, Hui KK, Xiao B, Li XS, Rusiewicz A.Acupuncture for chemotherapy-associated cognitive dysfunc-tion: a hypothesis-generating literature review to inform clini-cal advice. Integr Cancer Ther 2007;6:36–40.



301. Vickers AJ, Straus DJ, Fearon B, Cassileth BR. Acupuncturefor postchemotherapy fatigue: a phase II study. J Clin Oncol2004;22:1731–5.

302. Ernst E, White AR. Acupuncture as a treatment for temporo-mandibular joint dysfunction: a systematic review of ran-domized trials. Arch Otolaryngol Head Neck Surg 1999;125:269–72.

303. Zhang, Z. Effect of acupuncture on 44 cases of radiation rectitisfollowing radiation therapy for carcinoma of the cervix uteri. JTradit Chin Med 1987;7:139–40.

304. Yan LS. Treatment of persistent hiccupping with electro-acu-puncture at “hiccup-relieving” point. J Tradit Chin Med1988;8:29–30.

305. Wong R, Sagar SM. The treatment of persistent yawning withacupuncture. Acupunct Med 2000;18:124–6.

306. Feng R. Relief of oesophageal carcinomatous obstruction byacupuncture. J Tradit Chin Med 1984;4:3–4.

307. Filshie J, Penn K, Ashley S, Davis CL. Acupuncture for the reliefof cancer-related breathlessness. Palliat Med 1996;10:145–50.

308. Vickers AJ, Feinstein MB, Deng GE, Cassileth BR. Acupunc-ture for dyspnea in advanced cancer: a randomized, placebo-controlled pilot trial [ISRCTN89462491]. BMC Palliat Care2005;4:5.

309. Hammar M, Frisk J, Grimas O, Hook M, Spetz AC, Wyon Y.Acupuncture treatment of vasomotor symptoms in men withprostatic carcinoma: a pilot study. J Urol 1999;161:853–6.

310. Tukmachi E. Treatment of hot flushes in breast cancer patientswith acupuncture. Acupunct Med 2000;18:22–7.

311. Cumins SM, Brunt AM. Does acupuncture influence the vaso-motor symptoms experienced by breast cancer patients takingtamoxifen? Acupunct Med 2000;19:28–9.

312. Fontanarosa PB, Lundberg GD. Alternative medicine meetsscience. JAMA 1998;280:1618–19.

313. Sagar SM. Unproven cancer therapies. Ann R Coll PhysiciansSurg Can 1998;31:160.

314. Sagar SM. Alternative views on alternative therapies. CMAJ1999;160:1697–9.

315. Sagar SM. Restored Harmony: An Evidence-based Approachfor Integrating Traditional Chinese Medicine into Complemen-tary Cancer Care. Hamilton, ON: Dreaming DragonFly Com-munications; 2001.

316. Tagliaferri M, Cohen I, Tripathy D. Complementary and alter-native medicine in early-stage breast cancer. Semin Oncol2001;28:121–34.

317. Bensoussan A, Talley NJ, Hing M, Menzies R, Guo A, Ngu M.Treatment of irritable bowel syndrome with Chinese herbal me-dicine: a randomized controlled trial. JAMA 1998;280:1585–9.

Correspondence to: Stephen M. Sagar, Juravinski Can-cer Centre, 699 Concession Street, Hamilton, OntarioL8V 5C2.E-mail: [email protected]

* Departments of Oncology and Medicine,McMaster University; Juravinski Cancer Program,Hamilton Health Sciences Corporation; and TheBrain–Body Institute, St. Joseph’s Healthcare Sys-tem, Hamilton, Ontario, Canada.

For in-depth information, readers may want to visitthese linked sites:Society for Integrative Oncology (SIO)Shanghai International Symposium:Integrative Oncology Theory, Research, and PracticeApril 25-26, 2008, Shanghai, ChinaandSociety for Integrative Oncology

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