ORIGINAL RESEARCH

Review of Complementary and Alternative Medicineand Selected Nutraceuticals: Background for a

Pilot Study on Nutrigenomic Interventionin Patients with Advanced Cancer

Kimberly A. Varker, MD; Adam Ansel; Glen Aukerman, MD; William E. Carson, III, MD

ABSTRACTAs commonly defined, complementary and alternative

medicine (CAM) is a broad category that includes biologicallybased practices, mind-body medicine, manipulative and body-based practices, and energy medicine as well as complete medi-cal systems such as naturopathy, homeopathy, Ayurvedic medi-cine, and traditional Chinese medicine. Several CAM method-ologies show promise for the treatment of chronic conditionssuch as depression and pain disorders or have demonstratedeffects upon the immune response in experimental studies.There is growing interest in the use of integrative medicine—the combination of CAM methodologies with a conventionalmedical approach—^for the optimization of treatment of vari-

ous cancers.The Ohio State University Center for Integrative Medicine

has developed a specialized nutrigenomic protocol for integra-tive cancer care. The center uses a comprehensive nutritionaland medical evaluation, including a panel of proinflammatorymolecules and physiologic parameters, to guide a program ofindividualized dietary interventions. Dietary supplementationis a current focus of study, including: (1) Omega-3 fatty acidsand B vitamins, which are thought to play important roles inimmunomodulation; (2) Magnesium oxide, which has beensbown to decrease inflammation and improve insulin resi.s-tance and lipid profiles; and (3) Cinnamon extract, whichreportedly decreases serum glucose levels. This article presentsa brief overview of CAM and integrative medicine and a discus-sion of the relevant nutraceuticals. (Altern Ther Health Med.2012;18(2):26-34.)

Kimberly A. Varker, MD, is a visiting scholar, Adam Ansel is amedical student, and William E. Carson, in, MD, is a professorin the Division of Surgical Oncology, Department of Surgery,and Associate Director for Clinical Research, the Ohio StateUniversity Comprehensive Cancer Center, Columbus. GlenAukerman, MD, is a professor in the Ohio State UniversityCenter for Integrative Medicine, Department of EamilyMedicine, the Ohio State University Medical Center,Columbus.

Corresponding Author: William E. Carson III, MDEmail: william. carson@osumc. edu

Author Disclosure Statement: National Institutes of HealthGrants UOl CA76576, NOl CM62207, K24 CA093670, andCA093071 supported this work.

Complementary and ahemative medicine (CAM) refersto diverse health care systems, practices, and productsthat are not presently considered to be part of conven-tional medicine.' Major domains of CAM, as definedby the National Center for Complementary and

Alternative Medicine (NCCAM), include biologically based practic-es, mind-body medicine, manipulative and body-based practices.

and energy medicine. Whole medical systems such as homeopathy,naturopathy, and traditional Chinese medicine are complete sys-tems of theory and practice that cut across all of the domains ofCAM. Integrative medicine refers to the combination of treatmentsfrom conventional medicine and CAM.' The use of integrativemedicine in cancer care is a holistic approach that uses CAM ofproven effectiveness as an adjunct to conventional medical treat-ment.^ A goal of holistic treatment is to address the person who hasthe disease individually—unique personality, life experiences, andcurrent state of being—rather than simply treating the disease.^

BIOLOGICALLY BASED PRACTICESBiologically based practices include botanicals, animal-derived

extracts, vitamins and minerals, fatty acids, amino acids, pre- andprobiotics, whole diets, and functional foods.' The use of dietarysupplements, especially vitamins and minerals, has grown consider-ably in tbe past two decades, primarily as a way to improve generalhealth but also as a means to treat specific illnesses.' Functionalfoods are usual parts of the diet that may contain biologically activecomponents (such as polyphenols, phytoestrogens, fish oils, andcarotenoids) that provide additional health benefits beyond basicnutrition.'' In contrast to some of the other modalities, a large quan-tity of data is available firom clinical studies (mainly phase II) ofsupplements containing single chemical constituents (eg, vitamins

26 ALTERNATIVE THERAPIES. MAR/APR 2012. VOL. 18, NO. 2 CAM and Nutrigenomics

and minerals). For example, vitamins C, F, and coenzyme Q^^^ haveshown disappointing results for the prevention or treatment ofcancer and cardiovascular disease,^* despite positive results fi-omearly observational studies. In contrast, a Cochrane review thatassessed the use of cranberry products vs placebo for prevention ofurinary tract infection (UTI) demonstrated that the use of cranberryproducts significantly decreased the incidence of UTI at 12 months,particularly in women with recurrent UTIs," Many other dietarysupplements are currently being studied in clinical trials,

HERBAL MEDICINE

Herbal medicine has existed for thousands of years, having itsbasis in the Ayurvedic and traditional Chinese medicine .systems.Two well-known longitudinal studies fi-om Harvard in the 1990sdemonstrated increasing u,se of self-prescribed herbal medicines inthe general population of the United States (2,5% in 1990,12,1% in1997) and increasing consultation of herbal-medicine practitionersduring the same period," Common motivations for using herbalmedicines are promotion of well-being, prevention of future illness,or treatment of a life-threatening condition," whereas surveys showthat disappointment with conventional medicine is not a primarymotivation for use of alternative therapies,'" The stereotypical userof herbal medicines is female, affluent, college-educated, middle-aged, and likely to be using conventional medicines as well," Herbalmedicines are generally perceived to be safe and effective and toprovide the user with some control over his or her treatment.

Although many traditional herbal medicines have been usedover hundreds or thousands of years," few medicines have proveneffective in placebo-controlled randomized trials. Those herbalmedicines proven to be effective include Gingko biloba as treatmentfor dementia or intermittent claudication, St John's wort {Hypericumperforatum) as therapy for mild to moderate depression, kava (Pipermethysticum) as an herbal anxiolytic, and horse chestnut (Aesculushippoeastanum) seed as a treatment for chronic venous insufficien-cy," Other herbal medicines have doubtful efficacy (such as Asianginseng for any indication) or no clinically relevant efficacy (such asevening primrose oil and garlic),'

Many herbal medicines have important adverse effects or maycause herb-drug interactions. For example, gingko potentiates anti-platelet drugs, and St John's wort induces cytochrome p450, affect-ing metabolism of other drugs. Licorice acts as a mineralocorticoidand may lead to potassium loss and to sodium and water retention,especially when used with antihypertensive medications,^ Otherherbal medicines have direct adverse effects upon organ systems.Perhaps the most well-known example is the ephedra species, whichcan cause heart and circulatory problems or death,' Importantly, allherbal medicines are contraindicated in pregnant or lactating womendue to a lack of reliable data regarding teratogenicity. Furthermore,important safety concerns exist regarding preparation of herbalmedicines. Botanical substitution is common (active ingredientsmay be underdosed), and multiple contaminants such as otherplants, microorganisms and microbial toxins, pesticides, fumigationagents, and heavy metals have been found in some herbal medicines.In the United States, the Dietary Supplement Health and EducationAct regulates herbal medicines as dietary supplements, and tbus,they are not under the same rigorous control as medications.

HOMEOPATHY

Homeopathy is a whole medical system whose principles wereoriginally outlined by Hahnemann in his "Fssay on the NewCurative Principle" (1796),'^ Two basic scientific tenets definehomeopathy: the Principle of Similars and the Principle of Dilutions,The Principle of Similars is based on the observation that a sub-stance that can cause symptoms in a healthy person possibly canstimulate self-healing in a person having an illness presenting withsimilar symptoms. This tenet is in contrast to allopathic medicine,which uses the principle of opposition or suppression to interferewith pathologic processes. Importantly, a mechanistic explanationfor the action of homeopathic preparations is lacking,'- The Principleof Similars states that remedies retain biologic activity when seriallydiluted by shaking, which extracts the vital nature of the substancein a process known as "potenization,""'" Although low concentra-tions of many substances have biologic activity, preparations with adilution of the active substance below the limit of molecular dilution(ie, less than Avogadro's number) are more problematic,'^ Thisprinciple is the most controversial and has led many to reject home-opathy as a valid treatment modality,'"'

The philosophical tenet underlying homeopathy is that thebody possesses a close mind-body connection and self-healingpotential. Illness is viewed as an imbalance in one's vital force, Acorrectly prescribed remedy restores balance to the body,'^ In classichomeopathy, homeopathic preparations are prescribed accordingto an extremely detailed characterization of symptoms obtainedfi-om the patient. The symptoms evoked by common remediesgiven repeatedly to healthy volunteers have been recorded in a pro-cess known as a "proving" (similar to a Phase I pharmacologie studybut with the goal of cataloguing side effects of each remedy). Thesesymptoms are catalogued in Materia Medica, the homeopathic bookon pharmacology,'^ A Repertory is a cross-reference tool that thepractitioner uses to find a group of remedies closely correspondingto the symptom complex with which the patient is presenting.Remedies are most effective when chosen based on the total set ofsymptoms presented (not necessarily based on the disease); thus,practitioners may treat 2 patients with the same diagnosis with dif-ferent potencies,"

Clinical homeopathy (homeotherapeutics) uses the prescrip-tion of preparations combining several remedies in lower potencies(so-called combination remedies) to treat symptomatic variationsof a condition, and thus, it is more similar to conventional drugtherapy," A few single-remedy preparations are reportedly suc-cessfiil for prophylaxis and relief of acute cold and influenza,'^Some positive studies show the efficacy of homeopathy for selectconditions such as asthma and allergic rhinitis; however, manystudies of homeopathic remedies are of low methodological qual-ity, often due to a lack of validated outcome measures or smallsample sizes,'^ Although homeopathy may be one of the most dif-ficult alternative-treatment methodologies for Western bioscien-tists to accept, it also may be one of the most frequently usedcomplementary therapies worldwide,"'

MIND-BODY MEDICINE (MBM)Mind-body medicine (MBM) focuses on ways in which health is

affected by emotional, mental, social, spiritual, and behavioral fac-

CAM and Nutrigenomics ALTERNATIVE THERAPIES, MAR/APR 2012, VOL. 18, NO. 2 27

tors.' The goal of these therapies is to respect and enhance eachperson's capacity for self-knowledge and self-care. Illness is viewedas an opportunity for personal growth and transformation. Mind-body medicine can address many common complaints about healthcare by affording greater control in treatment, less expensive alter-natives, methods for maintaining Wellness, and effective options fortreatment of chronic illnesses." Some examples of mind-body thera-pies are meditation, hypnosis, guided imagery, relaxation therapy,biofeedback, yoga, tai chi, qigong, and spiritual healing. Mainstreamtreatment has incorporated cognitive-behavioral therapies andgroup support, once considered to be forms of CAM.

Mind-body medicine may be especially helpful for chronic-paindisorders, anxiety, and insomnia and may be effective in the treat-ment of coronary artery disease."'" Guided imagery is a therapist-directed technique that uses the power of suggestion and imagery toharness specific biological effects that may not be accessible nor-mally to the conscious mind.^" Reviews show that imagery, usuallyin conjunction with a psychological intervention, may reduce mor-bidity and prolong survival in cancer patients.^ Furthermore, mod-est evidence suggests that guided imagery has positive effects onsurgical and cancer-treatment outcomes." Similarly, moderate evi-dence supports hypnosis for the treatment of acute- and chronic-pain conditions, including surgery."

Researchers have studied the effects of behavioral therapiesupon immune parameters in some detail. For example, Keicolt-Glaser et al demonstrated that subjects participating in a programof hypnotic-relaxation training were relatively protected from acutestress-related detriments in immune parameters as compared tocontrol subjects.'" Specifically, lymphocyte proliferation decreasedin the control group during acute stress but remained stable orincreased slightly in the hypnotic-relaxation group. Similarly, per-centages of CD3* and CD4* T lymphocytes remained relatively sta-ble in the hypnotic-relaxation group but declined in the controlgroup.^' In a study of 36 patients aged greater than 60 assigned to a15-week intervention program consisting of instruction in tai chichih vs control condition, varicella-zoster-virus-specific cell-medi-ated immunity increased 50% firom baseline to one week post-intervention in the tai chi chih group but was unchanged in thecontrol group.^" One-week-post-intervention SF-36 scores for role-physical and physical fiinctioning were higher in the interventiongroup. Importantly, mind-body interventions can reportedlyimprove mood, quality of life, and coping and can minimize treat-ment-related symptoms in cancer patients.^^ A randomized, wait-listcontrolled study of 90 cancer patients showed improvement indepression, anxiety, anger, and confiision as well as decreased physi-cal symptoms in patients treated with a mindfiilness meditation-based program.^* In a randomized clinical trial with Stage II and IIIbreast-cancer patients, Andersen et al showed that receipt of a psy-chological intervention impacted both immunity^^""' and diseaseendpoints (breast-cancer recurrence, breast-cancer death)^'' for thewomen in the intervention group as compared to those in the controlarm. This intervention incorporated progressive muscle relaxation,coping strategies, a dietary intervention, and other strategies.

MBM therapies may be most effective when used in combina-tion with each other or with conventional therapy." For example, ina study by Spiegel et al, the combination of group therapy and hyp-

nosis with standard oncological care improved survival in patientswith metastatic breast cancer.^" Research into potential neuro-chemical and anatomical bases for the effects of mind-bodyapproaches is ongoing.

MANIPULATIVE AND BODY-BASED PRACTICESManipulative and body-based practices include a long list of

therapies, of which the most commonly used are chiropractic andostéopathie manipulation and massage therapies.' In a study oftrends in use of alternative medicine in the United States, the com-bined visits to chiropractors and massage therapists represented50% of all visits to CAM practitioners." Many of these practices—which focus on the bones and joints, soft tissues, and circulatoryand lymphatic systems—originated in traditional systems ofmedicine from China, India, or Fgypt. Common tenets amongthese therapies are that the human body is self-regulating and hasthe ability to heal itself, and that parts of the body are interdepen-dent. Chiropractic is the largest alternative medical profession inthe United States. It is licensed in all 50 states, and studies esti-mate that chiropractors treat one-third of all patients with lowerbackpain.^""

Results of small clinical studies of spinal manipulation are dif-ficult to generalize due to factors such as patients' characteristicsand interpractitioner variability (major diversity exists within thefield as to the ideal techniques of manipulation).'-^" Many random-ized, controlled trials (RCTs) of spinal manipulation for back paincontaining at least one arm of sham control have been performed.Unfortunately, the methodological quality in general has beenweak, and results of these trials were mixed.^" A well-known meta-analysis of RCTs studying manipulation for lower back pain showedthat there is short-term benefit, especially for uncomplicated, acutelower back pain." Importantly, several surveys have shown thatpatients in general believe that chiropractic works for them, andthey are very likely to be satisfied with the treatment received." "

Research into potential mechanisms for the effectiveness ofmanipulative and body-based practices is ongoing. Animal studiessuggest that manipulation of the spine evokes changes in the outputof proprioceptive afferent neurons in paraspinal tissue, in turn alter-ing the outflow to the autonomie nervous .system.'"' Some studiessuggest that massage can alter chemical and immune parameters,such as levels of substance P, serotonin, and cortisol; natural killer(NK) cell number; and CD4* T-cell count."' These studies requirereplication. Both spinal manipulation and massage present rela-tively few risks to patients. Interestingly, despite the relative lack ofinformation regarding long-term effects, dosing, or cost-effective-ness, the majority of patients has high levels of satisfaction withboth chiropractic and massage therapy.^ ' '

TRADITIONAL CHINESE MEDICINE (TCM)According to the National Institutes of Health and the World

Health Organization, traditional Chinese medicine (TCM) origi-nated approximately 3000 years ago.-* Yin and yang are fijndamen-tal concepts representing opposites in nature. It is believed that thebody is traversed by a system of channels (known as meridians) thatcarries vital energy {qt), blood, and fluid. The goal of diagnosis andtreatment is to detect the internal imbalance by its external manifes-

28 ALTERNATIVE THERAPIES, MAR/APR 2012, VOL. 18. NO. 2 CAM and Nutrigenomics

tations and to devise a treatment plan for bringing yin and yangback into balance.'^ TCM encompasses multiple treatment modali-des including acupuncture, nutrition, herbal medicine, manipula-tive therapy, and movement exercises such as qigong and tai chi.Acupuncture, the most commonly used TCM modality, consists ofthe insertion of small, sterile needles at specific anatomic pointscorresponding to the physiological functions of the body, with thegoal of releasing energy blockages and reestablishing equilibrium,thereby allowing self-healing.^" Many Chinese and Western studiessince the 1950s have sugge.sted that acupuncture aids in the releaseof neurotransmitters such as endorphins and opiates, "' Noninvasiveacupuncture techniques include cupping and moxibustion. Othertherapies derived fiom acupuncture are acupressure, reflexology,shiatsu, and applied kinesiology, '

NATUROPATHYNaturopathy is another whole medical system that incorpo-

rates many CAM modalities. It is loosely defined as the use of natu-ral methods to approach health and illness,'" The nature cure con-sisting of medicinal herbs, exercise, and water originated in the1800s in Germany and was most popular in tbe United States in the1920s and 1930s, The unifying principles of nautropathy include (1)the healing power of nature (Vis Medicatrix Naturae), (2) identifica-tion and treatment of causes (Tolle causiim), (3) do no harm (Pritiiumnon nocere), (4) doctor as teacher (Docere), (5) treatment of the wholeperson, and (6) prevention,'" Primary modalides of treatmentinclude diet modification and supplementation, herbal and homeo-pathic medicine, hydrotherapy, physical medicine (therapeuticmassage and joint manipulation), and lifestyle counseling,^' Muchof the evidence supporting naturopathy is empirical, and althoughindividual modalities used by naturopathic physicians can be vali-dated (eg, nutritional approaches), naturopathy itself is difficult tostudy since tbe methods of healing may differ among patients. Fewstates have legislation regarding the practice of naturopathy, and instates without legislation, no specific educational requirementsexist for naturopathic physicians.

ENERGY MEDICINEEnergy medicine is based on the perception of patients and

therapists that subtle biological energies surround and permeatethe human body. Spiritual awareness (ie, the sense of being part ofsomething that is wiser and larger than oneself) is an importantcomponent of energy medicine and is thought to be especially help-ful when facing serious or terminal illness.' As previously stated onthe NCCAM website, energy medicine encompasses the use of mea-surable sources of energy such as sound, light, magnetism, andlasers as well as biofields or vital energy, known by various namessuch as (//, doshas, and homeopathic resonance. Magnetic therapy,music therapy, and high-intensity light therapy for seasonal affec-tive disorder are among the more familiar types of energ)' medicine.Practices that involve manipulation of vital energy include Reiki,qigong, healing touch, and intercessory prayer. Researchers reportthat prayer healing can be effective even from miles away.''^"Practitioners of spiritual-healing techniques claim to be able to pal-pate energy fields and/or perceive auras of colors around the body,layers of which indicate the physical, emotional, mental, relational.

and .spiritual condidons of the person.^'' Pracdtioners administertreatment by the laying-on of hands while holding in mind a mentalintent, meditative focus, or prayer for healing. The mechanism ofaction of energy therapy is unknown but may include: (1) unblock-ing the patient's own energies, (2) projection of the practitioner'senergy, (3) channeling of energies from nature, or (4) Interventionsof spiritual agents, ' The use of these practices remains controversialbecause the existence of the biofield and beneficial efiects of therapycan not be demonstrated biopbysically. Multiple studies, however,have shown that spiritual-healing practices can be effective for pain,anxiety, depression, AIDS, hypertension, and wound healing,among others, and spiritual healing has no known side efiects orinteracdons with other treatments, making it an excellent therapyof first choice.^

INTEGRATIVE CAREIntegrative care—the use of CAM in combination with conven-

tional therapy as part of a comprehensive treatment plan—is anincreasingly common phenomenon in treatment of cancer. In anobservational study of 200 padents attending an oncology clinicwho voluntarily answered a questionnaire, 22% (with a prepon-derance of young female patients) reported using CAM. Therespondents' most common reasons for using CAM were to makethemselves feel better and to help with their cancer. -' Thesepatients seldom believed that more evidence exists for CAM thanfor traditional medical therapies or that CAM would cure them,and they were not turning to CAM therapies due to dls.satisfactionwith their doctors. In a study of 404 patients attending the TomBaker Cancer Centre in Calgary and 303 patients calling Its CancerInformation Service, patients most often desired informationregarding the safety of complementary therapies, the ways inwhich complementary therapies work, and their anticipated sideeffects.''" Importantly, although patients were aware of the mean-ing of scientific evidence, they often made decisions based onnonscientific evidence such as tesdmonials.

Gage et al attempted to assess the use of CAM as a part of inte-grative care in a CAM unit located within a conventional cancercenter.^' In a 6-month prospective observational study, 15.8% of alloutpatients attending the cancer center visited the CAM unit, and9.2% accessed therapies. Padents visiting the CAM unit were morelikely to be younger, female, have breast or gynecological cancer,and live within the local area.

Stein et al, in a review of CAM use among 252 male and 277female, colorectal-cancer survivors found that use of CAM was morecommon among women, people with greater levels of education,and individuals who had received chemotherapy and radiationtherapy.* Psycho.social functioning bad a significant eifect on thelikelihood of CAM use among female survivors: for any CAM withspiritual-body methods, fear of recurrence, fatigue-inertia, tension-anxiety, and vigor-activity were significantly and positively associ-ated with the likelihood of CAM use, but depression-dejection wasassociated with decreased use of any CAM; whereas for any CAMwithout spiritual-body methods, only tension-anxiety and depres-sion were significantly related to CAM u.se among female survi-vors.""* Among males, the only demographic variable associatedwith CAM use was fatigue.""

CAM and Nutrigenomics ALTERNATIVE THERAPIES, MAR/APR 2012, VOL. 18, NO, 2 29

Steinsbekk et al studied 1406 patients fiom a total-populationsurvey. Among patients who presently have or previously had can-cer, 16.1% visited a CAM practitioner in the previous 12 months ascompared to 12.8% for the total population.^' The likelihood ofconsulting a CAM practitioner increased among those having auniversity degree, having lower perceived global health, and havinga health complaint within the last 12 months.

The use of dietary supplements in particular is importantamong cancer patients due to the potential of some supplements tointeract with other therapies. In a study of 827 cancer survivorsfiom the American Cancer Society's longitudinal Study of CancerSurvivors-1,573 patients (69.3%) reported the use of dietary supple-ments afier receiving their cancer diagnosis.^" Again, female genderand higher educational levels were associated with dietary-supple-ment use. The most common reasons patients cited for using sup-plements included "something they could do to help themselves"(56.2%) and "to boost their immune system" (51.1%).

SELECTED NUTRACEUTICALSNutrigenomics is a personalized approach to food, nutrition,

and health that involves tailoring food to the individual genotype.^'It is now known that many bioactive food components may eitherincrease the risk of or protect against cardiovascular disease and thedevelopment of cancer. In particular, it is thought that substancesthat can reduce chronic infiammation may potentially reduce therisk of cancer. Included in this group are amino acids such as argin-ine and glutamine; carbohydrates such as the beta-glucans, whichappear to act as biological-response modifiers; lipids, especiallyomega-3 fatty acids; minerals such as zinc, iron, and selenium; vita-mins such as the antioxidant vitamins C and E; carotenoids; polyphe-nols such as curcumin; phenyl isothiocyanates; and pro- and prebiot-ics."' Chronic hyperinsulinemia such as occurs with the consumptionof a high glycemic-index diet may increase the risk of cancer."''

At the Ohio State University Center for Integrative Medicine, aspecialized nutrigenomic protocol for integrative cancer care hasbeen developed. This protocol includes comprehensive nutritionaland medical evaluation, a program of individualized dietary inter-ventions guided by levels of proinfiammatory molecules and otherphysiologic parameters, community-education classes, and periodicassessments. A current focus of study is dietary supplementationwith omega-3 fatty acids, magnesium oxide, high-dose B-complexvitamins, and cinnamon for patients with advanced or metastaticcancers. Omega-3 fatty acids and B vitamins were chosen due totheir important roles in immunomodulation."" ' ^ Studies haveshown that magnesium oxide decreases infiammation as well asimproves insulin resistance and serum lipid profiles.'''' Finally, theintake of cinnamon extracts reportedly decreases serum glucoselevels." Each supplement is discussed in more detail below.

Omega-3 (n-3) Polyunsaturated Fatty AcidsOmega-3 (n-3) polyunsaturated fatty acids (PUFAs) are fatty

acids in which the first double bond resides in a position three car-bon atoms fiom the methyl terminal. The precursor to omega-3PUFAs, a-linolenic acid, cannot be synthesized in the human body;thus, omega-3 PUFAs must be ingested either by intake of plantsources or of eicosapentanoic acid (EPA) and docosahexanoic acid

(DHA), found in marine sources and available as supplements.^'The Western diet, typically high in omega-6 PUFAs and low inomega-3 PUFAs, is thought to contribute to cardiovascular disease,infiammation, and cancer.^' In a recent review, researchers reportedthat intake of omega-3 PUFAs is beneficial to reduce multiple car-diometabolic risk factors.' " It reduces the risk of coronary heartdisease; decreases triglycérides, blood pressure, and inflammatorymarkers; improves endothelial function; prevents certain cardiacarrhythmias; reduces platelet aggregation and vasoconstriction;enhances fibrinolysis and reduces fibrin formation; and decreasesthe risk of microalbuminuria and sudden cardiac death.''" Similarly,a review ofthe literature and ofthe FDA's guidelines for the use ofomega-3 PUFAs suggests that omega-3 PUFAs significantly reducecoronary mortality and sudden death in patients without prior car-diovascular disease and reduce aU-cause and cardiac mortality whenused as secondary prevention.""'

In addition to the beneficial cardiovascular effects associatedwith omega-3 PUFAs, several studies have demonstrated immuno-modulatory effects. In general, omega-6 PUFAs such as arachadonicacid are proinfiammatory, whereas omega-3 PUFAs inhibit inflam-mation. This inhibition occurs both by inhibiting the formation ofthe omega-6-PUFA-derived pro-infiammatory eicosanoids and byforming potent antiinflammatory mediators, resolvins and protec-tins. Resolvins and protectins suppress the activity of nuclear tran-scription factors and decrease production of proinflammatory fac-tors such as COX-2, TNF-a, and IL-ß."^ Awareness of these effects isimportant because the oral administration of EPA and DHA canalter the composition of human immune cells, typically high inarachadonic acid, leading to a change in the expression pattern ofeicosanoids. This change in turn affects phagocytosis, T-cell signal-ing, and antigen presentation capability.^^ In a group of healthyhuman volunteers consuming either an anti-inflammatory blendrich in PUFAs including alpha-linoleic acid, EPA, stearidonic acid,and gamma-linolenic acid (group A) or an inflammatory fat blendcontaining arachidonic acid (group B) for 2 weeks, researchersobserved significantly increased plasma concentrations of EPA andalpha-linoleic acid in group A.""' Afier ex vivo lipopolysaccharidestimulation, release of PGEl and leukotriene B4 were significantlydecreased in group A, whereas PGE2 and IL-10 concentrations weresignificantly increased in group B.' ' These results demonstrate animmumomodulatory effect of low-dose dietary PUFA supplementa-tion.

A recent study of 42 patients who underwent radical resectionof colorectal cancer with an indication for postoperative total paren-teral nutrition compared supplementation with soybean oil or acombination of soybean oil and omega-3 fish oil.'*'' Patients in theomega-3 group had significantly lower levels of IL-6 and higherratios of CD4VCD8* cells afier completion ofthe supplementationthan patients in the control group, again suggesting that omega-3oils may diminish or otherwise modulate the immune response.''"Importantly, omega-3 PUFAs may have effects on processes contrib-uting to carcinogenesis. Omega-3 PUFAs are natural ligands forperoxisome proliferator receptor activator (PPAR) gamma, a media-tor known to affect cell proliferation, survival, and differentiation.''''In vitro studies have shown that Omega-3 PUFAs inhibit cell prolif-eration and induce apoptosis in cancer cells. ^ Some studies have

30 ALTERNATIVE THERAPIES, MAR/APR 2012, VOL, 18, NO. 2 CAM and Nutrigenomics

demonstrated decreased risk of prostate, colon, and breast cancerwith consumption of a diet high in omega-3 PUFAs, leading to theuse of omega-3 PUFAs for cancer prevention and treatment, as wellas for nutritional support of cancer patients to reduce weight lossand modulate the immune system.^' Finally, omega-3 PUFAs appearto have a beneficial effect on tumor cachexia. A recent literaturereview showed that administration of omega-3 PUFAs (EPA andDHA) oral supplements to patients with advanced cancer led toincreased weight and appetite, improved quality of life, and reducedpostsiirgical morbidity. Supplementation is indicated in patientswith cancers of the upper digestive tract and pancreas."

Fish oil has generally regarded as safe (GRAS) status (FDA) atdoses up to 3 g per day."' Higher doses may impair blood clotting,increase LDL levels, or impair glucose control and may be associat-ed with impairment of the immune response, particularly inpatients who are immunosuppressed.*^" A moderate risk of interac-tion with antihypertensive drugs (enhancement of antihypertensiveeffect) and a minor risk of interaction with anticoagulant or anti-platelet drugs (risk of bleeding) exist. In a randomized, placebo-controlled trial with 84 schizophrenic patients given 2 g per day ofEPA or placebo, in addition to prescribed antipsychotic medica-tions, the EPA group showed a significant increase in bleeding timeand body mass index.'" Common side effects offish oil include fishytaste, belching, heartburn, nausea, and diarrhea.'*'"

Magnesium Oxide

Magnesium has multiple roles in cardiovascular function,energy metabolism, insulin signaling, release of neurotransmitters,and endothelial cell function.""'' Studies have shown that increaseddietary intake of magnesium (Mg) confers benefits such as improvedinsulin resistance and serum lipid profiles as well as decreasedinflammation, endothelial dysfiinction, oxidative stress, and plate-let aggregation.* Experimental magnesium deficiency in rats induc-es an inflammatory syndrome consisting of leukocyte and mac-rophage activation, release of inflammatory cytokines and acutephase proteins, and excess production of ftee radicals." In addition,multiple studies have found an association between magnesiumintake and colorectal cancer risk.

Total magnesium intake in the East Asian population, whichhas a low overall risk of colorectal cancer, does not differ ftom thatin the US population, but in the US population, the ratio of calciumto magnesium intake is higher.'- A study of 688 patients with ade-noma, 210 with hyperplastic polyps, and 1306 polyp-ftee controlsftom the Tennessee Colorectal Polyp Study linked total Mg con-sumption to a decreased risk of colorectal adenoma, especially inthose patients with low ratio of calcium to magnesium (Ca:Mg)intake.'^ In addition, those patients with a common polymorphismin the transient receptor potential melastatin 7 (TRMP7) gene,which is essential for magnesium absorption, had an increased riskof adenomatous and hyperplastic polyps, and the polymorphismappeared to interact with the ratio of calcium to magnesium intake.Participants who had the polymorphism and consumed diets witha high Ca:Mg intake ratio had a higher risk of adenoma and hyper-plastic polyps than subjects who did not have the polymorphism.'^The Netherlands Cohort Study on Diet and Cancer found signifi-cant inverse trends in risks of colon and proximal colon cancer

across increasing quintiles of magnesium intake in overweight sub-jects." Similarly, in a cohort of women aged 55 to 69, the hazardratios of colorectal cancer declined across increasing quintiles ofmagnesium intake.'''

Researchers have not documented hypermagnesemia ftomintake of dietary magnesium in the absence of intestinal or renaldisea.se.''' The Food and Nutrition Board of the National Institute ofMedicine has established tolerable upper limits for magnesiumsupplementation (adults, including pregnant or nursing women,350 mg daily)."' The development of hypermagnesemia is rare inindividuals with normal renal function, even with excessive supple-mentation, but may occur in patients with renal insufficiency. Themost common side eftect of excessive magnesium supplementationis diarrhea, sometimes accompanied by nausea and cramping. Atserum magnesium concentrations greater than 2 to 3.5 mmol perliter, neurologic and cardiac symptoms such as muscle weakness,breathing difficulty, and cardiac arrest may ensue."

B-Complex VitaminsThe B vitamins and folate are related through one-carbon

metabolism and together with methionine have an important rolein DNA methylation, synthesis, and repair.^ '* In addition, adequateintake of vitamins B , Bj , folate, vitamins C and E, .selenium, zinc,copper, and iron all support a T l cytokine-mediated immuneresponse, leading to elaboration of proinflammatory cytokines;intake of vitamins A and D support a T||2-mediated anti-inflamma-tory cytokine response.''^

Many observational studies have supported the impact ofdietary factors on the incidence of colorectal cancer. Data from thecase-control arm of the Melbourne Colorectal Cancer Study, com-paring 715 incident cases with 727 matched controls, suggest thatfolate, methionine, and vitamins B and B ,, together with the anti-oxidants selenium and vitamins C and E, lead to lower colorectalcancer (CRC) risk.'" Similarly, a large Scottish case-control studydesigned to investigate the association between dietary and supple-mentary intake of vitamin B , and CRC, found an inverse dose-dependent association between CRC and dietary B . (OR = 0.77) andCRC and total B (OR = 0.86)." Furthermore, in a prospective studyof dietary folate and vitamin B and colon cancer according to micro-satellite (MSI) instability and KRAS mutational status,Schernhammer et al concluded that high vitamin B^ or B ^ intakewas inversely associated with colon cancers, regardle.ss of MSI orKRAS status.'" Recent advances in the understanding of the biologyof CRC carcinogenesis highlight the importance of epigenetic modi-fications such as DNA methylation. Micronutrients such as folieacid and selenium may have a direct influence on DNA methylation,and thus have therapeutic potential as nutraceuticals."'

The vitamin-B-complex formulation that the Center forIntegrative Medicine employs in its program contains thiamin 100mg (vitamin B,), riboflavin 100 mg (B,), niacin 100 mg (B,), pan-tothenic acid 100 mg (B,), pyridoxine Í00 mg (B ), biotin 100 meg(Bj), folie acid 400 meg (B,,), and cyanocobalamin 100 meg (B^).

Thiamine. This vitamin is relatively nontoxic even at highdoses, with no tolerable upper level of intake established. Rare casesof dermatitis or other hypersensitivity have been reported.*^

Riboflavin. This vitamin is likewise very safe, with insufficient

CAM and Nutrigenomics ALTERNATIVE THERAPIES. MAR/APR 2012. VOL 18. NO. 2 31

data reported to establish an upper intake level (UL) in adults. Largeoral doses (400 mg) have been reported to cause diarrhea andpolyuria,'^

Niacin, This vitamin has a number of well-known toxicities, themo.st common of which is prostaglandin-mediated flushing, itch-ing, and headache at doses of greater than 30 mg per day,"Premedication with aspirin can alleviate these symptoms,*'Gastrointestinal symptoms are more common with time-releasepreparations,*^ The most serious adverse effect is hepatotoxicity,manifested by jaundice and elevated transaminases. At dosesgreater than 3 g per day, fulminant hepatitis has been reported,*^ *'Impaired glucose tolerance and increased hepatic output of glucosehas been reported, although a meta-analysis of 10 randomized,controlled trials conducted on patients with recent-onset, insulin-dependent diabetes mellitus (DM) did not show significant adverseeffects,' *" Other potential adverse effects of niacin administrationinclude elevated plasma uric acid; tachycardia, arrhythmia, andsyncope in hypertensive patients on medication; and elevated plas-ma homocysteine levels,*^

Pantothenic Acid, Use of this vitamin is considered to be verysafe, having insufficient data to establish UL,*

Pyridoxine, Sensory neuropathy may be observed at doses of500 mg per day (the UL is 100 mg/d),"'

Biotin, This vitamin is reported to be safe in humans. There isinsufficient data to establish UL,*

Folie acid. This vitamin is well-tolerated at doses of less than 1mg per day (the UL), At doses of greater than 5 mg per day, abdom-inal cramps, diarrhea, and rash may develop, while at doses ofgreater than 15 mg per day, irritability and increased frequency ofseizures may occur,*^

Cobalamin, This vitamin is considered to be very safe. No UL isestablished,*^

CINNAMON EXTRACT, GLYCEMIC LOAD, AND CANCER RISKIt has been suggested that consumption of a high glycémie

index (GI) or glycémie load (GL) diet may lead to chronic hyperin-sulinemia, which is thought to increase the risk of cancer, '"' In ameta-analysis examining five studies of GI or GL intake in relationto endometrial cancer risk, MulhoUand et al observed an increasedrisk of endometrial cancer with high GL consumption, which wasfurther increased in obese women,*"" Other studies have suggestedthat high GI intake is also associated with increased risk of esopha-geal adenocarcinoma*'' and thyroid*' cancers, and a meta-analysisperformed to explore the association between GI and GL and cancerrisk ftjrther supports a direct association between high GI and GLintake and colorectal and endometrial cancers,*" Epidemiologiedata suggests that patients with metabolic syndrome have an elevat-ed risk of colon cancer, possibly due to the effect of hyperinsuline-mia on concentrations of insulin-like growth factor,*'' Determinantsexamined in relation to the risk of colon cancer or adenoma includ-ed obesity, abdominal fat distribution, physical inactivity, type 2diabetes, hypertension, hypertryglyceridemia, hyperglycemia, lowHDL cholesterol, and markers of hyperinsulinemia (insulin andC-peptide levels). In a retrospective review of 652 patients with type2 diabetes mellitus who were diagnosed with adenomatous polyps,poorly controlled diabetes (HbAlc 17,5%) predicted a greater prev-

alence of right-sided polyps, more advanced lesions, and a greaternumber of polyps,'"' The Risk Factors and Life Expectancy Projectstudied more than 37000 patients over a period of 7 years. Thisstudy was important because it demonstrated that patients withhigh blood glucose and metabolic abnormalities linked to insulinresistance had a significantly increased risk of colorectal-cancermortality as compared to patients who did not have this cluster ofmetabolic abnormalities,'"

Although researchers have not as yet definitively proven theeffectiveness of dietary supplementation with cinnamon(Cinnamomum cassia),^'^'^^ several studies have reported modesteffects in lowering blood glucose levels after cinnamon supple-mentation,"" Anderson et al reported that consumption of 1 to 6g of cinnamon daily for 40 days reduced mean fasting serumglucose, TAG, total cholesterol, and LDL-cholesterol in subjectswith type 2 DM,"

The literature suggests some possible mechanisms for theeffect of cinnamon on glucose levels. In vitro studies have shownthat cinnamon increases the expression of PPARs Y and a (tran-scriptional factors known to be involved in the regulation ofinsulin resistance and adipogenesis) and their target genes in3T3-L1 adipocytes,''^ Additionally, Cao et al have demonstratedthat cinnamon polyphenol extract can regulate anti- and proin-flammatory and glucose-transporter gene expression in mousemacrophages,"*

Both common and cassia cinnamon are generally safe wheningested in amounts commonly found in food,"^ Three random-ized, controlled trials employing cassia cinnamon at intakes of upto 6 g per day for 40 days,"' 1,5 g per day for 6 weeks,'' and 3 g perday for 4 months,'"* respectively, demonstrated no significantadverse effects. The most common adverse effect ftom common orcassia cinnamon ingestion, as described in several case reports andcase series, is contact irritation or allergic reaction involving skin ormucus membranes, eg, contact dermatitis and stomatitis,'^

CONCLUSIONThere is growing interest regarding the integration of elements

of complementary and alternative medicine into conventionalmedical treatments. In particular, integrative medicine is a currentarea of research interest for the multidisciplinary treatment of can-cer patients. Researchers have studied various biologically-basedpractices extensively, especiaüy the use of specific vitamins andminerals. There is less good-quality evidence supporting the use ofherbal medicine and homeopathy, yet these modalities continue tobe used widely by patients. The use of mind-body-medicinemodalities may be helpful for certain chronic conditions and is acurrent focus of study, particularly with regard to its potentialeffect upon immune parameters. Other potential sources of alter-native approaches to healing include manipulative and body-based practices such as chiropractic and massage; traditionalChinese medicine including acupuncture; naturopathy; and ener-gy medicine, Nutrigenomics is a personalized approach thatinvolves tailoring nutrition to the individual genotype in hopes ofeffecting disease prevention. In particular, it is thought that reduc-tion of the extent of chronic inflammation may reduce the risk ofcancer development.

32 ALTERNATIVE THERAPIES, MAR/APR 2012, VOL 18, NO. 2 CAM and Nutrigenomics

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