138 P.J. Manskyet al. recently conducted a systematic review ofCAM use in pediatric cancer based on a review of28 studies with survey data (collected from 1975–2005) from 3,526 children. In 20 studies with 2,871participants, the prevalence of any CAM use (sincecancer diagnosis) ranged from 6 to 91 %; consider-able heterogeneity across studies precluded meta-analysis. Herbal remedies were the most popularCAM modality, followed by diets/nutrition andfaith-healing (Bishop and Prescott 2010).Herbs and botanicals are predominantly usedin a supportive role for symptom relief andimprovement of quality of life. As children mayreact and respond differently to medications thanadults, there is a need for well-designed clinicaltrials to evaluate and support the use of botani-cals and herbs in pediatric cancer. Most childrenwith cancer are treated with complex multiagentchemotherapy regimens, often over months andfrequently as part of a clinical trial. There istherefore a particular concern about potential ofbotanical/drug interactions, which could give riseto different additional symptoms and affect theresponse of the patient to the prescribed cancertherapy.There are only a few published clinical trialsevaluating the use of botanical preparations forsymptom management in children with cancer.10.2 Chemotherapy and CancerRelated Side Effects10.2.1 Hepatotoxicity: Milk ThistleThe herbal plant milk thistle (Silybum marianum)has been used for the treatment of liver toxicity inhepatitis and cirrhosis. It is available as a nutri-tional supplement in the USA. In clinical trials,protective effects against hepatic and renal toxic-ity have been observed (Tamayo and Diamond2007). A recent randomized, placebo-controlledpilot study explored the effects of milk thistle onhepatotoxicity in children undergoing treatmentfor ALL (Ladas and Kroll 2010). Fifty childrenwere enrolled. At day 56, the milk thistle grouphad a signiﬁcantly lower AST and a trend towarda lower ALT. Milk thistle did not affect theefﬁcacy of the administered chemotherapeuticagents, and the authors concluded that futurestudies of dosing, duration of treatment, and theimpact on hepatotoxicity and leukemia survivalwere warranted.10.2.2 Mucositis: TraumeelTraumeel-S R is a homeopathic complex prepara-tion used in Europe for the past 50 years for thetreatment of mucositis as an over-the-counter rem-edy. A randomized, placebo-controlled, double-blind clinical trial of 32 patients ages 3–25 yearswho had undergone allogeneic or autologous stemcell transplantation observed lack of stomatitis inﬁve patients (33 %) in the TRAUMEEL S treat-ment group compared to one patient (7 %) in theplacebo group. Stomatitis worsened in only 7patients (47 %) in the TRAUMEEL S treatmentgroup compared with 14 patients (93 %) in the pla-cebo group. The mean area under the curve stoma-titis scores were 10.4 in the TRAUMEEL Streatment group and 24.3 in the placebo group.This difference was statistically signiﬁcant(P<0.01) (Oberbaum et al. 2001).Subsequently, the Children’s Oncology Groupconducted a larger, randomized, controlled clinicaltrial. Results of this study have not been published.10.2.3 Chemotherapy-Induced FebrileNeutropenia: MSCThere is limited information on the reduction ofthe risk of febrile neutropenia in pediatric cancerpatients. Garami et al. conducted an open-label,matched-pair pilot clinical trial in children withpediatric solid cancers to test whether the com-bined administration of the medical nutrimentMSC (Avemar) with cytotoxic drugs and the con-tinued administration of MSC on its own mighthelp to reduce the incidence of treatment-relatedfebrile neutropenia compared with the same treat-ments without MSC. Twenty-two patients(11 pairs) were enrolled in this study. Thirty febrileneutropenic episodes (24.8 %) were observed inthe MSC group versus 46 (43.4 %) in the control
13910 Botanicals in Pediatric Oncology and the Issue of Botanical/Drug Interactionsgroup (Wilcoxon signed rank test, P<0.05). Theauthors concluded that “the continuous supple-mentation of anticancer therapies with the medicalnutriment MSC helps to reduce the incidence oftreatment-related febrile neutropenia in childrenwith solid cancers” (Garami et al. 2004).10.2.4 Nausea and Vomiting: GingerNausea and vomiting are two distressing sideeffects associated with chemotherapy treatmentfor cancer. Two RCTs concluded that cancerpatients suffering from nausea and vomiting mayﬁnd some relief in the antiemetic properties ofginger. A systematic review by Ernst and Pittleridentiﬁed an RCT in 41 leukemia patients. Thetrial studied the effects of ginger capsules versusplacebo on the severity and duration of chemo-therapy-induced nausea. Results showed a statis-tically signiﬁcant decrease in severity andduration of nausea in the ginger group.Unfortunately, this trial was only published as anabstract, and therefore further details are unavail-able (Ernst and Pittler 2000).A second RCT by Sontakke and Thawani com-pared the effects of ginger root powder to meto-clopramide and ondansetron in 50 cancer patients.Results showed that 62 % of the patients givenginger had complete control of nausea. Similarly,58 % of those given metoclopramide had controlof nausea. However, ondansetron was the mosteffective given that 86 % of these patients hadcomplete control of nausea. Results for control ofvomiting were similar; 68 % of the ginger group,64 % of the metoclopramide group, and 86 % ofthe ondansetron group achieved complete controlof vomiting. Results show that ondansetron is asuperior antiemetic drug, and the difference inginger and metoclopramide is not statisticallysigniﬁcant (Sontakke et al. 2003).10.2.5 Chinese Herbal MedicinesChinese herbal medicines (CHM), such asHuangqi decoctions, have demonstrated efﬁcacyin reducing chemotherapy-induced nausea andvomiting (Mansky and Wallerstedt 2006). Sevenrandomized, controlled studies of variable qualityare worth discussing in support of CHM. However,studies speciﬁcally evaluating the beneﬁt ofbotanical preparations for the treatment of nauseain pediatric cancer patients are lacking.10.2.6 PainPain associated with cancer and cancer treatmentcan be debilitating and reduces patient’s QOL.Conventionalanalgesicssuchasanti-inﬂammatorymedications and opioids have distinct adverseeffect proﬁles.Chinese herbal medicine may be beneﬁcial inthe treatment of cancer pain. A comprehensivestudy by Xu et al. reviewed 115 trials from bothChinese and English databases, which comparedthe effects of CHM to conventional analgesics orplacebo. Although 41 of the studies reviewedwere randomized, controlled trials, most werenot of high-quality design and had many limita-tions such as lack of randomization process orcontrol group, small sample size, or deﬁcienciesin the masking process. Furthermore, due to inad-equatefollow-up,itcannotbedeterminedwhetherCHM has comparable long-term effects to con-ventional medicine. Another technical limitationis the use of established analgesic as control, asethical concerns prevented the Chinese studiesfrom using a placebo.Despite these limitations, it is possible to drawsome signiﬁcant ﬁndings from these studies.Most importantly, the review concludes thatCHM may be effective for short-term cancer-related pain, having similar outcomes to those ofconventional western medicine. Additionally,CHM may produce fewer side effects than con-ventional treatments and helps to enhance overallquality of life. Furthermore, there were no seri-ous adverse events associated with the CHMregimens. Finally, the review found that CHM iseffective through multiple modes of application,such as oral, topical, and intravenous (Xu et al.2007). Although pain is mostly treated externally,these studies show some promise in using botani-cals as an analgesic and call for larger and more
140 P.J. Manskyrigorous clinical trials of botanicals in the treat-ment of cancer pain. However, the review did notspeciﬁcally address the role of CHM in pediatriccancer pain.10.2.7 Fatigue: Chinese HerbalMedicine and GinsengResearch shows that 80–90 % of cancer patientsoften have prolonged fatigue, categorized as adisturbance in circadian patterns. This type offatigue is not relieved by rest and relaxation andhas distressing effects on quality of life. Chineseherbal medicine (CHM) may be effective inrelieving cancer-related fatigue (Zhang et al.2007; Taixiang et al. 2005). These studies conveythat CHM may be effective for reducing fatigue;however, larger, controlled clinical trials are nec-essary in order to safely advocate its use, and dataspeciﬁcally reporting on the beneﬁt in pediatricpatients are not available.Ginseng has been known to increase energy andphysical stamina. A study by Elam et al. evaluatedthe efﬁcacy of ginseng in reducing fatigue andimproving sleep quality in cancer patients. Thisrandomized, double-blinded, placebo-controlledstudy used American ginseng. A number of unfore-seen problems prevented the completion of thestudy, such as the inability to mask the potent tasteand smell of the ginseng to secure adequate blind-ing. Additionally, the measurement devices used tomeasure sleep and wake activity were inaccurate,and recruitment was challenging due to rigorousinclusion and exclusion criteria; this was especiallyrelated to contraindications between ginseng andcurrent medications (Elam et al. 2006).10.2.8 Insomnia: Valerian Rootand St. John’s WortInsomnia can be a detrimental side effect of can-cer. Research shows that patients who had seri-ously disturbed circadian rhythms had a shortersurvival time (Block et al. 2004). Primarilytreated with hypnotic drugs (benzodiazepines),there is little research regarding herbals andbotanicals for reduction of insomnia.Some literature shows that valerian (Valerianaofﬁcinalis L.) and St. John’s wort (Hypericumperforatum L.) may improve sleep; however,warnings about contraindications are serious.Other studies have explored the effects of botani-cals such as chamomile, hops, passionﬂower,lavender, and lemon balm and found the resultsto be encouraging. Many of these botanicalsshowed beneﬁcial effect in controlled clinical tri-als; however, the patient populations varied indisease, and data on pediatric patients arelimited. The need remains for these trials to beconducted in pediatric cancer populations, there-fore verifying whether or not the botanicals areeffective for cancer-related insomnia, speciﬁcally(Block et al. 2004).10.3 Botanicals Used for CancerTreatment10.3.1 GarlicNumerous animal and in vitro studies providedevidence for a relation between garlic intake andcancerriskreduction.Severalstudiesalsoreportedan inverse association in humans. However, noclaims have been made about garlic intake andcancer risk reduction with respect to food label-ing. With the use of the US Food and DrugAdministration’s evidence-based review systemfor the scientiﬁc evaluation of health claims, 19human studies were identiﬁed and reviewed toevaluate the strength of the evidence that supportsa relation between garlic intake and reduced riskof different cancers with respect to food intake.There was no credible evidence to support aCorrelation between garlic intake and a reducedrisk of gastric, breast, lung, or endometrial can-cer. Very limited evidence supported a Correlationbetween garlic consumption and reduced risk ofcolon, prostate, esophageal, larynx, oral, ovary, orrenal cell cancers (Kim and Kwon 2009).There are some recent reports suggesting thatgarlic-derived OSCs cause cell cycle arrest, gen-erate reactive oxygen species (ROS), activatestress kinases, and also stimulate the mitochon-drial pathway for apoptosis in malignant neuro-blastoma (Karmakar and Choudhury 2011).
14110 Botanicals in Pediatric Oncology and the Issue of Botanical/Drug Interactions10.3.2 Green TeaAn expanding body of preclinical evidence sug-gests that EGCG, the major catechin found ingreen tea (Camellia sinensis), has the potential toimpact a variety of human diseases. EGCG mayhave antioxidant properties, thus preventing oxi-dative damage in healthy cells, but also exert anti-angiogenic and antitumor effects. EGCG inducesapoptosis and promotes cell growth arrest by alter-ing the expression of cell cycle regulatory pro-teins, activating killer caspases, and suppressingoncogenic transcription factors and pluripotencymaintain factors. In vitro EGCG blocks carcino-genesis by affecting a wide array of signal trans-duction pathways including JAK/STAT, MAPK,PI3K/AKT, Wnt, and Notch (Singh and Shankar2011).Consumption of green tea (Camellia sinensis)may provide protection against chronic diseases,including cancer. Green tea polyphenols can bedirect antioxidants by scavenging reactive oxy-gen species or chelating transition metals as hasbeen demonstrated in vitro. Alternatively, theymay act indirectly by upregulating phase II anti-oxidant enzymes. Evidence of this latter effecthas been observed in vivo, yet more work isrequired to determine under which conditionsthese mechanisms occur. Green tea polyphenolscan also be potent pro-oxidants, both in vitro andin vivo, leading to the formation of hydrogen per-oxide, the hydroxyl radical, and superoxide anion.The potential role of these pro-oxidant effects inthe cancer preventive activity of green tea is notwell understood (Forester and Lambert 2011).Experimental studies have consistentlyshown the inhibitory activities of tea extracts ontumorigenesis in multiple model systems.Epidemiological studies, however, have pro-duced inconclusive results in humans. A com-prehensive review was conducted to assess thecurrent knowledge on tea consumption and riskof cancers in humans. High intake of green teahas been associated with reduced risk of uppergastrointestinal tract cancers. Limited data sup-port a protective effect of green tea on lung andhepatocellular carcinogenesis. Phase II clinicaltrials have demonstrated an inhibitory effect ofgreen tea extract against the progression ofprostate premalignant lesions. Green tea mayexert beneﬁcial effects against mammary car-cinogenesis in premenopausal women andrecurrence of breast cancer. There is no sufﬁcientevidence that supports a protective role of teaintake on the development of cancers of the col-orectum, pancreas, urinary tract, glioma, lym-phoma, and leukemia (Yuan and Sun 2011).Evidence for pediatric cancer-speciﬁc anti-cancer effects is lacking.10.3.3 Turmeric (Curcuma longa L.),Curcumin, and RelatedCompoundsThere is a substantial body of preclinical evi-dence that curcumin targets multiple moleculesin the biochemical pathway of carcinogenesis,particularly in blocking transformation, prolifer-ation, and invasion of tumor cells (Aggarwal andKumar 2003; Shishodia et al. 2007).Turmeric and its active constituent, curcumin,have been found to have direct anti-inﬂammatoryeffects, inhibiting TNF-a, IL-8, monocyteinﬂammatory protein-1, IL-1B, and monocytechemotactic protein-1 (Abe et al. 1999). Itsigniﬁcantly inhibits lipoxygenase enzymes andCOX-2 activity (Rao et al. 1993), potentiallythrough suppression of NF-kB (Plummer et al.1999). Curcumin downregulates the expressionof cyclin D1 at the transcriptional and posttran-scriptional levels (Mukhopadhyay et al. 2002)and downregulates speciﬁc protein kinases,including EGFR and Her2neu (Korutla andKumar 1994; Korutla et al. 1995), as well asnumerous protein kinases (as reviewed in(Shishodia et al. 2007)).Evidence of curcumin’s effects on apoptosisincludes the ﬁnding that it suppresses activationof the NF-kB-regulated genes, including Bcl-2(Bharti et al. 2003, 2004a, b). It appears to havedirect antiangiogenic properties as well, sup-pressing proliferation of human vascular endothe-lial cells in vitro (Singh et al. 1996; Thaloor et al.1998) and inhibiting angiogenesis in LNCaPprostate cancer cells in vivo (Dorai et al. 2001).While preclinical evidence supports curcumin’spotential to interrupt carcinogenesis at multiple
142 P.J. Manskytarget sites, several preliminary clinical studieshave demonstrated its tolerability. In a phase Istudy, Cheng et al. found that a cohort of 25patients with high-risk or premalignant lesionstolerated up to 8 g/day of curcumin with noobserved treatment-related toxicities (Cheng andHsu 2001). In another phase I study conducted bySharma et al. (2004), 15 patients with advancedrefractory CRC tolerated up to 3.6 g/daily for4 months with no dose-limiting toxicity. Althoughcurcumin was well-tolerated in these phase I stud-ies, it appears to have poor bioavailability withoral dosing; however, detectable levels of cur-cumin have been measured in the urine (Sharmaet al. 2004). Dhillon and colleagues recently pub-lished a study of patients with advanced pancre-atic cancer who tolerated a dose of curcumin at 8g/day without toxicities (Dhillon et al. 2008). Ofthe 11 patients who were evaluable for response,4 had stable disease at 2–7 months posttreatment,and 1 had a brief partial remission for 1 month. Insummary, curcumin has demonstrated anti-inﬂammatory, antioxidant, antiangiogenesis, andpro-apoptotic effects in preclinical studies andhas been well-tolerated in several clinical trials.Thus, it has potential beneﬁts in cancer chemo-prevention studies as well (Sharma et al. 2007),which is currently being investigated in a numberof ongoing phase II–III clinical trials in the USAand internationally, as reviewed recently by Goeland colleagues (2008).Other curcuminoids such as demethoxycur-cumin and bisdemethoxycurcumin have not beenas widely studied as curcumin. Recent studiesin vitro suggest an inhibitory effect on cancer cellinvasion via downregulation of matrix metallo-proteinases, warranting further investigation(Yodkeeree and Chaiwangyen 2008).Several turmerones derived from turmeric haveshown anti-inﬂammatory and antiproliferativeproperties in vitro, although these compounds havenot entered clinical trials (Sandur et al. 2007).10.3.4 Mushroom and ImmuneStimulators in CancerTCM and other Asian native medical traditionsthat evolved from TCM document the use of wellover 270 species of mushroom for a wide rangeof ailments (Ying et al. 1987). Several mush-room-derived medicinal products are producedby Japanese, Korean, and Chinese pharmaceuti-cal companies and have been used as standardcancer therapy for over 30 years as adjuncts tosurgery, chemotherapy, and radiation for thetreatment of gastrointestinal and lung cancer(Smith et al. 2002). Current data do point toimproved survival trends that are incremental butsigniﬁcant. Polysaccharide-K (PSK), from themushroom Trametes versicolor, is an example ofan approved mushroom product used for cancertreatment in Japan and has been approved as anadjunctive cancer treatment since the mid-1970swith use in thousands of patients. The safetyrecord for PSK is well established in Japan, andthere are notably few adverse events reported.Subfraction analysis of PSK showed a 50-kdpolysaccharide-rich fraction was principallyresponsible for the anticancer effect (Mizutaniet al. 1992). Clinical studies of PSK in colorectaland gastric cancer treatment have shown reducedrecurrence and improvement in overall survivalwith adjuvant use.A meta-analysis of gastric cancer and PSKstudies included 8,009 patients from eight ran-domized, controlled trials after central random-ization. The overall hazard ratio for patients whoreceived PSK was 0.88 (95 % conﬁdence inter-val, 0.79–0.98; P=0.018) (Oba et al. 2007).In China, a similar product to PSK calledpolysaccharide peptide (PSP) is used for cancertreatment and is derived from the same mush-room. It is used in esophageal, gastric, and lungcancer (Ng 1998). Clinical investigation hasfocused on the role of medicinal mushrooms asbiological response modiﬁers (BRM), deﬁned asagents boosting or restoring the ability of theimmune system to ﬁght infections, cancer, andother diseases (2007).The principal medicinal mushrooms used incancer treatment in Asian countries are lentinan(L. edodes), schizophyllan (S. commune), PSKand PSP (T. versicolor), and Grifron-D (G. fron-dosa). PSK, PSP, and Grifron-D are taken orally,while lentinan and schizophyllan are puriﬁedbeta-d-glucans and are administered by the intra-peritoneal route (Sullivan et al. 2006).
14310 Botanicals in Pediatric Oncology and the Issue of Botanical/Drug InteractionsThe active components in medicinal mush-rooms are thought to be principally biologicallyactive polysaccharides in the form of beta-d-glu-cans with various protein linkages forming pro-teoglycans (Sullivan et al. 2006). There arepreliminary studies ongoing with some of theseagents with cancer patients in the USA as well asbeta-glucans derived from baker’s yeast.Medicinal mushrooms have not been studied inpediatric cancer.10.4 Botanical-Drug InteractionsWhile the concern of potential adverse botanical-drug interactions has been raised ever sincePiscatelli et al. reported the decrease of indinavirserum concentrations after use of St. John’s wortby patients with HIV (Piscitelli et al. 2000), thetopic gained relevance for cancer treatment whenMathijsen et al. demonstrated that the ingestionof St. John’s wort reduced the serum concentra-tion of irinotecan in patients on treatment for col-orectal cancer (Mathijssen et al. 2002), thusrendering the chemotherapy regimen potentiallyineffective. St. John’s wort induces severalenzymes of the hepatic p450 complex. One of thevarious p450 complex enzymes affected by St.John’s wort is CYP3A4, which is involved in themetabolism of 35 % of all oncology drugs.Increased enzyme complex activity may acceler-ate drug metabolism and result in lower, poten-tially ineffective plasma drug concentrations,while decreased enzyme activity may lead toincreased drug toxicity. Some of the properties ofSt. John’s wort to affect drug metabolism areshared by several other commonly used herbsincluding Echinacea, Ginkgo, Valerian, andGrape seed. Sparreboom et al. provide a detailedreview of the mechanistic understanding of thehepatic metabolism of chemotherapeutic agentsand the impact of botanicals on these processes(Sparreboom and Baker 2009).Hepatically metabolized chemotherapeuticagents commonly used in pediatric oncologyinclude:BusulfanCisplatinCyclophosphamideDacarbazineAnthracyclinesTaxanesEtoposideIfosfamideImatinibIrinotecanMethotrexateTeniposideTopotecanVinca alkaloidsSt. John’s wort also affects the p-glycoproteinpathway, which could result in resistance todrugs such as anthracyclines, epipodophyllotox-ins, taxanes, and vinca alkaloids (Mansky andStraus 2002).Concern has been raised about induction ofCYP3A4 by milk thistle. However, clinicallyachievable concentrations of silymarin, one ofthe main active constituents, did not inhibit thisenzyme pathway to an extent that would justify aclinical concern (van Erp et al. 2005).Another potential adverse effect of botanicalsis the interaction with the metabolism of warfa-rin. While the incidence of deep vein thrombosis(DVT) in pediatric patients is much lower than inadults, cancer and cancer treatment may increasethe risk for DVT, making this a valid concern inchildhood cancer as well. Commonly used botan-icals such as Allium sativum (garlic), Ginkgobiloba (Ginkgo), and Panax ginseng (ginseng)affect the metabolism of warfarin (Mansky andStraus 2002; van Erp et al. 2005).An informative source for botanical druginteractions is the Natural Standards Database(http://www.naturalstandard.com/databases/).10.5 Product Quality and SafetyThere has been ongoing concern about the prod-uct quality and safety of botanical products, bothwith respect to the quantity and quality of thedesired active ingredients as well as the potentialfor contamination with chemicals and heavy met-als as well as adulteration with prescriptiondrugs. Guidance and oversight regarding manu-facturing and quality control in the USA are pro-vided through the FDA. However, as most
144 P.J. Manskybotanical products currently are approved andmarketed in the USA as dietary supplements,content standardization and veriﬁcation are lim-ited to the requirement for dietary supplementsand are not held to the same standards as FDA-approved drugs. The National Center forComplementary and Alternative Medicine(NCCAM, www.nccam.nih.gov) and the Ofﬁceof Dietary Supplements (ODS, http://ods.od.nih.gov/healthinformation) at the National Institutesof Health (NIH), as well as the FDA (http://www.fda.gov/Food/DietarySupplements/), among oth-ers provide information about botanical safetyand quality.Equivalent to the FDA for the USA, there is theEuropean Medicines Agency (EMA) for theEuropean Union (http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000208.jsp&murl=menus/regulations/regulations.jsp&mid=WC0b01ac05800240cf,accessed: 16.11.2011). The EMA is a decentral-ized agency located in London. Its main task ﬁeldis the evaluation and supervision of medicines forboth human and veterinary use. The process oflicensing and marketing of herbal products in theEU is regulated in a European Parliament andCouncil Directive from 2004 (Directive2004/24/EC). It also implies general deﬁnitionsfor herbal medicinal products, herbal preparations,and substances. The aim of the Directive is tobring the process of licensing and information onherbal substances and preparation into accordancewithin the EU, while most of the herbal productsare licensed nationally by Member States. Forexample, in Germany, it is the Federal Institute forDrugs and Medical Devices (in German BfArM)(http://www.bfarm.de/DE/BfArM/BfArM-node.html, accessed: 16.11.2011). Especially for herbalproducts, the Commission E Monographs holdinformationontheevaluationofsafetyandefﬁcacyof herbal medicine products in Germany (http://www.bfarm.de/DE/Arzneimittel/2_zulassung/zulArten/besTherap/amPﬂanz/ampﬂanz-inhalt.html?nn=1013980, accessed: 16.11.2011). As aresult of the aforementioned European Directive,the Committee on Herbal Medicinal Products(HMPC) was founded in 2004 (http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/g e n e r a l / g e n e r a l _ c o n t e n t _ 0 0 0 1 2 2 .jsp&murl=menus/about_us/about_us.jsp&mid=WC0b01ac0580028e7d, accessed:16.11.2011). The main task of the Committee isthe establishment of herbal monographs thatinclude information on therapeutic use and safetyof herbal medicine products in the EU. Qualityconditions for herbal products are deﬁned in theEuropean Pharmacopoeia Monographs developedby a Committee of the European Directorate forthe Quality of Medicines (EDQM) (http://www.edqm.eu/en/Background-Legal-Framework-50.html, accessed: 16.11.2011).ReferencesAbe Y, Hashimoto S et al (1999) Curcumin inhibition ofinﬂammatory cytokine production by human periph-eral blood monocytes and alveolar macrophages.Pharmacol Res 39(1):41–47Aggarwal BB, Kumar A (2003) Anticancer potential ofcurcumin: preclinical and clinical studies. AnticancerRes 23(1A):363–398Bharti AC, Donato N et al (2003) Curcumin (diferuloyl-methane) down-regulates the constitutive activation ofnuclear factor-kappa B and IkappaBalpha kinase inhuman multiple myeloma cells, leading to suppressionof proliferation and induction of apoptosis. Blood101(3):1053–1062Bharti AC, Shishodia S et al (2004a) Nuclear factor-kap-paB and STAT3 are constitutively active in CD138+cells derived from multiple myeloma patients, andsuppression of these transcription factors leads toapoptosis. Blood 103(8):3175–3184Bharti AC, Takada Y et al (2004b) Curcumin (diferuloyl-methane) inhibits receptor activator of NF-kappa Bligand-induced NF-kappa B activation in osteoclast pre-cursors and suppresses osteoclastogenesis. J Immunol172(10):5940–5947Bishop FL, Prescott P (2010) Prevalence of complemen-tary medicine use in pediatric cancer: a systematicreview. Pediatrics 125(4):768–776Block KI, Gyllenhaal C et al (2004) Safety and efﬁcacy ofherbal sedatives in cancer care. Integr Cancer Ther3(2):128–148Cheng AL, Hsu CH (2001) Phase I clinical trial of cur-cumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res21(4B):2895–2900Dhillon N, Aggarwal BB et al (2008) Phase II trial of cur-cumin in patients with advanced pancreatic cancer.Clin Cancer Res 14(14):4491–4499Dorai T, Cao YC et al (2001) Therapeutic potential ofcurcumin in human prostate cancer. III. Curcumin
14510 Botanicals in Pediatric Oncology and the Issue of Botanical/Drug Interactionsinhibits proliferation, induces apoptosis, and inhibitsangiogenesis of LNCaP prostate cancer cells in vivo.Prostate 47(4):293–303Elam JL, Carpenter JS et al (2006) Methodological issuesin the investigation of ginseng as an intervention forfatigue. Clin Nurse Spec 20(4):183–189Ernst E, Pittler MH (2000) Efﬁcacy of ginger for nauseaand vomiting: a systematic review of randomized clin-ical trials. Br J Anaesth 84(3):367–371Forester SC, Lambert JD (2011) The role of antioxidantversus pro-oxidant effects of green tea polyphenols incancer prevention. Mol Nutr Food Res 55(6):844–854Garami M, Schuler D et al (2004) Fermented wheat germextract reduces chemotherapy-induced febrile neutro-penia in pediatric cancer patients. J Pediatr HematolOncol 26(10):631–635Goel A, Kunnumakkara AB et al (2008) Curcumin as“Curecumin”: from kitchen to clinic. BiochemPharmacol 75(4):787–809Karmakar S, Choudhury SR (2011) Molecular mecha-nisms of anti-cancer action of garlic compounds inneuroblastoma. Anticancer Agents Med Chem 11(4):398–407Kim JY, Kwon O (2009) Garlic intake and cancer risk: ananalysis using the Food and Drug Administration’sevidence-based review system for the scientiﬁc evalu-ation of health claims. Am J Clin Nutr 89(1):257–264Korutla L, Kumar R (1994) Inhibitory effect of curcuminon epidermal growth factor receptor kinase activity inA431 cells. Biochim Biophys Acta 1224(3):597–600Korutla L, Cheung JY et al (1995) Inhibition of ligand-induced activation of epidermal growth factor receptortyrosine phosphorylation by curcumin. Carcinogenesis16(8):1741–1745Ladas EJ, Kroll DJ (2010) A randomized, controlled,double-blind, pilot study of milk thistle for the treat-ment of hepatotoxicity in childhood acute lympho-blastic leukemia (ALL). Cancer 116(2):506–513Mansky PJ, Straus SE (2002) St. John’s Wort: more impli-cations for cancer patients. J Natl Cancer Inst94(16):1187–1188Mansky PJ, Wallerstedt DB (2006) Complementary medi-cine in palliative care and cancer symptom manage-ment. Cancer J 12(5):425–431Mathijssen RH, Verweij J et al (2002) Effects of St. John’sWort on irinotecan metabolism. J Natl Cancer Inst94(16):1247–1249Mizutani Y, Nio Y, Yoshida O (1992) Effect of PSK andits subfractions on peripheral blood lymphocytesmediated cytotoxicity against urinary bladder tumorcells. J Urol 148(5):1571–1576Mukhopadhyay A, Banerjee S et al (2002) Curcumin-induced suppression of cell proliferation correlateswith down-regulation of cyclin D1 expression andCDK4-mediated retinoblastoma protein phosphoryla-tion. Oncogene 21(57):8852–8861Ng TB (1998) A review of research on the protein-boundpolysaccharide (polysaccharopeptide, PSP) from themushroom Coriolus versicolor (Basidiomycetes:Polyporaceae). Gen Pharmacol 30(1):1–4Oba K, Teramukai S et al (2007) Efﬁcacy of adjuvantimmunochemotherapy with polysaccharide K forpatients with curative resections of gastric cancer.Cancer Immunol Immunother 56(6):905–911Oberbaum M, Yaniv I et al (2001) A randomized, con-trolled clinical trial of the homeopathic medicationTRAUMEEL S in the treatment of chemotherapy-induced stomatitis in children undergoing stem celltransplantation. Cancer 92(3):684–690Piscitelli SC, Burstein AH et al (2000) Indinavir concentra-tions and St John’s wort. Lancet 355(9203):547–548Plummer SM, Holloway KA et al (1999) Inhibition ofcyclo-oxygenase 2 expression in colon cells by thechemopreventive agent curcumin involves inhibitionof NF-kappaB activation via the NIK/IKK signallingcomplex. Oncogene 18(44):6013–6020Rao CV, Simi B et al (1993) Inhibition by dietary cur-cumin of azoxymethane-induced ornithine decarboxy-lase, tyrosine protein kinase, arachidonic acidmetabolism and aberrant crypt foci formation in the ratcolon. Carcinogenesis 14(11):2219–2225Richardson MA, Sanders T et al (2000) Complementary/alternative medicine use in a comprehensive cancercenter and the implications for oncology. J Clin Oncol18(13):2505–2514Sandur SK, Pandey MK et al (2007) Curcumin,demethoxycurcumin, bisdemethoxycurcumin, tetrahy-drocurcumin and turmerones differentially regulateanti-inﬂammatory and anti-proliferative responsesthroughaROS-independentmechanism.Carcinogenesis28(8):1765–1773Sharma RA, Euden SA et al (2004) Phase I clinical trial oforal curcumin: biomarkers of systemic activity andcompliance. Clin Cancer Res 10(20):6847–6854Sharma RA, Steward WP et al (2007) Pharmacokineticsand pharmacodynamics of curcumin. Adv Exp MedBiol 595:453–470Shishodia S, Chaturvedi MM et al (2007) Role of cur-cumin in cancer therapy. Curr Probl Cancer 31(4):243–305Singh BN, Shankar S (2011) Green tea catechin, epigallo-catechin-3-gallate (EGCG): mechanisms, perspectivesand clinical applications. Biochem Pharmacol82(12):1807–1821Singh AK, Sidhu GS et al (1996) Curcumin inhibits theproliferation and cell cycle progression of humanumbilical vein endothelial cell. Cancer Lett 107(1):109–115Smith JE, Rowan NJ, Sullivan R (2002) Medicinal mush-rooms: their therapeutic properties and current medi-cal usage with special emphasis on cancer treatments.University of Strathclyde, Strathclyde, pp 1–256Sontakke S, Thawani V et al (2003) Ginger as an antie-metic in nausea and vomiting induced by chemother-apy: a randomized, cross-over, double blind study.Indian J Pharmacol 35(1):32–36Sparreboom A, Baker SD (2009) CAM: chemo interac-tions – what is known? In: Abrams D, Weil A(eds) Integrative oncology. Oxford University Press,New York
146 P.J. ManskySullivan R, Smith JE et al (2006) Medicinal mushroomsand cancer therapy: translating a traditional practice intowestern medicine. Perspect Biol Med 49(2):159–170Taixiang W, Munro AJ et al (2005) Chinese medical herbsfor chemotherapy side effects in colorectal cancerpatients. Cochrane Database Syst Rev (1):CD004540Tamayo C, Diamond S (2007) Review of clinical trials eval-uating safety and efﬁcacy of milk thistle (Silybum mari-anum [L.] Gaertn.). Integr Cancer Ther 6(2):146–157Thaloor D, Singh AK et al (1998) Inhibition of angiogenicdifferentiation of human umbilical vein endothelialcells by curcumin. Cell Growth Differ 9(4):305–312van Erp NP, Baker SD et al (2005) Effect of milk thistle(Silybum marianum) on the pharmacokinetics of irino-tecan. Clin Cancer Res 11(21):7800–7806Xu L, Lao LX et al (2007) Chinese herbal medicine forcancer pain. Integr Cancer Ther 6(3):208–234Ying JZ et al (1987) Icons of medicinal fungi from China(trans: Xu YH). Science Press, BeijingYodkeeree S, Chaiwangyen W (2008) Curcumin,demethoxycurcumin and bisdemethoxycurcumin dif-ferentially inhibit cancer cell invasion through thedown-regulation of MMPs and uPA. J Nutr Biochem20(2):87–95Yuan JM, Sun C (2011) Tea and cancer prevention: epide-miological studies. Pharmacol Res 64(2):123–135Zhang M, Liu X et al (2007) Chinese medicinal herbs totreat the side-effects of chemotherapy in breast can-cer patients. Cochrane Database Syst Rev (2):CD004921