Safety and Efficacy of Phytomedicines in Cancer Prevention and Treatment

Modern Ayurveda

Ayurveda the Science of Life

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Giuseppina Benoni and Laura Cuzzolin

Abstract In this review we discuss some aspects of herbal use either to prevent cancer or to treat the disease or the side effects of chemotherapy. The most powerful reasons, for cancer patients, to use phytomedicines are related to the wish to leave no option untried and to the dissatisfaction with mainstream oncology treatments. In the review, herbs commonly used in cancer and their mechanism of action are referred. Moreover, clinical trials about the use of some herbs for treating the side effects of chemotherapy and radiation are cited. As regards the safety data of phytomedicines in cancer patients, considering the narrow therapeutic window of chemotherapic drugs, the risk of clinically relevant herb-drug interactions can increase: in the USA more than 100,000 deaths per year can be attributed to drug interactions, most of them connected to the use of herbs. Some experts believe that the potential risk of herb drug interactions is enough to recommend patients on chemotherapy not to use herbal therapies. At present, oncologists must be encouraged to discuss herbal use with their patients, and they should be aware of possible herb anticancer drug interactions. Furthermore, physicians should advise patients to refrain from using herbs, especially when their effects have not been well investigated.

Keywords Herbal drugs • Cancer • Chemoprevention

13.1 Introduction

Many people are keen to use herbal medicines either to prevent cancer or to treat the disease or side effects of chemotherapy, but most remain unaware of the limited scientific evidence regarding the efficacy of these remedies and the potential drug interactions and adverse effects that may result from their consumption. Most trials are small, open-label, uncontrolled and not randomised. Preliminary evidence suggests that some herbs may have a role in preventing cancer or adjoin therapies for

Department of Medicine & Public Health-Section of Pharmacology, University of Verona, Italy, Policlinico G.B. Rossi, Piazzale L.A. Scuro, 37134 Verona, Italy e-mail: [email protected]

K.G. Ramawat (ed.), Herbal Drugs: Ethnomedicine to Modern Medicine, DOI 10.1007/978-3-540-79116-4_13, © Springer-Verlag Berlin Heidelberg 2009

its treatment, but it appears that herbal medicines are unlikely to provide a miracle cure for cancer [1], and their effects are not always predictable.

Most cancer patients combine, rather than replace, conventional therapy with herbs [2]. Studies on cancer patients sampled from the general population indicate that herb users are mostly young women high on the social ladder [3, 4] who are looking for miraculous cures [5]. In addition, they tend to be more health conscious [6], are willing to spend out of pocket [7] or are being treated with chemotherapy [8].

Several studies indicate that young patients and those who live long after receiving a cancer diagnosis are more likely to seek some forms of complementary and alternative medicine (CAM) [9]. One concern is the fact that approx. 70% of those who report using herbs do not inform their physicians of their decision [10]. Furthermore, the fact that most conventional medical practitioners have very little knowledge of herbs makes educating herb users a challenging task.

13.1.1 Reasons for Using Phytomedicines in Cancer Treatment and Prevention

Different reasons lead patients with acute, serious or life-threatening conditions and patients with chronic or benign diseases to try CAM. For cancer patients, the most powerful motivations relate to the desire to leave no option untried and to the dissatisfaction with mainstream oncology treatments [11]. In general, most cancer patients are satisfied with conventional treatment. Nevertheless, the attention paid to their symptoms and side effects is not satisfactory for them. It is currently estimated that more than half of the patients diagnosed with cancer have explored herbal medicines in an attempt to treat cancer and the adverse effects associated with conventional cancer treatments. For example, PC-SPES is sometimes used as the sole treatment for prostate cancer for its presumed action as an anticancer agent [12, 13].

According to a survey of gynaecological cancer patients on their reasons for using herbs [14], a large number of patients resorted to herbs to improve their quality of life and, if they were taking other drugs, to decrease their adverse effects, whereas 15% of patients used herbs to treat the cancer directly. Several products are under investigation in clinical trials for this reason. However, they have not been under appropriate trial development so far [15].

Another reason for using herbs is related to their cancer-prevention properties. For example, the more or less conscious use of green tea by men has become more and more popular. Indeed, in a recent case-control study, supported by in vitro research, a protective effect of green tea against prostate cancer was suggested [16,17]. The risk was thought to decline along with the increase in frequency, duration, and quantity of green tea consumption. However, conflicting results on the use of green tea as a protective substance in relation to prostate cancer have been reported by epidemiological studies [16]. In general, there is a lack of evidence on the efficacy of most herbs in the prevention of cancer.

In addition to these reasons, cancer patients generally have the same reasons as other people for using CAM [18]. Most cancer patients want to increase their body's ability to fight the disease (50%) and improve their physical and emotional health (40% and 35% respectively) [19]. In a recent report, a study performed at a community hospital with a cancer centre found that dietary supplement users have a better quality of life than non-users [20]. In contrast, previous data showed opposite results [4-21].

13.2 Methods

Medline and Embase searches were performed between 1990 and 2007 using the terms "phytotherapic compounds", "phytomedicine", "efficacy", "safety" and "epidemiological data" combined with the terms "cancer", "patients", "chemopreven-tive", "chemotherapy", "side effect" and "antitumour activity".Information about the use of herbal products on the examined subpopulations derived from medical records, prescription data, personal interviews, self-completion questionnaires or a combination of these.

13.3 Epidemiological data

It is estimated that up to one third of the entire population of the USA has used CAM, and most individuals in that country have used herbal products on a routine basis [10]. Most research on the use of CAM is conducted in the USA, with multiple recent surveys suggesting that 25 to 84% of US cancer patients have used CAM therapies and 13% to 63% herbal preparations [10], with vary utilization rates according to geographic areas and types of cancer. Apparently, patients with breast cancer tend to use more herbal products than individuals with other types of malignancy, since women use CAMs more than men [10]. In particular, it seems that colorectal and breast cancer patients are more likely to use dietary supplements than lung cancer patients [22].

A recent descriptive survey conducted in 14 European countries has shown that 36% of cancer patients used some kind of CAM. Among those countries, the utilization rates range from 15% to 73% of the population in Greece and Italy, respectively [19]. Furthermore, herbs have resulted to be the most common CAM therapy in 13 countries, most of them being specific in each country, i.e. mistletoe in Switzerland, olive leaf paste in Greece and Aloe vera in Serbia and Spain. An Australian study has reported that herbal treatments and naturopathy are the most popular CAMs used by cancer patients, representative over 30% of the recorded CAM use [23].

In a nationwide, cross-sectional survey carried on in Japan, 92% of the CAM users with cancer use products such as mushrooms, herbs and shark cartilage [3].

A Canadian survey has reported that 25% of breast cancer patients use herbal products [9]. In a study by Richardson et al. [24] regarding various CAM approaches, a statistic on 453 male and female patients from 8 different cancer outpatient clinics has shown that 62% of these cancer patients reported use of herbs and vitamin products. Navo et al. [14] have reported that gynaecologic oncology patients use CAM (49.6% to 56.3%) among all herbal products. In general, most of them gathered information about herbs on their own from internet and media, but also looked for the opinion of their friends and family.

Data from the Women's Healthy Eating and Living study have shown that up to 80% of non-stage IV breast cancer patients took dietary supplements such as vitamins, antioxidants and herbs [25]. Recently, an important increasing trend in the use of herbal products rather than other supplements has been observed [26]. A recent study on patients enrolled in early-phase chemotherapy trials at the Mayo Clinic Comprehensive Cancer Centre reports a high use of herbal products. More than 80% simultaneously used vitamins, herbs and minerals in addition to their experimental chemotherapeutic agents [27], although this is often an exclusion criterion formally not allowed during this type of treatment.

13.4 Herbs Commonly Used in Cancer Treatment and Prevention

Several herbs and herbal compounds are believed to suppress the transformative, hyperproliferative and inflammatory process that initiates carcinogenesis [28]and dramatically inhibit the vascular endothelial growth factor (VEGF), whose production is considered essential for the migration of cancer cell and for angiogenesis.

Polyphenols are receiving considerable attention for the potential implications in cancer therapy, particularly resveratrol, (grapes), quercetin (broccoli, onions and tea), curcumin (turmeric), genistein (soy), epigallocatechin (green tea) and their sources. In particular, quercetin strongly inhibited in a time and dose-dependent the expression of the mutated p53 protein in breast cancer, while the anti-tumour activity of resveratrol occurs through p53-mediated apoptosis [29, 30]. Another mechanism for anticancer activity of resveratrol is the inhibition of a wide range of angiogenic growth factors including VEGF expression [31].

Curcumin, found in turmeric and its derivatives, has demonstrated a significant inhibition of VEGF and directly inhibits angiogenesis in vivo and in vitro. Moreover, curcumin is also known for interfering with the endothelial cell function by inhibiting the specific integrin engagement. However, it does not interfere with normal cell function; this being the beauty of these safe compounds [32]. Moreover, Aggarwal et al. [33] reported that the ability of curcumin stems of suppressing the proliferation of a wide variety of tumour cells entails the anticancer effect of down-regulating the Nf-kB, AP-1 and Egr-1 transcription factors and the expression of COX2, LOX, NOS, MMP-9, uPA, and TNF.

Regarding green tea and its extracts, findings have shown that they suppress chromosomal abnormalities induced by carcinogens. For this reason, interest in these compounds has grown as they also play a role in delaying the cumulative genetic damage necessary for a cell to evolve from normality to one with aggressive metastatic capabilities [34]. An appropriate dose of VEGF blockade would be 2 to 4 g of standardized green tea extract. Each gram of this extract provides 400 to 500 mg of EGCG [35].

The seed cones from magnolia trees inhibited the growth of new blood vessels in mice. Silybin, a silymarin compound in milk thistle, bound to phosphatidyl-choline, was shown to inhibit VEGF when used as a single agent against human ovarian cancer [36].

Aloe-emodina, a hydroxyanthraquinone from Aloe vera and other plants, has been indicated as a new antiangiogenic compound with a remarkable photocytotoxic effect on tumour cells [37]. Emodin has been reported to be non-toxic for normal cells while possessing specific toxicity for neuroectodermal tumour cells [38, 39].

Edible berries (bilberry, cranberry, elderberry, raspberry seed) may have potent chemopreventive properties by inhibiting both H2O2 and TNF-a, which induced VEGF expression [40]. Ginkgo has multiple actions including antiedemic, antihypoxic, antioxidant, antiplatelet, free-radical scavenging and microcirculatory properties [10-41].

Terpenes, and especially triterpenes, due to their broad spectrum of biological activity, are studied by many researchers since there is growing interest in the evaluation of triterpenoid extracts for cancer treatment [42]. Several triterpene compounds that have recently appeared in the literature in preclinical studies suggest potential therapeutic opportunities. Betullinic acid, boswellic acid, squalene, urso-lic acid, oleanolic acid and triterpenoid saponins are among the growing number of compounds evaluated in preclinical and some clinical studies [43].

Alfa-bisabolol is a sesquiterpene alcohol present in the essential oil of chamomile and other plants which exerts, according to Cavalieri et al. [44], a strong time-and dose-dependent cytotoxic action against human pancreatic cell line. However, it failed to affect the viability of human fibroblasts. Based on these results, alfa-bisabolol should be considered a novel promising compound for inhibiting the growth and survival of transformed cells with high malignancy.

The efficacy of Ginseng in the treatment of physical performance, psychomotor performance, cognitive function and immune modulation has been investigated [45]. The conclusion of this analysis is that the efficacy of ginseng is not established beyond reasonable doubt for any of these indications. However, a retrospective trial involving 4634 patients suggested a dose-response relationship between ginseng consumption and a decrease in the risk of cancer, with a 40% relative risk reduction [46].

Iscador, a derivative of mistletoe, is an example of an immunostimulant causing either an increase in cytotoxic T lymphocytes or natural killer cells or endogenous production of interferon and interleukins. Iscador is available in many mainstream European cancer clinics. European governments have approved studies on the efficacy of iscador against cancer. The results are mixed, since some studies suffer methodological shortcomings [47]. According to another systematic review [1], none of the methodologically well-made trials showed efficacy in survival.

Several mushroom-derived compounds have been approved for use as cancer treatment in Japan. Trials on polysaccharide Kureha (PSK), an extract of the mushroom Coriolus versicolor, showed superior survival with PSK in both gastrectomy and esophagectomy [1]. Two randomized trials of PSK given after curative resection for colorectal cancer showed that both disease-free and overall survival rates were significantly higher in the PSK group [48]. Results were less encouraging in breast cancer and leukaemia [49, 50]. The proposed mechanism was immune modulation of a beta glucan, a natural carbohydrate, present in great quantities in mushroom, bound to specific receptors on neutrophils. An interesting association between the response to PSK treatment and HLA type was reported [51].

Several studies have been published on the chemistry, pharmacology and clinical applications of Echinacea, in particular E. purpurea. Among these, many have described the use of Echinacea for immune system stimulation [10]. Astragalus has been proved to have immunologic benefits by stimulating macrophage and natural killer cell activity and inhibiting T-helper cell type2 cytokines. McCulloch et al, [52] found evidence that Astragalus-based Chinese herbal medicine may increase the effectiveness (by improving survival, tumour response and performance status) and reduce the toxicity of standard platinum-based chemotherapy for advanced non-small-cell lung cancer. Garlic has been used in a variety of conditions as a chemo-preventive agent for gastrointestinal tumours [53].

13.5 Herbs for Treating the Side Effects of Chemotherapy and Radiation

Most adverse side effects of chemotherapy and radiotherapy are still a big concern for patients and their families. No provisions are made for the side effects of chemotherapy, and sometimes patients are not aware of these effects. In this respect, to treat the side effects of chemotherapy and radiotherapy, the use of "safe natural" herbs may be more appealing. Insomnia and other sleep disturbances are common in cancer patients. Insomnia is a multifactorial health concern that currently affects at least one out of three cancer patients, and yet most insomnia sufferers do not consult their physician regarding pharmaceutical options for their relief.

In a multicenter study in Baltimore, 44% of breast and lung cancer patients reported experiences of sleep disturbances [54]. In a cross-sectional survey, 31% of patients attending clinics for breast, gastrointestinal, genitourinary, gynaecologic and various skin cancers reported insomnia [55]. Up to 75% of cancer patients visiting an intensive care unit reported sleep disturbances [56]. Since long-term use of hypnotic drugs is associated with dependence and other risks, herbal remedies as sleep aids are required, especially when the disease has become chronic [57]. Many physicians have expressed the need to educate themselves and their patients to use, appropriately, these herbs and have questioned whether sufficient research data exist in order to make recommendations for insomnia relief and restoration of normal sleep quality. Some herbal sedatives have a long history of use in Europe but they are yet relatively new in the USA.

Valeriana contains constituents of the essential oil sesquiterpenes, which are of special interest for their sedative effects. Valeriana has shown sedative activity in a meta-analysis of clinical trials for the treatment of insomnia [58] and has been proved useful in sleep, since it is active against anxiety, which may interfere with sleep. Numerous studies have investigated the use of kava in the treatment of anxiety and sleep disorders. A meta-analysis reported that kava was effective in reducing anxiety [59].

Chamomile is very popular in the USA and Europe for its relaxing effect. Clinical trials on the sedative effects of chamomile are lacking and thus needed. In a pilot study, 10 out of 12 patients immediately entered into a deep sleep lasting an average of 90 min [58].

Lavender is used in aromatherapy as a holistic relaxant and, when inhaled, has been reported to have sedative effects in both animals and humans [60]. Patients undergoing radiation therapy were treated with lavender unscented carrier oil or other essential oils for inhalation: the carrier group experienced less anxiety than did the essential oil group. There are anecdotal and historical accounts of the sleep-enhancing benefits of hops and Lemon balm. Both herbs are purported to have sedative and hypnotic effects, but clinical evidence from MEDLINE is scarce [58].

Passionflower, another herb with mild sedative effects, is often combined with valerian in the herbal sleep aids found in health food stores. In a double-blind, randomized, placebo-controlled study, the effect on anxiety of passionflower did not differ from that of the oxazepam group [61].

A meta-analysis was conducted on St. John's wort including 23 randomized trials (M1757 outpatients) with mild to moderate depressive disorders. St. John's wort was found to be significantly more effective than placebo. Other authors concluded that St. John's wort was not effective in 200 adults with major depression [58].

Regarding the efficacy of topical Aloe vera in reducing the side effects on skin of radiation therapy, some authors [62, 63] reported no improvement in clinical studies compared to placebo or aqueous cream.

Ginger has demonstrated effectiveness with chemotherapy-induced nausea in a meta-analysis of randomized clinical trials [64]. Important adaptogens to consider in oncology include Eleutherococcus senticosus, Panax ginseng, Rhodiola rosea, Schisandra chinensis, Rhaponticum carthamoides and Aralia manchurica. Extensive studies using various cytotoxic therapies in animal and human models with tumours have demonstrated that these adaptogens reduced chemotherapic drug tox-icity, in combination with cytotoxic agents, particularly in bone marrow restoration, and they enhanced antitumour and antimetastatic effects [65, 66].

13.6 Safety Data of Herbal Compounds in Cancer Patients

There is relatively little quality information about the adverse effects of herbs and interactions between herbs and conventional medicines. This is due to a lack of knowledge by healthcare practitioners, particularly about the way these effects should be reported, and to the fact that consumers are less likely to report incidents associated with herbal products than those having to do with conventional medicines [9]. Cancer patients using herbal compounds should be warned that some of the adverse effects of these therapies are often similar to symptoms associated with their disease or treatment, thus making it difficult to discern if the disease or the "remedy" is the problem [67, 68]. In addition, given the relatively poor quality control standards of these products in many countries around the world, herbal medicines containing the wrong herbal product and/or potentially toxic adulterants have been reported [69, 70].

When adverse events and/or interactions with conventional drugs are reported in the literature, it is important, at first, to note whether the herbal product was authenticated. The quality of herbal products is highly variable with respect to the concentrations of its major and characteristic ingredients [71]. This appears to be the case both in countries where no strict regulation for these products exists (e.g. the USA) and in countries where a stricter regulation has been formulated (e.g. Germany). In addition pollution from pathogenic microorganisms, pesticides and heavy metals makes the health risks even greater [71].

As an example, regarding cannabis, sometimes used for palliative purposes by cancer patients [67], it has recently been demonstrated that the kind bought in Dutch " coffee shops" could be contaminated by bacteria and fungi that may seriously harm ill patients [72]. To avoid the risks associated with pollution, patients should be extra careful, because herbs that seem safe for healthy people under normal conditions might not be so safe for certain groups of patients such as cancer patients [73]. It has been clearly established, in any case, that a variety of herbal medicines may produce serious side effects [71].

Considering the narrow therapeutic window of chemotherapic drugs, the use of herbs, overall, increases the risk of clinically relevant herb-anticancer-drug interactions. It is estimated that the interactions are responsible for more unexpected toxicities of chemotherapic drugs in cancer patients [74].

Interactions between herbs and anticancer agents are currently not sufficiently documented. Basically, interactions are mostly thought to be the result of enzyme interactions (like those of cytochrome P450 metabolic pathways) and drug-trasporting proteins (ATP-binding transporters) which can be influenced in activity and expression by herbal medicine ingredients [74]. If given together, some herbs may indirectly induce the metabolism of cytotoxic agents, potentially leading to non-therapeutic systemic drug levels or inhibiting metabolism, in turn leading to potentially lethal toxicities. An additional consideration for cancer chemotherapy is that herb-mediated induction of various enzymes and transporters may also take place in tumour cells and subsequently result in resistance to chemotherapic drugs such as antracyclines, epipodophyllotoxins, taxanes and vinca alkaloids [75].

For St. John's wort, interactions with irinotecan, imatinib and docetaxel have been studied [76-78]. Regardless of the modulation of CYP3A4 and P-glycoprotein activity observed with St. John's wort, its crucial role in the elimination of many important anticancer drugs is of particular concern [10]. This suggests that interactions between St John's wort and such agents are likely to have clinical and toxi-cological implications and that rigorous tests for possible interactions are urgently needed. Currently, research is ongoing, for instance, to study the effects of medicinal cannabis on irinotecan and docetaxel metabolism [67]. Clinically significant interactions have been seen in some cases by Meijerman [74].

Some data suggest that Echinacea is likely to interact with anticancer drugs that are a substrate for CYP3A4 and that the interaction depends on the relative extraction of drugs at the hepatic and intestinal sites and on the route of administration [74]. Moreover, like several other herbal preparations, Echinacea found in retail stores often does not contain the labelled species [79]. Obviously, the high variability observed in the concentration of constituents of the herb may have implications for Echinacea's ability to modulate drug absorption and disposition.

Studies using in vitro and in vivo animal models have also indicated that various garlic constituents can induce the activity of CYP3A4 [80] and conjugating enzymes such as glutathione S-transferases and quinine reductase [81, 82]. Although the product composition and the designs of the clinical studies vary widely [83], there appears to be little likelihood of significant interactions between garlic and the anticancer drugs that are predominantly metabolized by CYP3A4.

Evidence indicates that some preparations of ginseng have phytoestrogens effects, which suggests that its use with soy supplementation should be discouraged in women with breast cancer or endometrial cancer [84]. Substantial variability in ginsenoside content has been reported among commercial ginseng preparations, indicating that significant, clinical effects on the pharmacokinetics of the anticancer drugs metabolized by CYP3A4 could be brand specific [85].

The most important concerns with kava toxicity are the reports of hepatotoxicity in kava users. Some cases have been sufficiently severe such that liver transplants have been required and three deaths have resulted from hepatotoxicity associated with kava [86]: it has been suggested that the genetic deficiency of CYP2D6 might be associated with a susceptibility to kava toxicity in some of the observed cases [87]. In the South Pacific, where the genetic deficiencies of this enzyme are not known, no reports of liver failure have been reported, while genetic deficiencies occur in about 10% of Europeans [88]. Two cases of hepatic insufficiency, in the South Pacific area, were reported after kava consumption which were resolved when the patients ceased taking kava and were explained as allergic reactions [89]. Cancer patients who are undergoing treatment, have recently undergone treatment or are taking medications should avoid kava. If a cancer patient sees no other feasible alternatives than kava, he or she should consume tea rather than a concentrated extract since no cases of actual liver failure are known to be associated with the traditional aqueous extracts.

An interaction between the pharmacokinetics of anticancer drugs and grapefruit juice has been described. Grapefruit juice intake resulted in a 26.2% lower AUC

of etoposide after oral intake. The median absolute bioavailability with and without pretreatment with grapefruit juice was 52.4% and 73.2%, respectively [90]. From clinical studies, it is reported that ginkgo may interfere with the pharmacokinetics of anticancer drugs metabolized by CYP2C19 or CYP3A4 [41].

Black cohosh, soy, may decrease the efficacy of tamoxifen, and therefore women taking this agent should especially avoid soy [91]. Moreover, at present it seems prudent to discourage soy-derived products in patients with estrogen-dependent tumours (e.g. breast cancer or endometrial cancer), as experimental data in mice indicate that soy can stimulate the growth of these tumours [92].

Selenium and squalamine may increase the toxicity of cisplatin, black cohosh, Echinacea, salicylate-containing herbs, while bilberry, cramp bark, meadowsweet, poplars, red clover, uva ursi, white willow, and wintergreen may increase the hepa-toxicity of metrotexate [93].

Valerian appears to have a wide margin of safety. No studies have been found indicating any effects of valerian on the cytochrome enzymes involved in drug metabolism. For this reason there is no evidence of any potential effects on the clearance of chemotherapic drugs. The major drug interactions with valerian are those involving the potentiation of effects of sedatives, hypnotics or anaesthetics. Cancer patients should be advised to quit valerian use before surgeries for its possible withdrawal symptoms [58].

No toxicity has been reported for lavender: however, the herb potentiated the sleep-inducing activity of several agents including alcohol and hexobarbital in laboratory studies [94]. There are several reports of skin reactivity to chamomile [95]. Chamomile showed a moderate inhibitory effect on CYP3A4 in vitro with unclear clinical relevance. The formation of sister chromatid exchanges by daunorubicin has been decreased in rats pretreated with chamomile essential oil as compared to those given corn oil. Since sister chromatid exchanges may be correlated with anti-tumour activity of this anthracycline, this finding is of potential concern for patients undergoing anthracycline therapy [96].

Boudreau et al. [97] evaluated the biological and toxicological properties of Aloe vera, as a topical and oral agent. Ingestion of Aloe vera is associated with diarrhoea, electrolyte imbalance, kidney dysfunction and conventional drug interactions; episodes of contact dermatitis erythema and phototoxicity have been reported from topical applications. Rabe et al. [98] described as a case study the first case of acute hepatitis due to this compound.

The controversy surrounding antioxidants in combination with conventional therapy has focused on drugs that are believed to achieve their cytotoxic effects by generating free radicals, such as alkylating agents, anthracycline, platinum compounds, topoisomerase II inhibitors and radiation.

Although it has been reported that antioxidant and free-radical scavengers can actually prevent cancer [99], there is evidence that these agents could also interfere with chemotherapy (e.g. alkylating agents, anthracyclines and platinum analogues) and radiation therapy by acting as free-radical scavengers [84].

However, particular adjunctive agents, such as Mesna, produce their effects by quenching free radicals and do not seem to decrease the efficacy of chemotherapy.

Individuals treated with drugs that deplete the antioxidant status may require replenishment of antioxidants after treatment. However, the published clinical reports do not clearly define the role of antioxidant supplementation [100]. In some cases, the combinations of herbs and drugs could be considered synergic if the efficacy is greater than the effect of the single agent. Some herbs are known to enhance the cytotoxic effect of drugs through unknown mechanisms. Herbs like Angelica sinensis or Zingiber officinale might increase the toxicity of anticancer drugs [101].

13.7 Conclusions

More than 100,000 deaths per year in the USA can be attributed to drug interactions, placing this problem between the fourth and sixth leading cause of death, most of these deaths being connected to the use of herbs [10]. As a result, it is of the utmost importance to clarify their use before exposing patients to drugs with a narrow therapeutic window, which includes most anticancer agents. In clinical practice, the clinician should, in every patient contact, consider that most cancer patients will not spontaneously report herb use. A study revealed that, of the 48% of cancer patients using concomitant CAM, the vast majority had acted without informing their doctor [102].

For this reason, it is important for healthcare practitioners to discuss herbal medicine with their patients. One of the biggest challenges for healthcare professionals is to face their lack of substantive knowledge about the herbs that patients are using. Herbal products are commonly perceived as "natural" and thus as "innocent", a perception that is hard to change [103]. For this reason, the patient will answer "no" if asked about herb use [18], as proved by the St. John's wort tea case. Some herbal teas, like the St. John's wort variants, are produced by companies regarded highly reliable and trustworthy in the community and are sold in the supermarket as normal tea. Patients who drink this tea may not be as consciously aware of the risks associated with herbs as they would be if they had bought such products in their local pharmacy or drugstore. Therefore, the physician should actively ask for herbal and supplement use while explaining their potential hazards [73-104].

Finally, there is almost no information on whether the commonly applied dose range of herbal medicine is critical for anticancer drug interactions in patients. In this respect, evaluation of the data obtained in vitro and in vivo methods must be carried out and verified in well-designed clinical trials.

Some experts believe that the potential risk of herb-drug interactions is enough to recommend patients on chemotherapy to not use herbal therapies and herbal preparations to be interrupted prior to surgery or radiation therapy [105]. At present, oncologists must be encouraged to discuss herbal use with their patients and they should be aware of possible herb-anticancer drug interactions. Furthermore, physicians should advise patients to refrain from using herbs, especially when their effects are well known.

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