Support Care Cancer DOI 10.1007/s00520-014-2261-9

ORIGINAL ARTICLE

Bridging cross-cultural gaps: monitoring herbal use during chemotherapy in patients referred to integrative medicine consultation in Israel Limor Almog & Efraim Lev & Elad Schiff & Shai Linn & Eran Ben-Arye

Received: 13 January 2014 / Accepted: 22 April 2014 # Springer-Verlag Berlin Heidelberg 2014

Abstract Introduction The high prevalence of the use of traditional herbs among patients with cancer is a cause for concern with regard to potentially adverse interactions with conventional oncology treatments. In this study, we explore herbal use among patients with cancer in northern Israel who are referred by their health care providers to complementary and traditional medicine (CTM) consultations provided to them within the conventional oncology department. The study’s objectives were to identify which herbs patients use and to examine the scope of current research on the efficacy and safety regarding the identified herbs. L. Almog : E. Ben-Arye (*) Integrative Oncology Program, The Oncology Service and Lin Medical Center, Clalit Health Services, 35 Rothschild St., Haifa and Western Galilee District, Haifa, Israel e-mail: [email protected] L. Almog Graduate Studies Authority, University of Haifa, Haifa, Israel E. Lev Department of Eretz Israel Studies, University of Haifa, Haifa, Israel E. Schiff Department of Internal Medicine, Bnai-Zion Hospital, Haifa, Israel E. Schiff Department for Complementary/Integrative Medicine, Law and Ethics, The International Center for Health, Law and Ethics, University of Haifa, Haifa, Israel

Patients and methods Herbal use by patients receiving oncology care was assessed prospectively from July 2009 to July 2012 by integrative physicians (IPs) trained in herbal medicine. Historical, ethnobotanical, basic research, and clinical data regarding the identified herbs were explored by using a keyword search in PubMed and Middle Eastern ethnohistorical literature. Results Disclosure of herbal use was reported by 154 of the 305 patients (50.5 %) interviewed by IPs. The use of 85 single herbs and 30 different herbal formulas was documented during the initial or follow-up IP assessments. Patients reported 14 quality of life-associated indications for herbal use. The ten most prevalent herbs displaying in vitro/in vivo anticancer activity and nine other herbs were preliminarily assessed concerning potential risks, safety, and interaction with chemotherapy. Conclusions Herbal use by patients with cancer in northern Israel is widespread and calls for further study in order to address issues of safety and effectiveness. We recommend constructing a multinational and multidisciplinary team of researchers with ethnopharmacological and clinical expertise that will explore the use of herbs among patients with cancer in a cross-cultural perspective attuned with patients’ affinity to traditional herbal medicine. Keywords Herbal medicine . Traditional medicine . Integrative oncology . Chemotherapy . Drug interactions . Cross-cultural medicine

S. Linn School of Public Health, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel

Introduction

E. Ben-Arye Complementary and Traditional Medicine Unit, Department of Family Medicine, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

The use of traditional and complementary and medicine (CTM) among people with cancer is evident worldwide and ranges from 40 % in developed countries to 65 % or more in developing countries [1]. Herbal medicine is one of the

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leading CTM modalities and is highly prevalent in societies with rich use of traditional medicine such as in India, China, and the Middle East. Extensive use of herbs by people suffering from cancer has been reported across the Middle East: in Turkey (32 %) [2], Jordan (35 %) [3], Arab patients in Israel (34 %) [4], and the Palestinian Authority (61 %) [5]. Patients’ motives for herbal use include relief of cancer-related symptoms, lessening of oncology medications’ side effects [3], slowing down disease progression, and cure of disease [3, 5]. In recent years, increasing numbers of clinical studies have emphasized the potential role of herbs in improving patients’ quality of life (QOL) during cancer treatment. Promising results on the efficacy of herbs in improving QOL and ameliorating chemotherapy side effects include ginseng (Panax quinquefolius L.) for chemotherapy-related fatigue [6], ginger (Zingiber officinale Roscoe) for chemotherapy-induced nausea and vomiting [7], and astragalus (e.g., Astragalus membranaceus Monech) for QOL improvement in patients with advanced nonsmall cell lung cancer [8]. The issue of herbal safety is challenging in numerous aspects which may include toxicity and adverse effects of herbs [9, 10], product quality issues ranging from correct botanic identification of plants picked in the field to controlled standardization processes (e.g., agricultural cultivation, manufacture, distribution, labeling, and avoidance of pollutants); and, most importantly, safety aspects regarding potential interactions between herbs consumed by patients and the medications prescribed by their oncologists. Sparreboom et al. studied 15 best-selling herbs in the USA and recommended refraining from the use of five herbs in combination with certain oncological drugs and caution with four other herbs due to known or suspected interactions with chemotherapy and other oncological drugs. The list of potential herb–drug interactions included cyclophosphamide (e.g., valerian via CYP2C19 inhibition), alkylating agents, antitumor antibiotics, and platinum analogues (e.g., Ginkgo biloba L.) [11]. In Norway, Engdal et al. studied 42 patients who used herbal remedies concurrently with chemotherapy and identified 47 different potential herb–drug interactions on the level of CYP metabolism and P-gp transport in vitro [12]. The matter of herbal–chemotherapy interaction is even more complex since interactions may not only reduce the effects of chemotherapy (e.g., Hypericum perforatum L., constituent hyperforin on docetaxel metabolism) [13] but may also increase elevation of the chemotherapeutic blood levels (e.g., concomitant use of G. biloba L. and paclitaxel) [14]. The need for evidence-based consultation regarding the safe use of herbs and other CTM modalities has generated the introduction of CTM-oriented programs in leading integrative oncology centers worldwide, as well as guidelines regarding optimal communication between health care practitioners on these issues [15]. Herbal-oriented consultations for patients receiving cancer care are needed specifically in

communities with a high prevalence of herbal use, such as in the Middle East and other traditional medicine-oriented populations. In Israel, integration of herbal consultation as part of oncology intake is especially needed due to the diverse sociocultural mosaic that characterizes Jewish and Arab patients who are challenged by tradition versus modern global influences. In this cross-cultural setting, an evidence-based approach needs to supplement a nonjudgmental approach that respects patients’ health beliefs. In the present study, we aimed to explore herbal use among patients with cancer in Israel who are referred by their oncologists and health care providers to CTM consultation provided by physicians trained in herbal medicine. The research setting is unique since the CTM consultant is fully integrated within the oncology team and the consultation is provided free of charge to patients receiving chemotherapy and/or palliative care. Our study objectives in these integrative oncology consultations were to identify the herbs patients use and the relatedness of the herbs to Arabic/Jewish traditional use in the context of medicine and nutrition and to examine the scope of current research on the efficacy and safety with respect to the identified herbs. Last but not least, we envision that this work will promote follow-up research based on a multidisciplinary team of researchers in Israel and neighboring Middle Eastern and Mediterranean countries which will integrate ethnopharmacological knowledge in clinical practice.

Methods–patients Study sites and participants In 2008, a novel Integrative Oncology Program (IOP) was introduced at the Oncology Service of the Haifa and Western Galilee District of the Clalit Health Services, the leading health maintenance organization in Israel [16]. The IOP’s mission is to promote QOL among patients who receive chemotherapy and/or palliative treatment. The IOP clinical activities are documented in a research-based registry protocol approved by the Helsinki Committee of the Carmel Medical Center, Haifa, Israel, and registered at ClinicalTrials.gov (NCT01860365). The IOP requires that patients receive a structured referral letter from their oncologist, oncologist nurse, or social worker. Patients’ referral was restricted only to patients receiving adjuvant, neoadjuvant, or palliative chemotherapy. Referral to integrative medicine consultation aimed to improve patients’ QOL by ameliorating chemotherapy side effects and patients’ concerns. Referring practitioners were instructed to specify the referral indication (e.g., chemotherapy-induced peripheral neuropathy, fatigue, nausea, insomnia, etc.). Following the referral, the patient is scheduled for an initial 1-h evaluation with an integrative physician (IP) who has

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extensive training in complementary medicine and supportive cancer care. The intake assessment consists of a semistructured interview which addresses previous and current use of CTM including specific questions on the use of herbs following cancer diagnosis. The IP intake also includes assessment of patients’ expectations regarding integrative CTM treatment; health belief models (including affinity with traditional medicine); specific concerns and symptoms; and finally, overall QOL and coping strategies. Following the initial IP evaluation, patients subsequently undergo CTM treatments administered by the IOP practitioners, which are individually tailored, based on patients’ preferences, symptom severity, and the level of research supporting efficacy and safety of potential treatments. The variety of complementary medicine treatments includes herbal and nutritional medicine, acupuncture, and manual and mind–body modalities. Followup assessments of patients’ concerns and well-being are performed at 6 and 12 weeks following the initial IP evaluation. Assessment of patients’ herbal use Records of patients’ evaluations by IPs were analyzed from July 2009 to July 2012. Documented initial IP assessments performed following oncology care practitioners’ referrals were evaluated, in terms of patients’ reported CTM use, for cancer-related outcomes. Specified CTM modalities reported by patients were evaluated for any association with herbal use. CTM modalities that were specifically assessed for herbcontaining ingredients included herbal medicine, traditional Arab/Jewish/Ayurvedic/Chinese medicine, nutritional therapies, dietary supplements, and anthroposophic medicine. Following documentation of herbal-related remedies or therapies, the authors identified the herb’s scientific name by employing one or more of the following procedures: (1) detection based on the IP’s record of the scientific name in the patient’s medical file; (2) in cases when only the common/ traditional herbal name was recorded by the IP, the authors interviewed the IP in order to ascertain the scientific name (in cases where no absolute identification was available, or where two or more herbs were popularly given the same name, only the genus name was recorded); (3) identification of herbs administered as dietary supplements (e.g., capsules, tablets, tinctures) was based on the manufacturer’s label of ingredients. Historical and ethnobotanical review of the identified herbs Identified herbs were reviewed for evidence of their use in relation to cancer care and quality of life improvement in Middle Eastern historical, mainly medieval, sources. This literature survey included primary sources in the form of dozens of medical books, with focus on the genre of Materia Medica and pharmacopeia, written in Arabic,

Hebrew, and Judeo-Arabic, as well as secondary sources and translated books and research [17]. Moreover, ethnobotanical and ethnopharmacological surveys and studies were reviewed as well; these were conducted by various research groups and scholars in the markets of Middle Eastern countries and within diverse ethnic groups. Searching for historical and traditional Middle Eastern medical uses was also performed by means of several electronic resources, such as JSTOR, using the following keywords: “cancer,” “tumor,” and “lump.” In addition, the Medline database was searched thoroughly for historical and ethnobotanical publications by matching the scientific name of each individual herb with the following keywords: cancer, ethnobotany, and traditional medicine. Clinical and basic research review of the identified herbs Identified herbs were also reviewed for scientific evidence of their efficacy in basic scientific and clinical studies. A literature search was performed in PubMed using the following keywords: cancer, chemotherapy, in vitro, in vivo, cell culture, cytotoxic, apoptosis, noncontrolled and randomized controlled studies, safety/risks, and interactions.

Results Overall herbal use during chemotherapy treatment Review of IP interviews, performed from July 2009 to July 2012, yielded 305 medical files of initial IP assessments followed by 1,574 follow-up consultations on herbal treatments. Patients’ demographics included a mean age of 62.4 years; a disproportionately high prevalence of females (228, 74.7 %); and Hebrew (214, 70.9 %), Russian (53, 17.5 %), and Arabic speakers (28, 9.3 %). The leading diagnoses included the following cancer sites: breast (124, 40.8 %), gastrointestinal origin (54, 17.8 %), and gynecological cancers (19, 6.2 %). Disclosure of herbal use was reported by 154 of the 305 subjects (50.5 %) in either the initial or follow-up appointments with the IP, but only 123 (40.3 %) patients reported herbal use at the initial IP meeting. Herbal use reported in follow-up appointments was mostly self-prescribed by patients and, in some cases, recommended by complementary medicine practitioners. Seven patients reported considering the use of specific herbs at the initial IP meeting. Of the 123 herbal users identified in the initial IP assessment, 48 (39 %) had previously consulted a CTM provider on herbal use. Overall, the use of 85 single herbs and 30 different formulas (containing two or more herbs) was reported by patients along the initial and follow-up IP assessments. Three additional single herbs were reported by three patients but were excluded from our study due to identification difficulties. The 85 single

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herbs reported by patients during the IP assessments are henceforth referred to in our article as “identified herbs.” Identified herbs reported by patients undergoing chemotherapy In Table 1, we present a list of 85 single herbs reported by patients assessed by the IP during the initial visit and followup appointments. The herbs’ scientific names follow the International Code of Nomenclature for algae, fungi, and plants (Melbourne Code) 2012 and include 80 genera and 48 families. The most common families documented in our report include Compositae (eight species), Lamiaceae (eight species), Apiaceae (six species), and Leguminosae (six species). The table also presents 14 different clinical indications reported by patients asked to explain their motive for the herb’s use. In the majority of cases, herbs were used with the purpose of improving patients’ quality of life during chemotherapy, while only two patients mentioned herbs in the context of cancer cure. Gastrointestinal symptoms were the leading motive for herbal use, mentioned by 20 patients, for the following concerns: constipation (eight), oral complaints (including aphtous stomatitis, six), abdominal and rectal pain (four), nausea (three), and diarrhea (two). Other indications included chemotherapy-related fatigue (four), vaginal bleeding (one), and eye irritation (one). Comparative ethnobotanical and medical research on leading herbs In Table 2, we present historical/ethnobotanical, basic scientific, and clinical data regarding the ten most used herbs. Six of these herbs (turmeric, pomegranate, mistletoe, flax, ginger, and sage) are cited in historical, ethnobotanical, and traditional medicine literature in the context of cancer care. All ten herbs display evidence of anticancer activity in vitro or in vivo. Clinical trials were available in the medical literature for nine of the ten herbs. However, the authors of these trials recommended follow-up studies. Preliminary data on the risk versus safe use of the leading herbs are available on nine of the herbs presented in Table 2.

Discussion In this study, we found that the prevalence of patients using herbs during chemotherapy is 40.3 % at the initial IP assessment, rising to 50.5 % in follow-up visits. This high incidence of herbal use is remarkable and clinically significant in a setting where patients are concomitantly treated with chemotherapy, because of three core aspects: (1) patients’ perspective of herbal use in the context of their tradition, culture, and health belief model; (2) safety concerns and potential

interactions of the herbs used with chemotherapy; and (3) potential effectiveness of at least some of the herbs in improving patients’ quality of life. The first aspect relates to the profound connectedness that some cancer patients have with herbs in multicultural societies. Indeed, patients may consider herbal use in order to cope with one of their fragile experiences with life-threatening disease, not necessarily based solely on research data. Our study indicates that although oncology treatment in Israel is modern and high-tech, patients still seek the use of herbs concomitant with chemotherapy. The affinity of herbal use in our study with traditional medicine and cultural aspects is supported by the extensive use of many of the identified herbs (46 of 71 herbs identified at the species level, 65 %) in the Israeli cuisine as food (e.g., pomegranate), beverages (e.g., herbal teas), and spices (e.g., turmeric) and in the extensive evidence in historical and ethnobotanical literature for their use in cancer care (Table 1). Although patients’ motives for this extensive use of herbs warrant further study, we suggest that in clinical practice, patients generally support the integration of herbs within their conventional medical care. The interface of the two domains, the oncologist’s prescribed chemotherapy and the self-use or herbalistrecommended herbs, meet in our study in a nonjudgmental setting where the CTM-trained IP consults the patient. Thus, we argue that the data mining of the 85 identified herbs during the IP visits is based on real-time anamnesis of skillful clinicians who documented herbal use in their patients’ medical files prospectively within the framework of a pragmatic trial. Another point for discussion concerns the data on the identified herbs’ efficacy and safety. In Table 2, we report on research conducted on the ten leading herbs listed, ranging from basic scientific to clinical studies on the potential efficacy and safety of the herbs in cancer care. Almost all of these ten herbs display evidence that cannot be disregarded in a clinical setting in which chemotherapy is prescribed in a narrow therapeutic range in terms of efficacy and toxicity. In contrast to many ethnopharmacological studies that focus on the role of herbs, both in the field and in the laboratory, we advocate another research perspective focusing on the clinical arena. Based on our results, we call for further studies to be conducted by a multidisciplinary team of ethnopharmacologists, clinicians, herbal medicine-trained practitioners, experts in traditional medicine, and ethnobotanists, who will explore the implications of herbal use at the time patients receive chemotherapy and biological treatment. A multidisciplinary team of researchers can pave the road linking the different domains and overcome current herbal use challenges that include the following concerns: (1) lack of reliable taxonomic identification of the herbs used by patients; (2) need for better quality assurance in the growing, collecting, manufacturing, storage, and distribution phases; (3) need for high-quality training for physicians and licensed herbal practitioners for acquisition of competency in herbal consultation skills in the cancer care

Support Care Cancer Table 1 List of 85 medicinal herbs mentioned by oncological patients during intake and following meetings with the integrative physician Scientific name (common name) [family name]

Purpose of use Type of Documentation Number of (number of patients) nutritional for use in traditional patients usea Arabic/Jewish reporting use medicineb

Reports of similar use across the Middle Eastc

Triticum aestivum L.d (wheat) [Poaceae]

3

2

31

Curcuma longa L. [Zingiberaceae] (common turmeric)

2

1

23

Punica granatum L. (pomegranate) [Lythraceae]

1, 2

1

16

Cannabis sativa L.e (marijuana) [Cannabaceae]

3

1

15

Viscum album L. (European mistletoe) [Santalaceae]

3

1

13

Linum usitatissimum L. (common flax) [Linaceae]

1

1

11

Constipation (4)

Palestine (Linum pubescens)

Zingiber officinale Roscoe (garden ginger) [Zingiberaceae] 2

1

11

Nausea (2)

Palestine

Salvia officinalis L. or Salvia fruticosa Mill. (kitchen sage/Greek oregano) [Lamiaceae]

2

1

9

Palestine (Salvia fruticosa)

Beta vulgaris L. (beet/English beet) [Amaranthaceae]

1

1

9

Abdominal pain(1) Sore mouth (1) Diarrhea (1) Weakness (1)

Ceratonia siliqua L. (carob, locust tree) [Leguminosae]

1

1

7

Lebanon

Daucus carota subsp. sativus (Hoffm.) Arcang. (Queen Anne’s lace) [Apiacae] Allium sativum L. (garlic) [Amaryllidaceae]

1

1

7

Sore mouth (3) Burning tongue (1) Weakness (1)

Palestine

1

1

6

Matricaria chamomilla L. (German chamomile) [Compositae]

1

1

6

Swelling gums (1) Burning eyes (1) Abdominal pain (1)

Palestine (Matricaria aurea) Turkey (a, b, c) Morocco

Silybum marianum (L.) Gaertn. (blessed milkthistle) [Compositae] Aloe vera (L.) (aloe vera) [Asparagaceae]

3

1

6

3

1

5

Hordeum vulgare L. (barley) [Poaceae]

1

1

5

Prunus domestica L. (plums) [Rosaceae]

1

1

5

Calendula officinalis L. (pot marigold) [Compositae]

3

2

4

Ointment for the anus (1)

Citrus limon (L.) Osbeck (lemon) [Rutaceae]

1

1

4

Nausea (1)

Salvia hispanica L. (chia) [Lamiaceae]

1

2

4

Echinacea sp. (purple coneflower) [Compositae]

Palestine Morocco Weakness (1)

Palestine

Palestine Turkey (a)

5

Vaccinium sp. (blueberry) [Ericaceae]

Palestine Constipation (4)

4

Apium graveolens L. (wild celery) [Apiaceae]

1, 2

1

3

Camellia sinensis (L.) Kuntze (tea) [Theaceae]

1, 2

2

3

Lawsonia inermis L. (henna) [Lythraceae]

3

1

3

Solanum lycopersicum L. (tomato) [Solanaceae]

1

2

3

Taraxacum officinale F.H. Wigg. (common dandelion) [Compositae] Ziziphus jujuba Mill. (common jujuba) [Rhamnaceae]

1

1

3

Fighting cancer (1)

1, 2

1

3

Constipation (1)

Artemisia arborescens L. (wormwood) [Compositae]

1, 2

1

2

Panax sp. (ginseng) [Araliaceae]

Palestine

Weakness (1) Lebanon Palestine

3

Arum palaestinum Boiss. (Palestine arum) [Araceae]

1, 3

1

2

Palestine

Brassica oleracea L. var. capitata L. (cabbage) [Brassicaceae] Cassia sp. (cassia) [Leguminosae]

1

1

2

Palestine

Chelidonium majus L. (celandine) [Papaveraceae]

3

1

2

Cinnamomum cassia (L.) J. Presl/Cinnamomum zeylanicum 2 Blume (cassia) [Lauraceae]

1

2

1

2

2

Convolvulus sp. (bindweed) [Convolvulaceae] Cuminum cyminum L. (cumin) [Apiaceae]

Palestine (Cinnamomum zeylanicum) Jordan

2 2

Mentha sp. (mint) [Lamiaceae]

Abdominal pain (1)

Palestine

2

Palestine Turkey (c) Turkey (c) Palestine (Anisum vulgare)

Pimpinella anisum L. (anise burnet saxifrage) [Apiaceae]

2

1

2

Uncaria tomentosa DC. (cat’s claw) [Rubiaceae]

3

2

2

Support Care Cancer Table 1 (continued) Scientific name (common name) [family name]

Purpose of use Type of Documentation Number of (number of patients) nutritional for use in traditional patients a use Arabic/Jewish reporting use medicineb

Reports of similar use across the Middle Eastc

Urtica dioica L./Urtica urens L. (stinging nettle/dwarf nettle) [Urticaceae]

1

1

2

Palestine (Urtica pilulifera) Turkey (a, b, c)

Actaea racemosa L. (black cohosh) [Ranunculaceae]

3

2

1

Aloysia triphylla Britton (lemon verbena) [Verbenaceae]

2

2

Angelica sp. (Angelica) [Apiaceae]

Weakness (1)

1 1

Annona muricata L. (soursop) [Annonaceae]

1

2

1

Arctostaphylos uva-ursi (L.) Spreng. (Kinnikinnick) [Ericaceae] Arnica montana L. or Arnica chamissonis Less. (mountain tobacco) [Compositae] Astragalus membranaceus Moench (milk vetch) [Leguminosae] Clematis alpina (L.) Mill. [Ranunculaceae]

1

2

1

3

2

1

3

2

1

1

2

1

Avena sativa L. (common oat) [Poaceae]

1

1

1

Brassica cretica Lam. (broccoli) [Brassicaceae]

1

2

1

Carica papaya L. (papaya) [Caricaceae]

1

2

1

Cymbopogon citratus Stapf (lemon grass) [Poaceae]

2

2

1

Eleutherococcus senticosus Maxim. (Siberian ginseng) [Araliaceae] Equisetum sp. (horsetail) [Equisetaceae]

3

2

1

Euphorbia pallasii Turcz. [Euphorbiaceae]

3

2

1

Filipendula ulmaria (L.) Maxim. (queen of the meadow) [Rosaceae] Ginkgo biloba L. (maidenhair tree) [Ginkgoaceae]

3

2

1

3

2

1

Hippophae rhamnoides L. (common seabuckthorn) [Elaeagnaceae] Hypericum perforatum L. (common St. John’s wort) [Hypericaceae] Lespedeza juncea (L.f.) Pers [Leguminosae]

1

2

1

3

2

1

3

2

1

Melaleuca alternifolia Cheel (tea tree) [Myrtaceae]

3

2

1

Nigella sativa L. (black cumin) [Ranunculaceae]

2

1

1

Oenothera biennis L. or Oenothera rosea Aiton (common evening primrose/rose evening primrose) [Onagraceae] Origanum majorana L. (marjoram) [Lamiaceae]

3

2

1

2

1

1

Palestine

Origanum syriacum L. (wild marjoram) [Lamiaceae]

2

1

1

Palestine (Majorana syriaca)

Origanum vulgare L. (oregano) [Lamiaceae]

2

1

1

Petroselinum crispum (Mill.) Fuss (parsley) [Apiaceae]

1, 2

1

1

Turkey (b) Palestine (Petroselinum sativum)

Quercus alba L. (white oak) [Fagaceae]

3

2

1

Palestine (Quercus calliprinos)

1

Moringa sp. (moringa) [Moringaceae]

1

Petasites sp. (pestilence wort) [Compositae]

Palestine (Nigella ciliaris) Lebanon Morocco Jordan Turkey (b) Fighting cancer (1)

1

Rhodiola sp. [Crassulaceae]

2

Rosa sp. (French rose) [Rosaceae] Rosmarinus officinalis L. (rosemary) [Lamiaceae]

Rectal pain (1)

1 2

1

Ruta graveolens L. or Ruta chalepensis L. (common rue/fringed rue) [Rutaceae] Salvia sclarea L. (Europe sage) [Lamiaceae]

2

1

1

3

2

1

Sambucus nigra L. (black elderberry) [Adoxaceae]

1

2

1

Sesamum indicum L. (sesame) [Pedaliaceae]

1

1

1

Rubus sp. (blackberry) [Rosaceae]

1

1

Palestine Lebanon Morocco Vaginal bleeding (1)

Palestine

Support Care Cancer Table 1 (continued) Scientific name (common name) [family name]

Purpose of use Type of Documentation Number of (number of patients) nutritional for use in traditional patients a use Arabic/Jewish reporting use medicineb

Reports of similar use across the Middle Eastc

Morocco Sophora flavescens Aiton (shrubby sophora) [Leguminosae] 3

2

1

Handroanthus impetiginosus (Mart. ex DC.) Mattos (pink trumpet tree) [Bignoniaceae] Trifolium pratense L. (red clover) [Leguminosae]

3

2

1

3

2

1

Valeriana officinalis L. (garden valerian) [Caprifoliaceae]

3

2

1

Vitis vinifera L. (wine grape) [Vitaceae]

1

1

1

Rheum sp. (rhubarb) [Polygonaceae]

Palestine

1

a

Nutritional use was defined with respect to Israeli and Middle Eastern cuisine as follows: 1=food, 2=a beverage or spice, 3=not known as a food, beverage or spice

b

1=Part of traditional Arabic/Jewish medicine, 2=not part of traditional Arabic/Jewish medicine

c

Palestine—[5], Morocco—[18], Lebanon—[19], Turkey (a)—[2], (b)—[20], (c)—[21], Jordan—[3]

d

Wheat grass juice

e

Cannabis is an illegal herb in Israel; it can be used only for medicinal purposes by personal approval of the Health Minister of Israel

setting; and (4) need for integrated basic scientific and clinical research prioritized to investigate the leading herbs used by patients. The report on the 85 single herbs recorded during the IP meetings requires further discussion in regard to other studies conducted in the Middle East in the oncology arena. In a previous study, a multidisciplinary team of researchers from six countries (Middle Eastern Research Group in Integrative Oncology (MERGIO) 2011) identified 59 articles focusing on regional herbal medicine and reported that the leading researched herbs in the Middle East are Curcuma longa L. (turmeric), Viscum album L. (mistletoe), and Nigella sativa L. (black cumin) [85]. In our current study, two of these three herbs are listed among the top ten herbs used by patients. Turmeric and European mistletoe are also highlighted in another Israeli–Egyptian–Turkish collaborative study of researchers who screened 44 herbs cited in Jewish and Arab traditional medicine in the context of cancer care [86]. Following a literature search on the potential of these herbs in cancer treatment, the authors prioritized five herbs for further research, three of which are also listed in our current study (C. longa L, V. album L., and Salvia spp.). These findings, which affirm the relevance of what we found in previous nonclinical studies, emphasize the need to conduct a multinational collaborative clinical study that will explore the rich herbal heritage of the Middle Eastern region and the role of herbs documented in other surveys [e.g., olives and dates (Jordan and Palestine), and Thymus spp. (Palestine, Morocco, Turkey)]. Our study has several limitations. Although the unique setting of IP consultation provided in a conventional oncology department is advantageous with respect to patients’

disclosure on herbal use, it may also be regarded as a potential selection bias of patients referred by their oncologists and other oncology care providers. Thus, the percentage of herbal users should be perceived in relation to the specific population of patients receiving chemotherapy in northern Israel who are referred to IP consultation. Another limitation concerns the identification of herbs by the IPs. Although IPs documented thoroughly the names of the herbs reported by their patients and often cross-referenced patients’ reports with the herb sample or picture, no laboratory study or formal botanical identification was able to confirm the taxonomy of the referred herb. Herb identification was also verified by examining herbcontaining product labels (in supplements produced by companies with good manufacturing practice standards) and by examining the herbs during IP appointments or during cuisine preparation workshops designed for patients receiving chemotherapy). Another limitation may be caused by the demographics of the cohort which represents a disproportionately high percentage of females and very low prevalence of patients from the Arab community. Further studies are warranted to explore the use of herbs among males and culturally diverse subpopulations of Arab (e.g., Muslims, Christians, Druze) and Jewish (e.g., immigrants from the former USSR) patients in Israel who, potentially, are affiliated with different schools of traditional herbal medicine.

Conclusions We found a high prevalence of herbal use by patients with cancer in northern Israel who are referred by their oncologists and health care providers to integrative medicine consultation

Historical, ethno-botanical, and traditional medicine sources

Not found

Al-kindy [28]

Leukemia [35]

Not found

Cancer in the mouth Al-kindy [28]. Cataplasm which open tumours [45] a.

The Cataplasm which drains soft lumps [62, 63]b. Tumor of the kidney and bladder Indurated tumors of all organs [45]b.

All manner of malignancy. Indurated Tumors [45, 63]b.

Juice of the plant is beneficial when washing cancer [74]a.

Scientific name

*Triticum aestivum L.

Curcuma longa L.

Punica granatum L.

Cannabis sativa L.

Viscum album L.

Linum usitatissimum L.

Zingiber officinale Roscoe

Salvia officinalis L. or Salvia fruticosa Mill.

Anticancer properties in human breast cancer cell lines [69]. Modulates angiogenic factors in ovarian cancer cells by inhibition of NF-kB activation [70]. In vivo: ginger extract reduced proliferation and apoptosis on prostate cancer [71]. Salvia fruticosa displays cytotoxic effect on human breast cancer cells [75]. Water extracts of Salvia fruticosa induce apoptosis in human colon cancer cell lines [76]. Anti-angiogenic in vitro and ex vivo, and antimigrative activity in vitro of the ethanol extract of S.officinalis [77].

Suppressed colon cancer cell growth, and induced apoptosis [64]. FSO reduced tumor size, tumor cell proliferation and increased apoptosis of breast cancer [65].

Apoptosis induction and higher degree of proteasome impairment [24] Flavonoid-related antimutagenic activity [25]. In vivo inhibition of tumor incidence, yield, and burden [26]. Growth inhibition of colorectal cancer cells [29]. Inhibition of proliferation and migration by apoptosis and NF-kappaBp65 downregulation in breast cancer cells [30]. Inhibition of lung and liver tumor genesis in mice [31]. Colon cancer chemo-preventive activities [36] Inhibition of androgen-independent prostate cancer growth through a nuclear factorkappaB-dependent mechanism [37]. Inhibition of tumor growth and decreased serum prostate-specific antigen levels [38] Cannabidiol induced cell death of breast cancer cells by apoptosis and autophagy [41] In xenografted mice Δ9-THC promote human hepatocellular carcinoma death via autophagy stimulation [42] Induced apoptosis [46] Cytotoxic activity [47] Angiogenesis inhibition [48] DNA repair in peripheral blood mononuclear cells [49].

Cancer-related activity in laboratory studies

73 % of patients reported difficulties in swallowing the juice; 20 % of patients failed to complete the juice intake due to worsening of nausea [27].

Safety and bioavailability study on colon cancer [33]. Dose-escalating studies have indicated the safety of curcumin at doses as high as 12 g/day over 3 months [34].

Pomegranate juice and extract had no effect on CYP2C9 activity in human subjects [40].

Safety concerns include dizziness, increased risk of developing schizophrenia, impairments in memory and cognition, and lack of safety packaging for medical cannabis formulations [44] Dose-dependent flu-like symptoms, fever, and local reactions at the injection site; Occasionally, allergic reactions were reported [61].

Drinking wheat grass juice during FAC chemotherapy may reduce myelotoxicity, dosage and the need for GCSF support, without diminishing efficacy of chemotherapy [27]. Preliminary results in open study on clinical response of patients with advanced and metastatic breast cancer treated with curcumin and docetaxel [32].

Consumption of daily pomegranate juice in patients with prostate cancer caused prolongation of PSA, doubling the time [39].

Anti-emetic effect in chemotherapy-induced nausea and vomiting [43]

Improves quality of life [50] in patients with the following cancer sites:; breast [51, 52] gastric [53] breast, ovarian, and non-small-cell lung cancer [54] May improve survival in the following cancer sites: breast [55], and cervix [56] ovary [57], uterus [58], colon [59] melanoma [60]. Flaxseed supplementation reduces prostate cancer proliferation rates in men pre-surgery [66].

May increase bleeding risk in patients receiving warfarin [73].

Sage tea drinking may increase CCl (4)-induced liver injury [79]. Sage tea may interfere with efficacy of alkylating agents used in cancer therapy [80], No adverse effects were reported nor any significant effects on the blood levels of SGOT, SGPT and creatinine in taking capsules of sage leaf 500mgx3 a day for 2 months [81].

Reduces the severity of chemotherapy-induced nausea [7, 72].

Non controlled pilot study assessing efficacy and safety of Salvia officinalis in controlling hot flashes in prostate cancer patients treated with androgen deprivation [78].

No toxicity at 60 days administration of linseed oil to rats [67]. Flaxseed oil did not interfere with Trastuzumab but rather enhanced its tumor-reducing effects [68].

Data on clinical safety

Clinical studies§

Table 2 Historical/ethno-botanical, basic scientific and clinical data regarding the ten most used herbs

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Not found

Conflict of interest The authors have declared no conflicts of interest.

§

*Wheat grass juice

The herb was part of a formula that was mentioned for this indication

Only the genus name was mentioned

Not found Ceratonia siliqua L.

b

Not found Beta vulgaris L.

a

Historical, ethno-botanical, and traditional medicine sources

In some herbs only selected studies are presented based on clinical research published in peer-review journals

References

Reduces nausea and mucositis in hematooncology settings in children and adults following bone marrow transplantation [87].

Potential interaction with doxorubicin [84].

Acknowledgments We thank Ms. Marianne Steinmetz for editing the English manuscript.

Cytotoxic effect on human prostate and breast cancer cells [82]. Significant tumor inhibitory effect against lung cancer [83]. Extracts from fruit pulps decreased the viability of different human cancer cell lines: breast, cervical, prostate and colon cell lines [85]. Leaf and pod extracts were able to alter cell proliferation and induce apoptosis in hepatocellular carcinoma cell line [86].

Not found

during chemotherapy. Assessments made by physicians trained in herbal medicine identified 85 single herbs and 30 herbal formulas. These findings indicate the need to study the implications of extensive herbal use on cancer care outcomes, particularly with respect to safety issues and the potential of specific herbs to improve patients’ quality of life during chemotherapy.

Scientific name

Table 2 (continued)

Cancer-related activity in laboratory studies

Clinical studies§

Data on clinical safety

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