Melanoma Research 2017, 27: a Department of Dermatology, b Department of Medical Biometrie, Epidemiology

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1 238 Original article Interactions from complementary and alternative medicine in patients with melanoma Carmen Loquai a, Irene Schmidtmann b, Marlene Garzarolli c, Martin Kaatz d, Katharina C. Kähler e, Peter Kurschat f, Frank Meiss g, Oliver Micke h, Ralph Muecke i, Karsten Muenstedt j, Dorothee Nashan k, Annette Stein l, Christoph Stoll m, Dagmar Dechent n, * and Jutta Huebner o, * Biological-based (BbCAM) methods from complementary and alternative medicine (CAM) may interact with cancer treatments, reduce efficacy, or enhance adverse effects. Although CAM usage has been evaluated well in other cancer entities, data on melanoma patients are still missing. The aim of this study was to determine CAM usage of melanoma patients using a standardized questionnaire to identify potential interactions with established and new systemic melanoma therapies. This multicenter study was carried out in seven German skin cancer centers. During routine care contact, CAM usage of former and current melanoma treatment was assessed in melanoma patients. The probability of interaction was classified into four categories ranging from interaction unlikely (I), possible (II), likely (III), or no data (IV). The questionnaire was filled out by 1157 patients, of whom 1089 were eligible for evaluation. CAM usage was reported by 41% of melanoma patients, of whom 63.1% took BbCAM such as vitamins, trace elements, supplements, or phytotherapeuticals. Of 335 patients with former or current therapy, 28.1% used BbCAM. The melanoma treatment included interferon, radiotherapy, chemotherapy, BRAF-inhibitor, or other tyrosine kinase inhibitors and ipilimumab. On the basis of our model of likelihood of interaction, we found that 23.9% of those on cancer therapy and 85.1% of those also using BbCAM were at some risk of interactions. The main limitation of our study is that no reliable and comprehensive database on clinical relevant interactions with CAM in oncology exists. Most patients receiving a melanomaspecific treatment and using BbCAM methods are at risk for interactions, which raises concerns on the safety and treatment efficacy of these patients. To protect melanoma patients from potential harm by the combination of their cancer treatment and CAM usage, patients should systematically be encouraged to report their CAM use, while oncologists should be trained on evidence of CAM, and patient guidance for saver CAM use. Melanoma Res 27: Copyright 2017 Wolters Kluwer Health, Inc. All rights reserved. Melanoma Research 2017, 27: Keywords: cancer, complementary and alternative medicine, interactions, melanoma a Department of Dermatology, b Department of Medical Biometrie, Epidemiology and Informatics, University Medical Center Mainz, Mainz, c Department of Dermatology, University Medical Center Dresden, Dresden, d Department of Dermatology, Wald Klinikum Gera, Gera, e Department of Dermatology, University Medical Center Kiel, Kiel, f Department of Dermatology, University Hospital Cologne, Cologne, g Department of Dermatology, University Medical Center Freiburg, Freiburg, h Department of Radio-Oncology, Franziskus Hospital Bielefeld, Bielefeld, i Department of Radio-Oncology, Ruhr University Bochum, Bochum, j Department of Gynecology and Obstetrics, Clinic Offenburg, Offenburg, k Department of Dermatology, Klinikum Dortmund ggmbh, Dortmund, l Practice of Dermatology, Dresden, m Clinic Herzoghoehe Bayreuth, Bayreuth, n Institute of Occupational Medicine, University Hospital, RWTH Aachen University, Aachen and o Dr. Senckenberg Chronomedical Insitute, J.W. Goethe University Frankfurt, Frankfurt, Germany Correspondence to Carmen Loquai, MD, Department of Dermatology, University Medical Center Mainz, Langenbeckstrasse 13, Mainz, Germany Tel: ; fax: ; carmen.loquai@unimedizin-mainz.de *Dagmar Dechent and Jutta Huebner contributed equally to the writing of this article. Received 22 June 2016 Accepted 28 December 2016 Introduction In western countries, 40 to more than 90% of all cancer patients use complementary and alternative medicine (CAM) at some time point of their disease [1 4]. The reasons for doing so vary considerably and include strengthening the body and/or the immune system, reducing side effects and stress, detoxifying, and fighting the cancer while using CAM. The opportunity for an active engagement is one of the main reasons for patients All supplementary digital content is available directly from the corresponding author. to engage with CAM and for professionals to accept CAM [5 7]. Physicians and nurses point to positive mental effects and to the potential to alleviate side effects [7,8]. Although CAM has been ignored by conventional medicine for a long time, counseling facilities have been established in many cancer centers in more recent times. However, risks may arise from the side effects of biologicalbased CAM methods (BbCAM) and interactions may reduce the efficacy of cancer treatments or enhance the adverse effects of cancer medication. Most CAM methods allegedly do not have serious side effects. Furthermore, Copyright 2017 Wolters Kluwer Health, Inc. All rights reserved. DOI: /CMR

2 Interactions from CAM Loquai et al. 239 only a small percentage of all professionals are aware of risks arising from these interactions [6 8].Yet,nocom- prehensive monitoring of side effects exists as most CAM substances are not licensed as drugs, are not prescribed by oncologists, and bought and administered by the patient herself/himself. In a recent survey on breast cancer patients, we found that about three quarters of all CAM users use substances at risk for drug interactions [9]. Although data on CAM usage of patients with widespread cancers such as breast and gynecologic cancer have been published from different western countries, data on melanoma patients are missing. In a pilot study, we asked patients with melanoma taking part in a clinical study on their CAM usage, their goals, and reasons [10]. In this study, more than half of the patients reported being interested in CAM. Thus, we set out to conduct a survey on melanoma patients in seven German skin cancer centers to learn about their CAM usage and potential interactions with conventional medical therapies. Patients and methods The survey took place in seven German skin cancer centers from March 2012 until March Inclusion criteria were diagnosis of melanoma, age older than 18 years, and the ability to understand and sign the patient information (written in German) and to answer the questions. In the survey, we used the questionnaire that was pretested in a pilot study together with an additional question on the use of other regular drugs [10]. The standardized questionnaire on CAM has been developed by the working group Prevention and Integrative Oncology of the German Cancer Society. This questionnaire has already been used in several studies in print version, as an online questionnaire, and in interviews [9,11,12]. The questionnaire for patients (see Supplementary Material) comprised six sections: (1) Demographic data and data on the tumor. (2) Lifestyle and assumed etiology of the tumor. (3) Interest in CAM and source of information. (4) Current use of different CAM methods and satisfaction with the methods used. (5) Reasons to use or not to use CAM. (6) Drugs taken regularly. All questions were closed questions for which different answers were suggested (yes/no/i do not know; list of sources of information or list of etiological concepts); satisfaction was ranked using a Likert scale from 1 to 5. The lists were derived from sources and concepts described in the literature on CAM in oncology. In section 5, we questioned several statements that we also derived from the literature and from the expertise of the members of the working group. Patients were asked whether they agree, do not agree, or are indifferent. The physicians were asked to complete a second questionnaire on tumor stage, date of diagnosis, current therapy, further diseases that need drug treatment, further tumor diagnoses, and ECOG functional status. In this article, we present an analysis of the potential interactions of CAM substances with cancer treatments. As, to our knowledge, no single comprehensive database on herb drug interactions exists, we evaluated each combination of a cancer drug and complementary substances using several sources of information (the methodology has been described in detail before [9,13]): (1) The website of the National Library of Medicine of the USA ( ). (2) The website of the National Institute of Health ( (3) The website of the Memorial Sloan Cancer Center dedicated to information on herbs ( org/cancer-care/treatments/symptom-management/integrative-medicine). (4) The book by Cassileth and Lucarelli [14]. From these databases, we derived the data on potential interactions summarized in Table 1. For each patient reporting CAM usage with biologic substances, we analyzed potential interactions matching his/her comedication with the data from this table. As some patients did not specify the supplements that they were taking, we had to make assumptions derived from clinical practice and our different surveys on CAM usage: (1) Homeopathy was interpreted as highly diluted extracts that may not cause interactions. (2) Supplements of vitamins and trace elements: if not specified, we assumed that a mixture also containing vitamin C and E was taken. (3) Chinese teas are comprised of different herbs. As none of the patients reported on the content in detail, we considered four substances often used in oncological indications: astragalus, turmeric, ginger, and licorice. We classified the probability of interaction into four categories [9,13] ( html ): (1) Interaction unlikely, but may not be denied (no evidence in the literature on interaction); ( unlikely ). (2) Interaction possible ( possible ). (3) Interaction likely ( likely ). (4) No interaction. (5) No data.

3 240 Melanoma Research 2017, Vol 27 No 3 Table 1 Classification of risks of interactions between conventional therapy and the complementary and alternative medicine substances Conventional therapy Complementary and alternative medicine substance group Radiotherapy Chemotherapy Interferon Ipilimumab BRAF-inhibitor Other drugs Vitamins Selenium Other supplements Mistletoe Homeopathy Enzymes Chinese herbs and teas Medical mushrooms Anthroposophical medicine a = interaction is unlikely, but may not be denied; 2 = interaction is possible; 3 = interaction is likely. a As anthroposophical medicine most often comprises mistletoe in combination with highly diluted substances and phytotherapy, we decided to use likely. The classification was proposed by one author (J.H.) and consented by the experts from the working group PRIO (O.M., R.M., K.M., C.S.). In case of ambiguous data, we decided to grade the interaction as possible. Table 1 provides an overview of the resulting classification of risks of interactions between conventional therapy and the CAM substances. Ethical approval The study has been approved by the Ethic Committee of the Statutory Physician Board of Rhineland-Palatinate, Germany. Statistics IBM SPSS Statistics 20 (IBM Corp., Armonk, New York) was used for data collection and all statistics. Results We received 1157 questionnaires, 1089 of which were eligible for evaluation. Reasons for exclusions were no diagnosis of melanoma (n = 54), uncertain diagnosis of melanoma (n = 13), or age under 18 years (n = 1). The demographic, tumor-specific, and lifestyle data are shown in Table 2. The mean age of the participants was 59.3 (SD 14.7) years. The sex distribution was even (female: n = 501 vs. male: n = 496). About one third of the patients had a melanoma in stage I at diagnosis, whereas about 11% of the tumors were in tumor stage IV. Most patients (n = 929, 85.3%) had ECOG stage 0. To estimate the number of patients at risk of some type of interaction, we focused on those patients using BbCAM methods and matched these data with data from the physicians part of the questionnaire on former and current treatment using the risk estimation described in the Patients and methods section. Four hundred and forty seven participants reported using CAM (41.0%; 95% confidence interval: %). BbCAM (vitamins, trace elements, other supplements, and phytotherapeuticals as Chinese herbs) were taken by 282 (25.9%) patients (Table 3). Vitamins (10.4%), selenium (6.8%), and other supplements (14.7%) were most Table 2 Demographic, tumor-specific, and lifestyle data of melanoma patients (n = 1089) Patients [n (%)] Age group (years) No answer 85 (7.8) < (9.6) (46.4) (24.8) > (11.4) Sex No answer 92 (8.4) Male 496 (45.5) Female 501 (46.0) Education (years) No answer 31 (2.8) < (66.8) (30.4) Stage at first diagnosis a No answer 16 (1.5) In situ 8 (0.7) I 358 (32.9) II 292 (26.8) III 294 (27.0) IV 121 (11.1) ECOG a No data 42 (3.9) Asymptomatic (0) 929 (85.3) Symptomatic but completely ambulatory (1) 112 (10.3) Symptomatic, < 50% in bed during the day (2) 5 (0.5) Symptomatic, > 50% in bed, but not bedbound (3) 1 (0.1) a Data from the physicians questionnaire. Table 3 Biological-based complementary and alternative medicine usage among 1089 patients with melanoma (multiple answers possible) Complementary and alternative medicine methods Number of participants [n (%)] Vitamins 113 (10.4) Selenium 74 (6.8) Other supplements 160 (14.7) Homeopathy 91 (8.4) Chinese herbs and teas 70 (6.4) Enzymes 23 (2.1) Mistletoe 13 (1.2) Medical mushrooms 11 (1.0) Anthroposophic medicine 4 (0.4) often used (14.7%), followed by homeopathy (8.4%) and Chinese herbs and teas (6.4%). From 335 of the 1089 (30.8%) participants, we had specified information on former or current therapy. Of these,

4 Interactions from CAM Loquai et al (28.1%) used BbCAM. Of 259 patients with interferon, 66 (25.5%) and of 40 patients with radiotherapy 12 (30.0%) used BbCAM. Of 28 patients with chemotherapy, 12 reported using BbCAM (42.9%). Twenty-nine patients received a BRAF-inhibitor and nine (31.0%) used BbCAM. Of seven patients with Ipilimumab, three used BbCAM (42.9%). Six patients received other anticancer drugs such as tyrosin kinase inhibitors. Of these, one used BbCAM. Table 4 presents the number and likelihood of interactions for the different types of cancer treatment and BbCAM used. We found 63 interactions that we rated as likely (18.8% of all patients with cancer therapy and 67.0% of patients also using BbCAM) and 51 as possible (15.2% and 54.3%). In sum, 80 (7.3% of all participants in the survey, 23.9% of those on cancer therapy and 85.1% of those also using BbCAM) patients were at some risk of interactions. Discussion To our knowledge, this is the first survey reporting on the possible interaction of CAM use with antineoplastic treatment of patients with melanoma. Furthermore, it is one of the biggest surveys on CAM usage at all, with more than 1000 participants. Nearly a quater of the participants reported using biological-based CAM and a quarter of patients on cancer therapy are at risk for interactions. The rate is lower than the data we found with breast cancer patients [11]. Yet, considering patients being treated and using BbCAM, 85% are at risk, which is even more than the three quarters of the breast cancer patients we interviewed [9]. There are some limitations to our analysis. The most important limitation of our study is that no reliable and comprehensive database on clinical relevant interactions with CAM in oncology exists. Cross referencing between different databases shows considerable differences. Most data are derived from preclinical studies and we had to revert to assumptions and hypotheses [9]. Furthermore, we had to make some assumptions on the kind of CAM substance used as we did not ask the patients to specify type and dosage. The assumptions on the CAM usage are described under methods. To minimize patients risks, we decided to assume the worst case if no high-level evidence from clinical studies exists. That is, in case of only preclinical data, we assumed this risk as existing. In case of contradictory data, we decided to assume that an interaction exists. For example, we rated interactions from vitamins as probable as most preclinical data point to reduced effects on tumor cells if antioxidants are applied. Although no data exist on interaction from mistletoe, we decided to rate the interaction with interferon and ipilimumab as probable as mistletoe leads to some activation of the immune system. The same applies to medical mushrooms. In contrast, for homeopathy, any interaction seems unlikely as the substances are highly diluted. Moreover, we do not have exact data on whether patients used the substances directly together with the conventional therapy. However, data on interactions that would allow for a more detailed analysis of risks do not exist. Another limitation of our survey might be that patients may not have disclosed using CAM at all or did so only partly. The rate of nondisclosure to the physician in general is high and data are heterogeneous [15,16]. Despite these uncertainties, the rate of 85% of patients with coadministration of conventional therapy and BbCAM raises some concerns on the safety of a substantial number of patients with melanoma. One might state that such a number may not go unnoticed in clinical practice. Most caveats are derived from preclinical experiments or are based on presumed indirect interactions by metabolizing enzymes. Only rare clinical cases are reported scientifically. For vitamins and trace elements and other biological-based dietary supplements with well-defined content, data on risks are often contradictory (as for example for vitamin C) [17]. Even more difficult is the risk estimation for herbs and other drugs from ethnomedical systems. We found a substantial proportion of patients taking herbs form TCM, for which nearly no data exist on interactions [9]. Often, these preparations are not defined according to standards of western medicine and products sold in Europe may vary in composition. Furthermore, case reports point to the genuine potential of side effects of these mixtures. Table 4 Patients at risk of interaction by the different complementary and alternative medicine substances (fields without numbers: no patient used this combination, rating of risk; see Table 1) Number of patients at risk for interaction Complementary and alternative medicine substance Radiotherapy Chemotherapy Interferon Ipilimumab BRAF-inhibitor Tyrosin kinase inhibitors Vitamins 8 (likely) 3 (likely) 25 (unlikely) 3 (unlikely) 2 (unlikely) 1 (possible) Selenium 7 (unlikely) 3 (unlikely) 12 (unlikely) 3 (unlikely) 1 (unlikely) 1 (possible) Other supplements 9 (likely) 8 (likely) 39 (possible) 3 (possible) 3 (possible) 2 (possible) Mistletoe 1 (possible) 1 (likely) Homeopathy 1 (unlikely) 1 (unlikely) 22 (unlikely) 1 (unlikely) 2 (unlikely) Enzymes 1 (unlikely) 3 (unlikely) 8 (unlikely) Chinese herbs and teas 1 (likely) 3 (likely) 24 (likely) 1 (likely) 2 (likely) Medical mushrooms 1 (possible) 1 (likely) Anthroposophical medicine 2 (likely)

5 242 Melanoma Research 2017, Vol 27 No 3 The question is by whom and how side effects and interactions should be noticed. Interactions may lead to lower efficacy against cancer yet, lower drug efficiency most probably will not be attributed to CAM usage by the patient or the physician. Side effects such as for example liver or renal toxicity will most probably be attributed to cancer treatment. As no registries exist and CAM usage is not regularly reported in clinical studies, nearly no data exist that help to discover interactions in the clinical setting of cancer treatment. The question is how to protect patients from adverse events because of CAM usage. If we accept that most patients prefer BbCAM to other types [1,3,18], four steps are mandatory to ensure safety: (1) Evidence must be collected systematically. Registries could help to collect data from routine care as well as from clinical studies if patients were systematically encouraged to report their CAM use. (2) CAM should be included in national practice guidelines pointing to evidence as well as missing evidence and risks. (3) Patients should be encouraged to talk to their oncologists about CAM and oncologists should be encouraged to respect these patients aims and provide guidance for safer CAM use. (4) Oncologists should be trained on evidence of CAM and skills of communication on CAM. The aim of all these activities is not to eliminate CAM from modern oncology, but to make it part of scientificbased treatments. Compliance of patients should be high because patients will voluntarily harm themselves by combining conventional and complementary treatments with unknown risks. Knowing patients motivation to use CAM will be a useful tool for the individual treatment plan. In contrast, it will be very useful to explore the individual patient s aims in using CAM and decide whether there is an evidence-based offer from the field of CAM that can be recommended. Acknowledgements Conflicts of interest M.K. has received advisory and speaker honoraria from Roche, BMS, MSD, and Novartis. M.K. has received travel reimbursement from Roche, MSD, and Janssen. P.K. has received advisory and speaker honoraria from Roche, BMS, MSD, Teva, and Novartis. P.K. has received travel reimbursement from Roche, BMS, and Teva. C.L. has received advisory and speaker honoraria from Roche, BMS, MSD, Amgen, and Novartis. C.L. has received travel reimbursement from Roche, BMS, MSD, and Amgen. F.M. has received advisory and speaker honoraria from Roche, BMS, MSD, Amgen, and Novartis. F.M. has received travel reimbursement from Roche, BMS, and MSD. D.N. has received advisory and speaker honoraria from MSD, BMS, Roche, Novartis, Almirall, and MEDA. For the remaining authors there are no conflicts of interest. References 1 Molassiotis A, Fernadez-Ortega P, Pud D, Ozden G, Scott JA, Panteli V, et al. 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