Press report

Report on the 7th Interdisciplinary Mistletoe Symposium:
The mistletoe in tumor therapy - basic research and clinic

The 7th Mistletoe Symposium took place in the European Academy Otzenhausen (Nonnweiler / Saarland) from 7-9 November 2019. Over 100 scientists and doctors from various disciplines met to present and intensively discuss current results from research and clinic on mistletoe extracts and their use in tumor therapy. For many patients in Germany, Austria and Switzerland, mistletoe preparations are used in addition to conventional forms of therapy such as chemotherapy or radiation based on medical prescription and control in tumor therapy. The aim of the mistletoe symposium was therefore to build bridges between different therapeutic directions in oncology and to illuminate mistletoe therapy on the basis of basic research, pharmacological data, preclinical and clinical studies, individual case observations and also psycho-oncology. Data on mistletoe and mistletoe therapy were presented in over 30 overview and short presentations and almost 30 posters.

The symposium was organized and funded by the Karl and Veronica Carstens Foundation and the Society of Anthroposophic Doctors in Germany (GAÄD) together with the Society for Medicinal Plant and Natural Product Research (GA), the German Pharmaceutical Society (DPhG), the Society for Phytotherapy (GPT) and the Central Association of Doctors for Naturopathic and Regulation Medicine (ZAEN). Cooperation partners were the Working Association for Pharmaceutical Technology (APV) and the European Society of Integrative Oncology (ESIO).

The conference was led by Dr. Rainer Scheer from the Carl Gustav Carus Institute (Niefern-Öschelbronn) and Prof. Dr. Harald Matthes, Hospital Havelhöhe, Charité - University Medicine (Berlin). In the scientific organization they were supported by Prof. Dr. Alban (Kiel), Prof. Dr. Becker (St. Ingbert), Prof. Dr. Beer (Hattingen), Prof. Dr. Blaschek (Kiel) Prof. Dr. Klein (Tübingen), Prof. Dr. Kreis (Erlangen), Dr. Leneweit (Niefern-Öschelbronn), Dr. Spahn (Mainz) and Dr. Stange (Berlin).

In the following, some interesting contributions will be discussed briefly. It has recently been shown (Prof. Braun, Institute of Plant Genetics, University of Hanover) that the mitochondrial respiratory chain, which normally takes place in animals, fungi and plants with the participation of complexes I - IV, is very unusual in the mistletoe plant. The NADH dehydrogenase complex (complex I) is not present in Viscum album, which shouldn't allow a functioning respiratory chain. Here, however, complexes III and IV form a super complex and a number of alternative oxidoreductases are available. As a result, the respiratory chain for energy production (ATP) can be less efficient, but still life-supporting for the mistletoe.

In a contribution by Prof. Pfüller (Univ. Hamburg), potential active ingredients in mistletoe were discussed. These include above all mistletoe lectins (ML-I, ML-II, ML-III, CBL) and viscotoxins. It was shown that various methods of isolating and storing mistletoe lectins and viscotoxins can have a significant impact on their stability and thus their reactivity. Pure mistletoe lectins can be made available in gram quantities and remain stable for years in suitable buffers as a suspension at low temperatures, whereas isolated viscotoxins have not yet been available in such high amounts, but as lyophilisate they have high stability at room temperature. Isolated mistletoe lectins or viscotoxins are therefore available for detailed investigations of mechanisms of action and interactions with the immune system as well as for use as standard substances for analysis.

Colloidal formulations of mistletoe extracts can be used for intravenous treatment in high doses (Dr. Leneweit, Carl Gustav Carus Institute, Niefern-Öschelbronn). For this purpose, heparin-coated liposomes (protection against the body's own immune system) are produced in special processes, which contain mistletoe extracts and which then can release their active components such as lectins in the target tissue.

The mistletoe occurs on different host trees and its ingredient pattern can thereby be influenced. Corresponding mistletoe extracts from mistletoe from various deciduous trees (apple tree, oak, elm) were examined in more detail by chromatography coupled with electrospray ionization (PD Dr. Baumgartner, Inst. Hiscia, Arlesheim, CH). In a metabolomic analysis, host tree-specific signal clusters and main signals could be assigned. An extract of elm mistletoe e.g. has a higher arginine content than the others, while apple mistletoe extract was distinguished by the presence of sinapoyl-quinic acid. Such host tree-specific ingredients in mistletoe extracts may be important for their pharmacological activity which requires further clarification.

An overview of stressful exhaustion (fatigue) and sleep disorders (insomnia) as concomitant diseases in breast cancer patients was offered by PD Dr. Kröz (Research Institute Havelhöhe, Berlin). According to various studies, there are several treatment options for both closely associated additional disorders, e.g. exercise therapy (yoga, aerobics), psychoeducation, sleep training or treatment with mistletoe preparations. Their contribution to improving these diseases has been demonstrated in randomized, controlled trials.

A controlled, randomized study in breast cancer patients showed that mistletoe therapy can improve symptoms of fatigue, which is accompanied by an improvement in some inflammation-specific immune parameters (Dr. Reif, Society for Clinical Research, Berlin).

Dr. Kienle (IFAEMM, Univ. Witten / Herdecke, Freiburg) provided an overview of current developments in clinical research on mistletoe therapy in cancer. In various studies, which often differ in design and quality, however, the influence of mistletoe therapy on survival time, on tumor growth and spread, on quality of life and on tolerance of surgical interventions or chemo and / or radiation therapy -therapy was examined. In general, there are the best indications of an improvement in the quality of life and the tolerability of treatment with chemotherapeutic drugs. In a controlled study of pancreatic cancer, a significant increase in survival was found. With local application of high doses of mistletoe extracts, tumor remission was also observed in various types of cancer.

Ms. Wode (Regional Cancer Center Stockholm, SE) reported on an ongoing prospective, randomized, multicenter, double-blind, placebo-controlled phase III study with 290 patients with primary and recurrent pancreatic cancer. Of particular interest are the effects of repeated subcutaneous application of mistletoe extracts on survival and quality of life as well as on various immune parameters such as the formation of antibodies against mistletoe lectins, the amount of cytokines, eosinophils and neutrophils or the NK cell cytotoxicity. We can look forward to the results of the study that has not yet been completed; initial results indicate a slightly longer survival time and a significant improvement in the quality of life.

Glioblastoma is the most common malignant and aggressive brain tumor in adults; despite intensive treatment, the mean survival time is usually less than 20 months. The influence on glioma cell mobility by mistletoe extracts and non-glycosylated mistletoe lectin-I (recombinantly produced in E. coli) was investigated specifically (Prof. Naumann, Hertie Institute for Clinical Brain Research, University of Tübingen). It could be shown that the migration ability of glioma cells under mistletoe treatment (intratumoral or subcutaneous) was reduced by changing the expression of genes that control migration, invasion and cell adhesion (TGF-β signaling pathway). Intratumoral application of mistletoe preparations could thus be helpful as an adjuvant therapy.

In pediatric oncology, in addition to chemotherapy and radiation therapy, mistletoe therapy is also carried out, sometimes also by very high-dose intravenous administration of mistletoe extract in 0.9% NaCl solution (Dr. Zuzak, Community Hospital Herdecke, Herdecke). It has been shown that etoposide and cisplatin resistant neuroblastoma cell lines were also more resistant to mistletoe treatment than the original cell lines. For combinations of chemotherapy and mistletoe therapy as well as radiation and mistletoe therapy, synergistic effects with regard to reduced colony formation could be determined.

Ms. PD Dr. Jüngel (Clinic and Polyclinic for Urology and Pediatric Urology, University of Mainz) presented preclinical studies on the therapy of urological tumors (renal cell, bladder and prostate carcinomas) with increasing concentrations of various mistletoe extracts (different host trees). A concentration-dependent effect on tumor cell growth and proliferation was shown. Growth inhibition correlated with a changed profile of integrin expression (integrins α-3, α-5, α-6) and a standstill of the cell cycle in the G0 / G1 phase or in the S phase. The data speak for the use of adjuvant mistletoe therapy in urological tumor diseases.

Numerous studies of mistletoe extracts concentrate on the mistletoe lectins and the viscotoxins. Mistletoe plants contain a number of other interesting ingredients, including various triterpenic acids such as oleanolic acid and betulinic acid. These lipophilic compounds are only present in small concentrations in conventional aqueous mistletoe extracts. Prof. Seifert (Otto Heubner Center for Pediatric and Adolescent Medicine, Charité, Berlin) reported on a process in which the ingredients of a lipophilic extract were solubilized with the help of cyclodextrins so that water-soluble extracts could be obtained that were rich in triterpenic acids (especially oleanolic acid). These were used in combination with conventional extract rich in mistletoe lectin for testing on various tumor cell lines (leukaemias, sarcomas, neuroblastomas, breast cancer, carcinomas). Apoptosis could often be induced with the combined extracts. Good efficacy has also been demonstrated in xenograft mouse models with patient tumor cells. The data suggest a promising application in tumor patients.

Dr. Müller (Clinic for Naturopathy, Hattingen) reported on a model for integrative oncology, which was realized together with the St.-Josef-Hospital at the Ruhr-Univ. Bochum. For patients with various tumor diseases, repeated consultations are held, in which, in addition to an oncologist, a doctor specializing in naturopathy is also involved. This enables different naturopathic forms of therapy, including mistletoe therapy, to be better communicated, which has a positive impact on the tolerance of conventional forms of therapy and improves the general well-being of the patient.

In addition to chemotherapy, an application of mistletoe extracts (oak mistletoe) by catheter in partially high concentrations was carried out in over 100 patients with primary liver carcinomas (Prof. Galun, Clinical Center of Serbia, Belgrade, SRB). The median survival in the mistletoe group increased from 246 to 430 days compared to the control group. If mistletoe therapy was associated with febrile episodes, this led to a slightly improved survival time. The background may be stimulation of the immune system.

Prof. Dingermann (Inst. Pharm. Biology, Goethe University Frankfurt) reported on the use of checkpoint inhibitors in tumor therapy, which has become increasingly important in recent years. Immune checkpoints are based on surface proteins with specific receptors that, together with their ligands, prevent the immune system from attacking the body's own cells. If these surface proteins are strongly expressed in tumors, the tumor cells avoid attack by the immune system. Checkpoint inhibitors are monoclonal antibodies (ending -mab) that bind to a receptor (e.g. PD-1 = programmed cell death receptor 1) or to its ligands (e.g. PD-L1 = programmed cell death receptor-ligand 1). The inhibitory signaling molecule PD-1 is mainly found on the surface of activated T cells (a checkpoint). Its ligands PD-L1 are expressed on the surface of cells of the hemodynamic system, the endothelium and epithelia, while PD-L2 is mainly expressed in organs such as the lungs and intestines. Binding of PD-1 to its ligands prevents an attack on the body's own cells. For camouflage (as normal body cells), tumor cells e.g. overexpress PD-L1; thereby immune cells such as cytotoxic T cells slow down in their activity against these tumor cells. The checkpoint inhibitor Nivolumab e.g. binds to PD-1, which can no longer bind to PD-L1 on tumor cells, and thus an effective immune defense against the tumor cells can be induced. In some cases, remarkable treatment successes were achieved with various types of tumor. However, the activation of the immune system by checkpoint inhibitors can also cause more or less severe autoimmune side effects such as fatigue, rash, itching, diarrhea and nausea.

Mistletoe and immune therapy was the subject of a contribution by Dr. Weissenstein (Association for Cancer Research, Hiscia Institute, Arlesheim, CH). Current research strives to find ways to influence immune checkpoints and thus the immunogenicity of tumors. Incidentally, mistletoe lectins also have an agonistic property for toll-like receptors (TLRs), which play a central role in innate immunity. Among other things, TLRs recognize pathogen-specific patterns (proteins, lipopolysaccharides, carbohydrates) on pathogenic agents that do not occur on the body's own cells. Mistletoe extracts can activate components of the innate and adaptive immune systems, including the release of pro-inflammatory cytokines or the maturation of dendritic cells. By presenting tumor antigens, tumor-specific cytotoxic T lymphocytes can then be activated. The elucidation of the effect of mistletoe lectins on immune checkpoints requires further intensive research.

Prof. Matthes (Hospital Havelhöhe, Charité - University Medicine, Berlin) reported on the status of mistletoe therapy for breast and lung cancer. There are 14 comparative studies available for mistletoe therapy for breast cancer that accompanies radio- and chemotherapy. In particular, with a good tolerance, the quality of life is improved and fatigue is reduced. There are 7 controlled clinical studies on the treatment of lung cancer with accompanying mistletoe therapy. Here, too, a positive influence on the quality of life was found. When administered directly into the lung tumor, a reduction in tumor mass and a significant increase in survival time were also found. Side effects of checkpoint inhibitors were alleviated by mistletoe therapy.

The therapy of non-small cell lung cancer with checkpoint inhibitors was also combined with mistletoe therapy (Dr. Grah, Hospital Havelhöhe, Berlin). A prospective observational study that has not yet ended provisionally showed that adjuvant mistletoe therapy can improve the quality of life.

The survival time of patients with metastatic non-small cell lung cancer with adjuvant mistletoe therapy was documented (B. Matthes, Hospital Havelhöhe, Berlin). Of 158 patients, 108 received chemotherapy and 50 received additional mistletoe therapy. The survival time of combined therapy was increased from 8 to 17 months on average. The tolerability of chemotherapy was improved by mistletoe therapy.

In 95 patients with non-metastatic breast cancer, extensive consultation and biography discussions were held before, during and after oncological treatment (Dr. Schad, Hospital Havelhöhe, Berlin). It was shown that significant improvements in terms of general health, quality of life, fatigue and emotional, psychological, social and cognitive problems could be achieved.

Dr. Thronicke (Hospital Havelhöhe, Berlin) examined the impact of financial stress problems of patients with lung or breast cancer on their quality of life and survival. A total of 314 patients were interviewed. Financial stress problems were associated with anxiety, discouragement, and depression. Younger patients were particularly affected. There were effects on the general state of health.

Prof. Matthes (Hospital Havelhöhe, Charité - University Medicine, Berlin) reported on psycho-oncology, i.e. the psychological care of patients with lung or breast cancer. If this is carried out intensively, the quality of life of affected persons will improve and the survival time may also be extended. Up to 30% of cancer patients develop mental disorders, which can largely be prevented by psycho-oncology. According to current knowledge, there is no typical cancer psyche. Common problems for the sick are that they feel to act without emotions or that they feel unable to act. Different therapy concepts can be helpful: art therapy, yoga, meditation, movement exercises and also mistletoe therapy. Discussions about social relationships, family involvement, discussions of the future and the possibilities of shaping the future are important.

Dr. Grah (Hospital Havelhöhe, Berlin) went on to speak about the peculiarities of the psycho-oncological care of patients with lung cancer. Self-guilt feelings play a major role, especially among smokers. The disease processing is often problematic, the expectation is that there is a risk of imminent, terrible death. Distress, anxiety and depression affect 50-60% of the patients. At the Hospital Havelhöhe, an additional therapy program was developed for these patients, which could be coupled with mistletoe therapy (IV application).

Dr. Flür (practice in Gevelsberg) presented individual case reports on tumor patients with accompanying mistletoe therapy. These concerned 3 patients with B-cell lymphoma and one breast cancer patient. The observation period was between 5 and 10 years. The tolerability of mistletoe therapy with different preparations was good even with high doses. Mistletoe therapy had no negative impact on therapy with checkpoint antibodies. A positive influence on the quality of life and the immune status allowed long-term use of conventional therapies.

Dr. Wiebelitz (Hospital Prignitz, Perleberg) reported on intraperitoneal, intrapleural and intratumoral application of mistletoe extracts. The 6 patients suffered from metastatic tumors (breast cancer, small cell lung cancer, peritoneal cancer). Various mistletoe preparations and dose increases up to sometimes very high doses were used (e.g. Abnobaviscum fraxini 60 - 1200 mg IV). An improvement in the general condition was found and in some cases also a sustainable tumor control.

Systemic inflammatory reactions after i.v. administration of mistletoe extracts in patients with advanced tumor diseases were investigated in more detail (Dr. Kuehn, Center for Integrative Oncology, Olten, CH). Flow cytometric studies and cytokine and acute phase protein analyses were carried out and body temperature was determined. Intravenous mistletoe application (20-100 mg once a week) raised body temperature and stimulated the immune system. An increase in the number of white blood cells and neutrophils was found, also an increased concentration of pro-inflammatory cytokines (e.g. IL-12). Bone marrow stimulation resulted in a higher number of lymphocytes after 24 h, the neutrophil: lymphocyte ratio decreased and the acute phase protein level increased. Mistletoe application stimulates the cellular and humoral immune system and promotes the formation of immune-competent cells in the bone marrow.

Prof. Bar-Sela (Emek Medical Center, Afula, ISR) also reported on intravenous application of mistletoe extracts in tumor patients. 20 corresponding studies were evaluated. In principle, higher doses can be used than with subcutaneous application. The quality of life, fatigue or shortness of breath in lung cancer patients were often influenced positively. In a started Phase I study, intravenous doses of 2,000 mg mistletoe extract were well tolerated. Further results of the study have to be awaited.

In osteosarcoma patients, maintenance therapy after a second relapse with etoposide (topoisomerase inhibitor) or mistletoe extract (Viscum album Fermentatum Pini, s.c. application) was carried out over a longer period of time (Dr. Reif, Society for Clinical Research, Berlin). After 10 years, disease-free survival was significantly better with mistletoe therapy than with etoposide.

The past development of different directions in integrative medicine was highlighted by Dr. Meyer (General Practitioner, Nuremberg). Complementary medicine and conventional medicine can usefully complement each other. This can result in more effective healing methods and improved health. In addition to medical measures, also the social life, the culture, the education, the society and the environment have an influence on health and healing processes that should not be underestimated.

Dr. Reif (Society for Clinical Research, Berlin) reported on the influence of supplementary mistletoe therapy on pain and painkiller consumption in pancreatic tumor patients, who often already had metastases in the abdomen, back or legs. With adjuvant mistletoe treatment  (subcutaneous application in increasing doses up to 10 mg / 3 times a week), the pain decreased and pain medication consumption was reduced.

Prof. Ostermann (Univ. Witten / Herdecke) provided a systematic overview and a meta-analysis on the influence of mistletoe therapy (Iscador) on the survival time of cancer patients. Various databases were used to search for corresponding publications and clear inclusion criteria were raised. 82 controlled studies were evaluated, which concerned different types of tumors. The best effect of mistletoe treatment on prolonged survival was in cervical cancer, the least effects were found in lung tumors. The general hazard ratio was 0.59 in favor of mistletoe therapy. The data suggest an improvement of survival in tumor diseases through adjuvant mistletoe therapy.

In two interesting evening lectures, the history of medicine, naturopathy and phytotherapy was presented against the background of political and social events and changing world views (Prof. Beer, Clinic for Naturopathy, Hattingen) as well as a look at the self-management of patients in the present and future health system as a challenge for the future (Annette Bopp, journalist and author, Hamburg).

In two poster sessions, many interesting studies on the ingredients of mistletoe and the use of mistletoe extracts were shown. Here was the good opportunity to have intensive discussions directly with the authors.

The mistletoe symposia have taken place every four years since 1995, so the next symposium is to follow in November 2023. Further information on all mistletoe symposia is available at this homepage. The abstracts of the contributions to the 7th Mistletoe Symposium are published in Phytomedicine 61 (2019) Supplement 1 (Elsevier) in English and are freely available on the Internet at https://www.sciencedirect.com/journal/phytomedicine/vol/61/suppl/S1 . As in the past, the detailed articles will probably be published as a book by the KVC publishing house (Karl and Veronica Carstens Foundation) by the end of 2020.

Prof. Dr. Wolfgang Blaschek, December 1, 2019

Further publications:

Newsletter of the Society for Medicinal Plant and Natural Product Research, pp. 23-24.