MISTLETOE IN TUMOUR THERAPY
Basic Research and Clinical Practice
8th Mistletoe Symposium
9–11 November 2023
Nonnweiler-Otzenhausen, Germany
Publication: Journal of Integrative and Complementary Medicine
Volume 29, Issue Number S1
LECTURES OF ONLINE TRAINING “PRACTICE OF MISTLETOE THERAPY”
1. Immunology of Mistletoe Extracts
Reinhild Klein
Department of Internal Medicine II, University of Tuebingen, Tübingen, Germany
E‐mail address: [email protected]‐tuebingen.de
Mistletoe extracts are applied to patients with malignant tumors or chronic inflammatory disorders in order to enhance tumor defense and modulate immunoregulatory functions. A lot of in vitro and in vivo studies are available, showing that different antigens present in these extracts can modulate various cell types of the innate and the adaptive immune system. However, one is still confronted with an equation with multiple unknowns – different mistletoe antigens, different components of the immune system, altered immune system in tumor patients, different kinds and stages of tumors etc. Also, the various kinds of application – subcutaneously, intratumorally, orally – have to be taken into consideration.
Mistletoe lectin (ML‐1) is responsible for a variety of immunological reactions, but also other antigens such as viscotoxins or further lectins present in mistletoe extracts could be shown to be involved. Thus, it became evident that the different components can interact with Toll‐like receptors on antigen presenting cells but also with macrophages, natural killer cells, neutrophils, and eosinophils hereby altering the inflammatory response and the innate immune system. Furthermore, it was shown that mistletoe extracts activate specifically T‐ and B‐cells leading to mistletoe‐specific cellular immune responses and the production of antibodies towards its components. Whether they may activate also tumor‐specific immune responses – probably when injected intratumorally by inducing apoptosis and release of tumor antigens – has still to be evaluated.
Despite all efforts during the last 30 years in analyzing the effect of mistletoe extracts on immunocompetent cells it is still a matter of debate whether the observed alterations of immunological reactions during mistletoe therapy have, indeed, a positive effect on tumor defense; correlations with the clinical outcome including lifetime extension and life quality are, therefore, an important task for further studies. Moreover, these immunological effects of mistletoe extracts may explain, why this kind of therapy may be helpful also in other chronic inflammatory disorders beyond cancer.
2. Current State of Clinical Studies on Mistletoe Therapy in Oncology, Including Systematic Reviews, Meta‐Analyses and Guidelines
Matthias Rostock
University Cancer Center Hamburg (UCCH), Universitätsklinikum Hamburg‐Eppendorf, Germany
E‐mail address: [email protected]
Current systematic reviews of mistletoe therapy in oncology have led to very different assessments. Ostermann et al. [2020] confirmed the antitumoral efficacy of fermented mistletoe extract in their systematic review of controlled trials. Regarding non‐fermented mistletoe extracts, Loef and Walach [2020 and 2022] saw both anti‐tumor efficacy and efficacy regarding quality of life. Freuding et al. [2019 a and b], on the other hand, did not report any positive effects of mistletoe therapy in two systematic reviews evaluating its effects on survival, tumor response, and quality of life.
As an example of the use of mistletoe extract in adjuvant therapy, randomized controlled trials (RCTs) have repeatedly been carried out with breast cancer patients during adjuvant chemotherapy. An improvement in quality of life (QoL) could be shown with different QoL questionnaires, also in two placebo‐controlled trials [Semiglasov 2004 and 2006], but only in two smaller RCTs with current chemotherapy concepts [Tröger et al. 2009 and 2014a].
As an example of the use in palliative care, an RCT with advanced pancreatic cancer patients compared a group receiving best supportive care plus mistletoe extract with a group receiving best supportive care alone and showed improvements in both quality of life as well as overall survival [Tröger et al. 2013 and 2014b]. It currently remains to be proven whether a recently completed replication attempt through a randomized controlled double‐blind trial in Sweden will succeed.
Based on the evaluation of current data, the S3 guideline on complementary medicine in the treatment of oncological patients, which was first published in 2021, did not result in any recommendation for or against the prescription of mistletoe extract with the aim of prolonging survival. However, the therapeutic use of mistletoe extract can be considered with the aim of improving the quality of life of cancer patients, according to the guideline.
A continuous evaluation of the effects of mistletoe therapy based on methodologically high‐quality studies is essential. Such evaluation efforts should reflect the rapidly changing therapy concepts in oncology. Of particular interest is the safety and effectiveness of mistletoe therapy when used in combination with immune checkpoint inhibitors, to give one example.
References
Ostermann T, Appelbaum S, Poier D, Boehm K, Raak C, Bussing A: A systematic review and meta‐analysis on the survival of cancer patients treated with a fermented Viscum album L. extract (Iscador): An update of findings. Comp Med Research 2020:1‐9.
Loef M, Walach H: Quality of life in cancer patients treated with mistletoe: a systematic review and meta‐analysis. BMC Complementary Medicine and Therapies 2020;20:227.
Loef M, Walach H: Survival of cancer patients treated with non‐fermented Mistletoe extract: A systematic review and meta‐analysis. Integrative Cancer Therapies 2022;21: 1–10.
Freuding M, Keinki C, Micke O, Buentzel J, Huebner J: Mistletoe in oncological treatment: a systematic review: Part 1: survival and safety. J Cancer Res Clin Oncol 2019;145:695‐707.
Freuding M, Keinki C, Kutschan S, Micke O, Buentzel J, Huebner J: Mistletoe in oncological treatment: a systematic review: Part 2: quality of life and toxicity of cancer treatment. J Cancer Res Clin Oncol 2019;145:927‐939.
Semiglasov VF, Stepula VV, Dudov A, Lehmacher W, Mengs U: The standardised mistletoe extract PS76A2 improves QoL in patients with breast cancer receiving adjuvant CMF chemotherapy: a randomised, placebo‐controlled, double‐blind, multicentre clinical trial. Anticancer Res 2004;24:1293‐1302.
Semiglazov VF, Stepula VV, Dudov A, Schnitker J, Mengs U: Quality of life is improved in breast cancer patients by standardised Mistletoe extract PS76A2 during chemotherapy and follow‐up: a randomised, placebo‐controlled, double‐blind, multicentre clinical trial. Anticancer Res 2006;26:1519‐1529.
Tröger W, Jezdić S, Ždrale Z, Tišma N, Hamre HJ, Matijašević M ‐ Quality of life and neutropenia in patients with early‐stage breast cancer: A randomized pilot study comparing additional treatment with Mistletoe extract to chemotherapy alone. Breast Cancer: Basic and Clinical Research 2009:3 35–45.
Tröger W,Galun D, Reif M,Schumann N,Stankovic´ N,Milic´evic´ M: Viscum album [L.] extract therapy in patients with locally advanced or metastatic pancreatic cancer: A randomised clinical trial on overall survival. Eur J Cancer 2013;49:3788‐97.
Tröger W, Cdrale Z, Tišma N, Matijaševi M.: Additional therapy with a Mistletoe product during adjuvant chemotherapy of breast cancer patients improves quality of life: An open randomized clinical pilot trial. Evidence‐Based Complementary and Alternative Medicine 2014a.
Tröger W, Galun D, Reif M, Schumann A, Stankovic N, Milićević M: Quality of life of patients with advanced pancreatic cancer during treatment with mistletoe ‐ a randomized controlled trial. Dtsch Aerztebl Int 2014b;111:493‐502.
3. Mistletoe Therapy in Clinical Application: Real World Data and Guidelines
Friedemann Schad1,2
1Research Institute Havelhoehe at the Hospital Gemeinschaftskrankenhaus Havelhöhe, Berlin, Germany, 2Oncological Center and Department of interdiscplinary Oncology and Palliative Care, Hospital Gemeinschaftskrankenhaus Havelhöhe, Berlin, Germany
E‐mail address: [email protected]
The treatment with extracts of the European white‐berry mistletoe (Viscum album L, VA) has been shown to improve health‐related quality of life (HRQL), reduce standard‐oncological and cancer‐related side effects, and mediates the prolonged survival of oncological patients. This may be resembled by the fact that the international ASCO‐endorsed SIO guideline recommends that VA extracts can be utilized to improve the HRQL of breast cancer patients. In addition, our national guideline (S3 Leitlinie) for complementary therapy recommends VA extracts to be used in addition to standard oncological therapy for the improvement of health‐related quality of life (HRQL). Recent systematic reviews and meta‐analyses attest VA extracts their HRQL‐improving, survival‐prolonging and cancer‐related fatigue reducing effects of VA. In addition to randomized controlled trials, these systematic reviews increasingly include the results of real‐world data (RWD) studies in their analyses. Real‐world evidence (RWE) research has become increasingly important in health care decision making over the past decade. Treatment decisions based on RWE can help target specific patient subpopulations that will effectively benefit from a particular treatment and may result in cost saving aspects as well. RWE research can be used to study the benefits and applications of integrative oncology therapies, including mistletoe therapy. In the near future, registry data as primary data in non‐interventional studies or arms of clinical trials will also contribute to the development of RWE. This presentation will consider the aforementioned aspects in the field of mistletoe research, examples from guideline‐based proposals, results from systematic reviews as well as RWD research.
4. Mistletoe Therapy as a Basic Care Intervention for Patients with Cancer in General Medical Practices
Frank Meyer
Primary‐Care joint practice for General and Integrative Medicine, Nuremberg, Germany
E‐mail address: [email protected]
For about three decades, we have witnessed the global development of integrative oncology as an academic field that has gained increasing importance in universities and clinics and begun to penetrate and even transform conventional medicine from the top‐down. The concepts of this novel approach primarily aim to offer evidence‐based complementary and traditional therapeutic options which are in‐line with the current state of clinical research and can be seamlessly integrated into standardized, guideline‐based procedures – to individuals affected by cancer. In Central Europe, an independent integrative cancer therapy had already been established since the introduction of mistletoe therapy for cancer in the second decade of the 20th century.
This is mainly applied at the base of the healthcare system in general practitioners' practices, as well as a few naturopathic and anthroposophical clinics, with the application of the European mistletoe (Viscum album L.) as a central element. Its holistic approach, with origins in anthroposophical and naturopathic medicine, is based less on academic traditions and more on the individual preferences of patients who specifically seek out holistic or naturopathic practices, the individual medical expertise and intuitive knowledge of the treating physicians, and the complementary concepts and methods in which such physicians are trained in addition to conventional medicine.
Considering both the academic‐rational and intuitive‐practical integrative approaches, as a long‐time practitioner in a walk‐in practice, I will discuss the importance and special aspects of mistletoe therapy in the basic care of patients with cancer in an ordinary general practice setting. I will argue that mistletoe therapy and other holistic, complementary, or integrative treatments should not be reserved solely for specialized clinical oncological centers but are increasingly important and must remain available as part of daily primary care for all patients with cancer and all common cancer‐associated issues.
5. The Future of Mistletoe Therapy
Harald Matthes
Charité, University of Berlin, Germany, and Community Hospital Havelhöhe, Berlin, Germany
E‐mail address: [email protected]
Mistletoe therapy in oncology shows the greatest quality‐of‐life‐improving effect as an adjuvant when chemotherapy and radiation are administered simultaneously.
The data on the improvement of quality of life through mistletoe therapy is quite heterogeneous for the different tumour entities. The best data are available for breast carcinoma. The data on the prolongation of life through mistletoe therapy is less reliable for the various tumour entities.
Further studies and real‐world data (RWD) must be conducted in order to further validate the overall survival extension in the various tumour entities.
Future research questions include whether other forms of mistletoe application, such as intravenous and intratumoral forms of application, have an increased effect. Adjuvant mistletoe administration during cytostatic chemotherapy and radiotherapy is well established. Only few data are available on the improvement of tolerability of checkpoint/PD‐1 inhibitor therapy with mistletoe.
Basic data on combinations of an aqueous extract in combination with a lipophilic extract (mistletoe with triterpenes = mistletoe TT) indicate a clear enhancement of the effect of such mistletoe extract in animal experiments. Clinical data in humans are completely lacking here and are reserved for future research. Future investigations are of great interest as to whether aqueous and lipophilic extract as a total extract or also applied separately leads to analogous clinical effects.
While the majority of mistletoe studies refer to an antitumour effect, mistletoe also has an immunomodulating and immunostimulating effect as well as a fever‐inducing effect, which should be systematically investigated in the future to expand the indications for autoimmune and rheumatic diseases. The first very interesting indications for mistletoe extracts are in the treatment of post‐Covid and post‐Vac syndrome. The potential of mistletoe therapy in its application, routes of administration and indications outside of oncology must be further explored in the future.
6. Mistletoe Therapy in Clinical Applications Other than Oncology (e.g., in Autoimmune Diseases; Post/Long Covid; Rheumatology, Sarcoidosis etc.)
Severin Pöchtrager
Klinik Arlesheim, Arlesheim, Switzerland
E‐mail address: severin.poechtrager@klinik‐arlesheim.ch
Mistletoe therapy plays a central role in integrative cancer therapy. There is a broad range of scientific data, supporting its efficacy. But what about using mistletoe therapy outside of oncology? Actually, mistletoe therapy is applied in a number of fields beyond oncology. It is an important remedy in the treatment of autoimmune diseases, such as rheumatoid arthritis or collagenoses. It is also used to treat pain in arthrosis or complex pain syndromes such as fibromyalgia.
A disease which came into awareness in is the post‐ and/or long‐COVID syndrome, for which a variety of therapeutic measures have been researched in the last few years. Many anthroposophical hospitals in Germany and Switzerland, as well as General Practitioners have implemented mistletoe therapy to tackle this condition. Unfortunately, we still have to gather systematic data about its efficacy.
In a case report, I report about clinical observations about the efficacy in the practical application of mistletoe therapy beyond oncology in the Clinic Arlesheim, Switzerland.
LECTURES OF INVITED SPEAKERS
7. The Energy Metabolism of European Mistletoe (Viscum album L.)
Hans‐Peter Braun
Institute of Plant Genetics, Leibniz Universität Hannover, Hannover, Germany
E‐mail address: [email protected]‐hannover.de
In 1923, exactly 100 years ago, the Munich botanist Professor Karl von Tubeuf published his highly regarded book “Monographie der Mistel” (Tubeuf 1923). On almost 1000 pages, he summarized the knowledge at that time about V. album and came to the much‐quoted conclusion: “Nothing about this plant is normal”. V. album is an evergreen obligate semi‐parasitic flowering plant that grows on numerous trees. Its life cycle is fundamentally different from that of other flowering plants and also other parasitic flowering plants. V. album is meanwhile intensively investigated at the molecular level. It has been found to contain an extremely large genome consisting of almost 100 billion base pairs (nucleotide pairs). The genome has not yet been sequenced, but most of the protein‐coding regions are meanwhile known (Schröder et al. 2022a). It turned out that the nucleotide composition of the protein‐coding genes of V. album is unusual for flowering plants, as the proportion of the nucleotides deoxyguanosine monophosphate (G) and deoxycytidine monophosphate (C) is comparatively high. This implies increased DNA stability, but at the same time increased energy demand for the transcription of its genes. Cell division in V. album also requires a great amount of energy, as the genome has to be duplicated before each cell division. How can V. album provide this energy? It was found that V. album mitochondria, which are responsible for the formation of the energy‐rich compound ATP, lack a key protein complex that is actually considered indispensable for ATP formation (Senkler et al. 2018). In the meantime, we have investigated the energy metabolism of V. album chloroplasts. We found that the chloroplasts also have a limited capacity to form ATP (Schröder et al. 2022b). This gives us a picture that V. album can live with a comparatively reduced energy metabolism despite an increased energy requirement for its genetic system. “Nothing about this plant is normal”, this also holds true for the molecular biology of V. album. We assume that the host trees supply V. album with energy‐rich compounds to a greater extent than previously thought.
References
Schröder L, Hohnjec N, Senkler M, Senkler J, Küster H, Braun HP (2022a) The gene space of European mistletoe (Viscum album). Plant J. 2022 Jan; 109(1):278‐294.
Schröder L, Hegermann J, Pille P, Braun HP (2022b) The photosynthesis apparatus of European mistletoe (Viscum album). Plant Physiol. 190, 1896‐1914.
Senkler J, Rugen N, Eubel H, Hegermann J, Braun HP (2018) Absence of complex I implicates rearrangement of the respiratory chain in European Mistletoe. Curr. Biol. 28, 1606‐1613.
Tubeuf K (1923) Monographie der Mistel. R. Oldenbourg Verlag, München/Berlin.
8. The Meridian System as the New Basis of Mistletoe Therapy
Johannes Wilkens
Alexander von Humboldt Hospital, Bad Steben, Germany
E‐mail address: [email protected]
Most previous scientific studies were guided by the idea of documenting their physical effectiveness on tumour cells. An important basis for research has thus been laid. However, this procedure corresponds only in part to the intentions of its founder, Rudolf Steiner. According to him, the mistletoe effect varies depending on the host tree and primarily strengthens the soul and the functional system. In anthroposophic medicine, these forces are known as the astral body and the etheric body. At least the understanding of the etheric body is intrinsic in traditional Chinese medicine.
Dr Johannes Wilkens was able to demonstrate 21 years ago that the 13 mistletoe host trees that have been used in oncology to date correlate less with the physical organs and more with the qualities of the 12 meridians used in TCM. After 2002, Johannes Wilkens attempted to demonstrate the individual significance of each tree in case series and tree representations. As a consequence, it was confirmed that the system of meridians borrowed from Chinese medicine is more suited to finding the appropriate mistletoe for the patient. Of course, oak mistletoe has an effect on the liver, but more so on all complaints that correlate with the liver meridian. A sycamore mistletoe can be used specifically for neuroendocrine tumours but displays almost exactly the symptoms associated with the spleen‐pancreas meridian Willow mistletoe can be used effectively for bladder carcinoma, but also ‐ because the bladder meridian runs paravertebrally ‐ for numerous serious diseases of the spine such as fibromyalgia.
The meridian system is therefore ideal when searching for the right mistletoe and expands the possibilities of therapy. The system of the 12 meridians will be presented in its special relationship to mistletoe.
9. Integrative Oncology: How Can We Implement It into Daily Practice?
Ralf Hofheinz
Mannheim Cancer center, University of Heidelberg, Germany
E‐mail address: [email protected]
According to a large survey conducted by the “Working group for medical oncology” (AIO) of the German cancer society among about 2,000 cancer patients, about 40.5% of the polled patients used integrative oncology. This survey is unique because data were collected stratified and comprised out‐ as well as inpatients from all federal states in Germany and all kind of institutions (university as well as community hospitals and oncology practices) painting a more holistic picture than other surveys conducted in single treatment settings. N = 317 patients applied vitamins/mineral nutrients (16.0%), n = 261 phytotherapy/herbs/naturopathy (13.2%), n = 163 dietary supplements (8.2%), n = 114 homoeopathy (5.8%), and n = 632 techniques of self‐help (31.9%). Most patients reported a subjective benefit by using these measures: n = 369 (42.8%) patients regarded them as helpful, while n = 187 patients (22.4%) were unable to estimate their effect. Of note, less than half of the patients dis‐cussed the use IO methods with their physicians. Other surveys have shown that up to 70% of cancer patients expect general practitioners (GP) to provide IO support, while only one fifth of GPs offer IO methods to their patients. These data show that a considerable percentage of patients are left alone while trying to choose appropriate IO methods. Thus, undoubtedly, there is a need for well‐trained physicians (be it oncologist or GPs) in order to avoid for instance drug interactions with anti‐cancer treatments. In this regard it may be regarded a step forward that the S3 guideline “Complementary medicine for oncological patients” has been published about two years ago. However, while reading this guideline, it is obvious that many IO measures and drugs have not been subject to properly planned and conducted clinical trials. In all, while IO is used or requested by many cancer patients very few physicians are trained in this field and there is a large need for well conducted trials in the field of integrative oncology.
SHORT LECTURES
Biology, Pharmacy, Immunology, in vitro Testing
10. Morpho‐Anatomical Detailed Study of Leaves, Stems, Berries and Seeds of Viscum album L. subsp. album Growing on Malus domestica
Valter Paes de Almeida1, Irailson Thierry Monchak1, João Vitor da Costa Batista2, Mirio Grazi2, Hartmut Ramm2, Vijayasankar Raman3, Stephan Baumgartner2,4, Carla Holandino2,5, Jane Manfron1
1Universidade de Ponta Grossa, 84017‐220, Paraná, Brazil; 2Society for Cancer Research, Hiscia Institute, 4144 Arlesheim, Switzerland; 3National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, Mississippi, USA; 4Institute of Complementary and Integrative Medicine, University of Bern, 3010 Bern, Switzerland; 5Laboratório Multidisciplinar de Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, 21941‐902 Rio de Janeiro, Brazil
E‐mail address: [email protected]
Background: Viscum album subsp. album is a hemi‐parasite growing on the branches of host trees and shrubs; it develops as dichasium with pseudo‐dichotomous branching stems and well‐developed green leaves with parallel veins; the dioecious inflorescences usually consist of three flowers, with female flowers generating white fleshy berries, in which a seed is embedded in the mucilaginous mesocarp, normally containing two embryos. This work provides detailed morpho‐anatomical characteristics of the leaves, stems, berries, and seeds of Viscum album L. subsp. album (Santalaceae) growing on the branches of Malus domestica.
Methods: Fresh specimens of leaves and stems, as well as the berries and seeds of V. album subsp. album were collected in April 2021 and February 2022 in the same location in Switzerland (Rütti), Himmelried. The samples were prepared for light microscopy and were submitted to a series of multiple histochemical tests conducted using different chemical reagents and stains. Microchemical analyses of all tissues and Energy Dispersive X‐Ray Spectroscopy (EDS) were conducted using samples fixed in FAA 70 (formalin, acetic acid, 70% ethanol, 5:5:90 v/v/v) after dehydrated process by increasing concentrations of ethanol in water.
Results: The analyzed V. album leaves were isobilateral, amphistomatic, and showed straight anticlinal epidermal cell walls, thick cuticles with epicuticular wax crystalloids, and paracytic stomata. The midrib is flat on both sides and has a single vascular bundle, whereas the strongly shortened petiole is concave‐convex in shape and contains five bundles. The stems show a primary structure with a ring of nine vascular bundles enclosing the pith. The microchemical analyses and EDS showed four morphotypes of calcium oxalate crystals in mistletoe tissues. The EDS spectra of druses exhibited prominent peaks for calcium, carbon, and oxygen. However, other elements such as magnesium, phosphorous, and potassium were also found in minor concentrations in the cubic and rectangular prisms, and platy aggregation crystals time.
11. Novel Formulations of Mistletoe Extracts for Targeted Cancer Therapies
Gero Leneweit, Josanna Kaufmann, Larissa Lubitz, Harden Rieger
Carl Gustav Carus‐Institut, Association for the Promotion of Cancer Therapy, Niefern‐Öschelbronn, Germany
E‐mail address: gero.leneweit@carus‐institut.de
Background: Highly concentrated mistletoe extracts administered to the tumour microenvironment by intratumoural injections or instillations show very promising therapeutic outcomes.
Methods: To enhance the accumulation of mistletoe extracts, liposomal formulations of mistletoe extracts are established. Since conventional formulation technologies are not applicable to complex plant extracts with proteins as active pharmaceutical ingredients (API), novel technologies are developed.
Results: Liposomal drug delivery systems produced from emulsions in an innovative flow process show the capacity for high encapsulation efficiency of API from mistletoe inside phospholipid bilayers. Release of mistletoe lectins from liposomes and anti‐tumoural activity are proven. Protection against innate immune reactions by novel biodegradable heparin coatings on the liposomal surface is benchmarked against standard PEG coatings. The protective liposome coating is prepared to enable long blood circulation and to avoid the immunogenicity of PEG which leads to rapid drug clearance. Active tumour targeting is developed by using different ligands that support transfer across functional barriers such as the blood‐brain barrier and by targeting tumour‐specific receptors. A multi‐ligand concept is studied and evaluated in an in vivo model to assess the biodistribution for a set of novel formulations of mistletoe extracts.
Conclusions: Based on the pre‐clinical results, targeted mistletoe therapies will be planned for first clinical trials in humans. These will focus on tumour entities which are difficult to access by established treatments, thus showing a high need for targeted therapies.
12. Selected Aspects on Biological Properties of miRNA from Viscum album L.
Wenyan Xie1, Catharina Delebinski2, Georg Seifert2, Matthias F. Melzig1
1Freie Universität Berlin, Institut für Pharmazie, Pharmazie, Germany; 2Charité‐Universitätsmedizin Berlin, Klinik für Pädiatrie m.S. Onkologie/Hämatologie, Germany
E‐mail address: [email protected]‐berlin.de
Background: Pioneering studies indicate the possibility of cross‐kingdom regulation of plant miRNAs on human health and diseases. In Viscum album L. from apple tree we identified 29 most genuine novel miRNAs.
Methods: To evaluate their bioactive effects, we selected six of these miRNAs with the most abundant expression. These miRNAs were synthesized and transfected into different tumor cell lines to check their biological effects in different tumor cell lines in comparison with three conserved miRNAs which were expressed not only in mistletoe, but also rich in many other plants to check the selectivity of mistletoe miRNAs effects.
Results: As a result, val‐miR218 significantly reduced cell viability among various tumor cell lines, especially in osteosarcoma U2OS, SAOS‐2 and 143B cells, indicating its promising therapeutic potential. Val‐miR218 strongly inhibited osteosarcoma cell proliferation, induced cell apoptosis and arrested cells at G0/G1 phase. By using high throughput sequencing technology, we identified a total of 61 human target genes. These transcripts were further confirmed by real‐time PCR, western blot and dual luciferase assay. Notably, among these 61 targets, most of them were related to basic cell functions, such as cell cycle; DNA replication, recombination and repair; cell morphology, cellular assembly and organization; and lipid metabolism. Extracellular vesicle (EVs) play an essential role in mediating the function of miRNAs. Mistletoe EVs has been successfully isolated and examined for their effect in protecting and transportation of val‐miR218. As expected, val‐miR218 was packaged in mistletoe EVs. After the uptake of mistletoe EVs by cells, val‐miR218 was delivered into the cytoplasm and interacted with its target genes. To check if mistletoe EVs contain bioactive proteins such as mistletoe lectin or viscotoxin, and if there are any synergistic effects between lectin or viscotoxin with mistletoe miRNAs, the protein profile of mistletoe EVs has been identified. Among the identified proteins were neither mistletoe lectin or viscotoxin detected.
13. In Vitro Analyses on the Relevance of Mistletoe Extracts for the Treatment of Urological Tumors
Sascha Markowitsch1, Olesya Vakhrusheva1, Jochen Rutz2, Moritz Meiborg2, Anita Thomas1, Nikita Fischer1, Igor Tsaur1, Axel Haferkamp1, Eva Jüngel1, Roman Blaheta1
1Department of Urology and Pediatric Urology of the University Medical Center Mainz, Mainz, Germany, 2Department of Urology, Goethe‐University, Frankfurt am Main, Germany
E‐Mail addresses: eva.juengel@unimedizin‐mainz.de, roman.blaheta@unimedizin‐mainz.de
Introduction: In recent decades, several new therapies, including targeted therapies, have improved progression‐free survival in patients with advanced urologic tumors. However, a good initial response to treatment often leads to resistance to therapy. In this case, natural substances may offer new therapeutic options. Mistletoe extracts are used in alternative medicine as antitumor substances. Data regarding the effect or mechanism of action are rare, especially with respect to urologic tumors. However, empirical studies are promising. Aim of the current in vitro study was to improve the data situation and clarify mechanisms of action.
Material and Methods: Urinary bladder cancer, prostate carcinoma and renal cell carcinoma cells were treated with mistletoe extracts grown on linden, poplar, willow and hawthorn in a dilution range between 8,000 and 800,000‐fold. Untreated cells served as controls. Subsequently, cell viability, cell proliferation, distribution of cell cycle phases and possible apoptosis induction by the different mistletoe extracts were investigated. In addition, modulation of involved proteins was analyzed by the western blot. Functional blockade studies and siRNA knockdown were used to verify the clinical relevance of the altered proteins.
Results: All mistletoe extracts inhibited cell viability in a time‐ and dose‐dependent manner in the tested tumor entities, depending on the extract, cell line and entity even at very low 160,000‐fold dilution. The effect could be particularly attributed to the changes in the cell cycle progression, with corresponding modulations of cell cycle regulatory proteins. Furthermore, the treatment with mistletoe extracts significantly increased the amount of apoptotic cells in vitro.
Conclusion: Treatment with mistletoe extracts contributes in distinct antitumor effects in all tested urological tumor entities. Thus, extracts from mistletoe could represent a promising adjunctive therapy for patients with advanced urologic tumor disease. Further studies need to verify this.
14. In Vitro Cytotoxic Activity of Homeopathic Viscum album L. in Glioma Cells
Ana Catarina Viana Valle1, Hilana dos Santos Sena Brunel2, Andreessa de Rezende Bastos Araujo2, Aloisio Cunha de Carvalho1
1Department of Research, Idis Lamasson Institute, Ribeirao Preto, Sao Paulo, Brazil, 2BioInnova Laboratory, Brasilia, Distrito Federal, Brazil
E‐mail address: [email protected]
Introduction: The incidence of cancer has dramatically increased around the world. Among the different cancer types, glioma represents the majority of diagnosed brain tumors and is known to be a rapidly developing tumor with a high mortality rate. Therapies with Viscum album (VA) have performed well in cancer treatments and have been the subject of many studies. This study aimed to evaluate the in vitro action of homeopathic VA against glioma cells, proving its cytotoxic activity.
Material and Methods: The cytotoxicity assay used homeopathic VA in the D3, D6, D9, D12, D30 potencies in ampoules ‐ 1.1mL (Injectcenter®), by Hahnemann method. The cytotoxicity assay with MTT was performed in human glioma cells (KNS‐42), which were grown in 75cm2culture bottles with DMEM. The culture bottles were incubated (37°C, 5%CO2), and the culture medium was changed every 48h until cells reached a confluence between 60‐80%. Subsequently, these cells were trypsinized in 96‐well plates at 10,000 cells per well. After 24h of incubation, these cells were treated (VA 50μL/mL). The control group was not subjected to treatment. The plates were incubated again for another 48h in an oven. After that the cell culture treated with the product, 100 μL of MTT (5mg/mL) was added to each well. The viability reading and measurement were estimated by the absorbance at 570nm in a spectrophotometer. Data were analyzed by Tukey's comparison test using GraphPad Prism®7.04.
Results: A cytotoxic effect was observed of the 50μL/mL concentration on the cells. The comparison of the different potencies identified that medicines (VAD3, VAD6, VAD9) showed higher cytotoxic activity. The treated groups were compared with the control, showing viabilities of 35.9 ± 2.82% for cells treated with VAD3, 31.22 ± 4.54% for VAD6, 44.52 ± 3.02% for VAD9, 62.68 ± 2.1% for VAD12, and 90.1 ± 4.52% for VAD30.
Discussion and Conclusion: In this study, homeopathic VA had a higher cytotoxic effect on glioma cells (KNS‐42). As stated in other studies, this medicine can act as an immunomodulator (Steinborn et al., 2017), so this activity was possibly present in the most diluted potencies. Our data corroborated those of Valle et al. (2021), who evaluated VAD3 action in human breast cancer cells (MCF‐7). In this research, it was possible to verify that the product can decrease cell viability as the concentration increases in the in vitro tests. Additionally, it was possible to prove the cytotoxic activity of VAD3, D6, D9, D12, D30 potencies in glioma cells. This result broadens opportunities for homeopathy in cancer treatment. Its benefits may range from improved quality of life to direct action on cancer cells, as evaluated in this in vitro study.
15. Viscum album Mother Tinctures Interrupted the Warburg Effect in Breast Cancer Cells: Metabolite Profile and Antitumoral in vitro Mechanisms
Michelle Nonato de Oliveira Melo1,2, Alan Ochioni3, Patricia Zancan3, Adriana Oliveira1, Mirio Grazi4, Rafael Garrett2, Carla Holandino1,4, Stephan Baumgartner4,5,6
1Laboratório Multidisciplinar de Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, 21941‐902 Rio de Janeiro, Brazil, 2Metabolomics Laboratory, Chemistry Institute, Universidade Federal do Rio de Janeiro, 21941‐902, Rio de Janeiro, Brazil, 3Laboratório de Oncobiologia Molecular (LabOMol), Faculty of Pharmacy, Universidade Federal do Rio de Janeiro, 21941‐902, Rio de Janeiro, Brazil, 4Society for Cancer Research, Hiscia Institute, 4144 Arlesheim, Switzerland, 5Institute of Complementary and Integrative Medicine, University of Bern, 3010 Bern, Switzerland, 6Institute of Integrative Medicine, University of Witten/Herdecke, Herdecke, Germany
E‐mail address: [email protected]
Background: Viscum album is a semiparasitic plant used for over one hundred years in integrative cancer therapy. To increase the scientific information about the chemical differences related to the host trees and to clarify the seasonal influences, the metabolomes of V. album mother tinctures (VAMT) from three subspecies (abietis, album, austriacum), and five host trees (Malus domestica, Quercus sp., Ulmus carpinifolia, Pinus sylvestris, Abies alba) were evaluated using summer and winter harvests. The in vitro cytotoxic activities were investigated in cancer and normal cells lines.
Methods: V. album (whole plant) from each host tree was harvested in quintuplicate, in summer (2017) and winter (2018) from different sites in Switzerland. A total of fifty VAMT were prepared and analyzed by liquid chromatography coupled to a high‐resolution mass spectrometry (LC‐HRMS). The chemical results were pre‐processed using MZmine, followed by multivariate statistical analysis by principal component analysis (PCA) and Partial Least Squares Discriminant Analysis (PLSDA). The antitumor potential of selected VAMT was evaluated in human breast cancer cell line (MDA‐MB‐231) and in immortalized human keratinocytes (HaCaT) by MTT and glycolytic pathway analysis.
Results: The untargeted metabolomic approach was able to discriminate the mother tinctures according to respective botanical classes and harvest season. A total of 188 metabolites were annotated under positive and negative modes. Fourteen compounds were responsible for samples differentiation, and eight were described in the Viscum album species for the first time. The summer VAMT presented higher cytotoxic activity and V. album from Quercus petraea and Abies alba were able to promote the interruption of the Warburg effect, by inhibition of the following key‐glycolytic enzymes: hexokinase (HK), phosphofructokinase (PFK) and pyruvate kinase (PK). This activity was related to a reduction in glucose uptake and lactate production, which were host‐tree‐time‐dose‐dependent.
Conclusion: The multivariate statistical analyses using LC‐HRMS data were an efficient approach to screening and tracking metabolome differences concerning VAMT. The antitumor potential of V. album mother tinctures is associated with the inhibition of glycolytic enzymes inhibition, supporting their use as natural products for cancer treatment.
Clinical Practice and Clinical Research
16. Natural Philosophy as the Foundation of Host Tree Selection in ISCADOR® Therapy
Sarah Monz
Verein für Krebsforschung, Arlesheim, Switzerland
E‐mail address: [email protected]
Background: ISCADOR® is the first mistletoe preparation produced according to specific suggestions by Rudolf Steiner. Its production is characterized by plant fermentation, the 1:1 relation of winter and summer extracts, and a technically complex blending process. As mistletoe's typical constituents vary depending on the host tree, the manufacturer provides specific recommendations on the use in various tumor entities which are of empirical origin. The present work aims to elucidate the historical and philosophical basis of these recommendations.
Material and Methods: Anthroposophic medicine textbooks, publications on mistletoe therapy, Merkurstab articles as well as publications archived by the Society for Cancer Research in Arlesheim (VfK) were searched to identify sources by Rudolf Steiner and Ita Wegman pertaining to rules of host tree selection.
Results: Researched sources revealed that host trees were initially categorized according to characteristics reflecting the Doctrine of Signatures of Traditional European Naturopathy (TEN). Furthermore, polarity emerged as a main ordering principle of Anthroposophic Medicine reflected both in the manufacturing process of ISCADOR® as well as in the matching of host tree specific products to tumour location and a patient's gender. Both Doctrine of Signatures and Polarity serve as reference frames for diagnostics and therapy in traditional medicine systems throughout the globe. We found a high degree of consistency between these principles and the empirical use of host‐tree specific ISCADOR® preparations.
Conclusion: Historical recommendations and remarks by Rudolf Steiner and Ita Wegman on matching host tree‐specific preparations of fermented mistletoe extract to tumor entities and patient gender is consistent with the principles of the Doctrine of Signature and the concept of Polarity.
17. Individualized Treatment with Mistletoe Preparations in Oncology: Further Development of the “Vademecum”
Andreas Arendt1, Marion Debus2, Johannes Gutsch3, Lydia Garnitschnig4, Markus Karutz5, Angela Kuck6, Mathias Sauer7, Reinhard Schwarz8, Georg Soldner9, Markus Sommer9
1Praxis für Allgemeinmedizin, Liestal, Switzerland, 2Abteilung für Onkologie, Klinik Arlesheim, Switzerland, 3ehem. Onkologie, Gevelsberg, Germany, 4Praxis Kinder‐ und Jugendpsychiatrie, Berlin, Germany, 5ehem. Gemeinschaftspraxis Tobiashaus, Köln, Germany, 6Praxis Sonnenberg, Zürich, Switzerland, 7Paracelsus Krankenhaus Unterlengenhardt, Bad Liebenzell, Germany, 8Kinder‐ und Jugendarztpraxis, Graz, Austria, 9Praxisgemeinschaft, München, Germany
E‐mail address: marion.debus@klinik‐arlesheim.ch
Background: In 2017, the first edition of the Vademecum Mistletoe Therapy was published, including systematically recorded reports from 36 doctors experienced in mistletoe therapy as well as the extensive results of 35 structured interviews with mistletoe therapy experts on various aspects of mistletoe therapy (preparation and host tree selection, dosage and safety). The second edition in 2024 is intended to complete the content of these reports by adding as many already published, peer‐reviewed case reports on individual tumor entities as possible, which will be summarized for quick orientation.
Aim: The aim is to obtain as many instructive individual case reports as possible for different tumor entities. Where possible, the case reports are commented on by short editorial notes on the therapeutically relevant aspects or particularities of the case in order to increase the didactic value. With the same aim, the case collection for all common tumor entities is preceded by a short introductory text in order to develop an understanding of the disease based on the anthroposophic “Menschenbild”, taking into account current research results as well as tumor‐related general therapeutic aspects resulting from the case reports or the editors' own experiences.
Outlook: These extensions are intended to help enable the general practitioner to choose a therapy as independently and diverse as possible, to encourage individual decisions on a case‐by‐case basis and to generate hypotheses for further scientific research.
18. Might Viscum album L. Be a Therapeutic Option for Companion Animals Suffering from Neoplastic Diseases? A Systematic Review
Ulrike Biegel1, Meike Mevissen2, Simone Schuller3, Katja Ruess4, Ophélie Clottu1, Hannah Ayrle1, Christoph Koch5, Michael Walkenhorst1
1Research Institute of Organic Agriculture (FiBL), Department of Livestock Sciences, Frick, Switzerland, 2Department of Clinical Research and Veterinary Public Health, Division Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, Universität of Bern, Switzerland, 3Department of Clinical Veterinary Medicine, Division of Small Animal Internal Medicine, Vetsuisse Faculty, University of Bern, Switzerland, 4Department Medical Oncology and Internal medicine, Center for Veterinary Medicine, Marigin AG, Feusisberg, Switzerland, 5Department of Clinical Veterinary Medicine, Swiss Institut of Equine Medicine (ISME), Vetsuisse Faculty, University of Bern, Switzerland
E‐mail address: [email protected]
Background: Oncological diseases are also common in companion animals. Their treatment often confronts veterinarians with particular challenges. Pet owners are increasingly demanding complementary treatment options that reduce the treatment burden for their affected animals and at the same time improve the chances of successful treatment.
Objective: A systematic review was conducted to determine whether the use of preparations of European, white‐berried mistletoe is an effective therapy for neoplastic diseases in companion animals.
Methods: Only controlled studies (peer‐reviewed) were considered according to the PRISMA criteria (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) and the AMSTAR assessment tool (A Measurement Tool to Assess Systematic Reviews). All clinical studies, both in vivo and in vitro, were included to the extent that they allowed conclusions to be drawn regarding the efficacy of mistletoe extracts in the treatment of the most common neoplastic diseases of domestic animals. The efficacy of each study was compared using a point system.
Results: A total of 6148 references were identified. After duplicate removal and additional screening steps, 114 of these were included in the full‐text search and finally 61 were included in the analysis. Of these, 25 references included in vitro experiments, 26 included both in vivo and clinical experiments, and 10 included both in vivo and in vitro experiments.
A total of four clinical veterinary studies were identified, including three in dogs (sticker sarcoma, oral melanoma, adenocarcinoma of the mamma) and one study on mistletoe therapy for equine sarcoidosis. Most striking was the efficacy of mistletoe therapy in equine sarcoid, melanoma, sarcoma and mammary carcinoma.
19. Quality of Life in Breast Cancer Patients Treated with Mistletoe Extract: A Systematic Review and Meta‐Analysis
Martin Loef1, Daniela Paepke2, Harald Walach1,3
1Change Health Science Institute, Berlin, Germany, 2Spital Zollikerberg, Zürich, Switzerland, 3Next Society Institute, Kazimieras Simonavicius University, Vilnius, Lithuania
E‐mail address: hw@chs‐institute.org
Background: Breast cancer is the most common cancer type in women and quality of life an essential part of the patients' well‐being. It is a matter of debate whether the pharmacological treatment with mistletoe extracts (ME) can improve the quality of life of breast cancer patients.
Methods: This systematic review included randomized clinical trials (RCTs) and non‐randomized intervention studies (NRSIs) comparing breast cancer patients treated with ME to control groups. We searched previous systematic reviews and multiple databases until January 2023. We conducted a meta‐analysis and assessed the risk of bias via RoB 2 and ROBINS‐I and the certainty of evidence via GRADE, respectively.
Results: Nine RCTs and seven NRSIs with 833 and 2831 participants, respectively, were included. They received ME of different manufactures (e.g., Iscador, Helixor) with or without additional treatments as compared with multiple controls (e.g., no control, placebo). The pooled standardized mean difference for RCTs was SMD = 0.61 (95% CI 0.47 to 0.75; p < 0.0001) and for retrospective NRSIs was SMD = 0.46 (95% CI 0.10 to 0.82; p = 0.01). The risk of bias was medium to high for the RCTs and serious for all NRSIs. The GRADE was medium for RCTs and very low for NRSIs.
Discussion: The evidence is mainly limited due to the risk of bias. Our results indicate a moderate effect of ME on the quality of life in breast cancer patients. Further RCTs and real‐world evidence need to confirm this result and should make clear distinctions between different breast cancer subgroups and stages.
20. Reviews and Meta‐Analyses of Mistletoe Therapy for Cancer. Overview of the Past 14 Years
Wilfried Tröger, Stephan Baumgartner
Verein für Krebsforschung e.V., Arlesheim, Switzerland
E‐mail‐address: [email protected]
Background: There are several reviews and few meta‐analyses on mistletoe therapy for cancer. However, they are not consistent. Therefore, an overview of these reviews and meta‐analyses will be given here, in which the quality of these publications will also be considered.
Methods: A literature search was conducted to find all publications in journals published after the first Cochrane Review (2008) on mistletoe therapy for treating cancer. We searched ‘viscum’ OR ‘mistletoe’ OR ‘Mistel’ AND (‘review’ OR ‘meta‐analysis’) in Europe PMC, Cochrane Library, Google Scholar and the library of the VfK. The results of the meta‐analyses and reviews are presented in summary form and have been subjected to a quality review that included the usual criteria for reviews.
Results: In the period from 2008‐2023, 18 reviews or meta‐analyses were found on mistletoe therapy of cancer. Eleven reviews found an improvement in survival or quality of life and seven reviews concluded that there were barely or no effects of mistletoe therapy of cancer. However, some reviews are of inferior quality. Finally, an interpretation bias was found in all reviews concerning survival leading to a curtailment of the results and an augmentation of the heterogeneity.
Conclusion: The conclusions of reviews on mistletoe therapy show a correlation to the quality of their realization, and even Cochrane Reviews and HTA reports can have serious qualitative flaws.
21. Improvement of Quality of Life in Lung Cancer Patients Receiving Radiation and Viscum album L.: A Real‐World Data Study
Friedemann Schad1,2, Diana Steinmann3, Anja Thronicke1, Christian Grah4, Shiao Li Oei1
1Research Institute Havelhoehe at the Hospital Gemeinschaftskrankenhaus Havelhöhe, Berlin, Germany, 2Interdiscplinary Oncology and Palliative Care, Hospital Gemeinschaftskrankenhaus Havelhöhe, Berlin, Germany, 3Department of Radiotherapy and Special Oncology, Hannover Medical School, Germany, 4Lung Cancer Centre, Hospital Gemeinschaftskrankenhaus Havelhöhe, Berlin, Germany
E‐mail address: [email protected]
Purpose: Lung cancer (LC) is associated with high mortality and poor quality of life (QoL). The disease as well as adverse effects of oncological treatments can impair the QoL of LC patients. Add‐on treatment with extracts of Viscum album L. (white‐berry European mistletoe, VA) has been shown to be feasible and safe and to improve the QoL of cancer patients. The aim of this study was to analyze the changes in QoL of LC patients being treated with radiation according to oncological guidelines and add‐on VA treatment in a real‐world setting.
Methods: A real‐world data study was conducted using registry data. Self‐reported QoL was assessed by the evaluation of the European Organization of Research and Treatment Health‐Related Quality of Life Core Questionnaire scale (EORTC QLQ‐C30). Adjusted multivariate linear regression analyses were performed to analyze factors associated with changes in QoL at 12 months, using the software R.
Results: A total of 112 primary LC patients (all stages, median age 70 years) answered QoL questionnaires at diagnosis and 12 months later. Assessment of 12 months changes in QoL revealed significant improvement of 27 points for pain (p = 0.006) and 17 points for nausea/vomiting (p = 0.005) in patients who received combined radiation and VA. In addition, significant improvements of 15 to 21 points for role (p = 0.03), physical (p = 0.02), cognitive (p = 0.04), and social functioning (p = 0.04) were observed in guideline treated LC patients receiving no radiation but add‐on VA.
Conclusions: Add‐on VA therapy has a favorable impact on the QoL of LC patients. Particularly in combination with radiation a significant reduction in pain and nausea/vomiting has been observed.
22. Partial Analysis of a Prospective Non‐Randomized Observational Study of Combination Therapy with Immune Checkpoint Inhibitor (Pembrolizumab) and Viscum album L. Extract in Advanced Non‐Small Cell Lung Cancer (PHOENIX‐3)
Klaudia Kunc1,2, Marcus Reif6, Ulrike Weissenstein5, Claudia Leichnitz2, Timo Weiß2, Katarzyna Blazejczyk2, Hannah Wüstefeld2,4, Harald Matthes2,3, Christian Grah1,4
1Department of Respiratory Disease, Hospital Havelhöhe, Berlin, Germany, 2Research Institute Havelhoehe, FIH, Berlin, Germany, 3Stiftungsprofessur Integrative und Anthroposophische Medizin, Charité ‐ Universitätsmedizin Berlin, Germany, 4Lungcancer Center (DKG), Hospital Havelhoehe, Berlin, Germany, 5Verein für Krebsforschung e.V., Arlesheim, Switzerland, 6Gesellschaft für Klinische Forschung e.V., Berlin, Germany
E‐mail addresses: [email protected], [email protected]
Introduction: Targeted therapy (15%) or immune checkpoint inhibitor (ICI) mono‐ and combination therapies (85%) are established in modern lung cancer therapy. In the KEYNOTE‐024 trial, ICI monotherapy with pembrolizumab (PD‐1 receptor inhibitor) was well tolerated in the setting of high PDL‐1 expression. The adverse event rate was significantly decreased compared to chemotherapy, and OS and PFS were improved compared to combination chemotherapy. Despite these improved therapeutic approaches, a further search for better therapeutic concepts is evident and led to studies investigating an additive effect of immunotherapy with a PDL‐1 ‐ inhibitor and a CTLA4 inhibitor. However, for example, combination immunotherapy (KEYNOTE‐598) with pembrolizumab (PD‐1 receptor inhibitor) and ipilimumab (CTLA4 inhibitor) did not show better outcome in NSCLC patients but higher toxicity. In this prospective, non‐randomized observational study (AWB) we tested a postulated over‐additive effect (heating effect) of combination therapy with ICI and the immunomodulator Viscum album extract (VAE, in priority Iscador Q). Thereby, safety, tolerability as well as effects of this therapy in lung cancer should be systematically investigated before conducting a randomized‐controlled trial (RCT).
Methods: A total of 103 patients with metastatic, unresectable NSCLC and different PDL‐1 expression at baseline starting combination therapy of ICI with VAE with or without additional chemotherapy in different lines of therapy were included. Patients with driver mutation were excluded. Patients were ECOG stage 0‐2 and were documented for up to 6 months. In the sub‐analysis shown here, n = 43 patients were treated with pembrolizumab monotherapy and VAE in the first‐line setting (PDL‐1 expression >50%).
Limitations: This partial analysis of an AWB cannot guarantee the accuracy of an RCT. These are real‐life clinical data with inclusion of patients in ECOG stages 0‐2 and any comorbidity. Thus, this collective cannot be readily equated with that of the pivotal studies.
Results: At n = 43, mean age 69yrs (range 53‐86yrs), male = 56%, 98% Caucasian, ECOG:0 = 26%, 1 = 60%, 2 = 14%; smokers 16 (37%), ex‐smokers: 22 (51%), never smokers: 3 (7%); squamous LC: 8 (19%), non‐squamous LC: 35 (81%); Safety data examined were treatment‐related adverse events (AEs), serious AEs, AEs with treatment discontinuation, AEs with fatality, and effects of therapy in the Trial Outcome Index, quality of life, progression‐free survival, and overall survival at a median treatment duration of 6.0 months. Data analysis is currently ongoing and will be presented.
23. Safety of Combined Targeted and Helixor® Viscum album L. Therapy in Breast and Gynecological Cancer Patients: A Real‐World Data Study
Friedemann Schad1,2, Shiao Li Oei1, Patricia Grabowski2,3, Anja Thronicke1
1Research Institute Havelhoehe at the Hospital Gemeinschaftskrankenhaus Havelhöhe, Berlin, Germany, 2Interdiscplinary Oncology and Palliative Care, Hospital Gemeinschaftskrankenhaus Havelhöhe, Berlin, Germany, 3Institute for Medical Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt‐Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
E‐mail address: [email protected]
Purpose: Newer personalized medicines including targeted therapies such as PARP inhibitors and CDK 4/6 inhibitors have been shown to improve the survival of breast and gynaecological cancer patients, however outcomes may be hampered by adverse events related treatment discontinuation. Oncological studies have suggested that add‐on mistletoe (Viscum album L., VA) improves the quality of life and is involved in the amelioration of cytotoxic side effects of standard oncological therapy. The primary objective of this real‐world data study was to determine the safety profile of targeted therapy in combination with add‐on Helixor® VA therapy compared to targeted therapy alone in breast and gynecological cancer patients.
Methods: The present study is a real‐world data study utilizing patient's data from the accredited national Network Oncology (NO) registry. The study has received ethics approval. The safety profile of targeted therapies with or without Helixor® VA therapy and safety—associated variables were evaluated by univariate and adjusted multivariable regression analyses.
Results: In total 242 all‐stage breast and gynecological cancer patients (n = 242), on average 54.5 ± 14.2 years old were grouped into the control (CTRL, targeted therapy, n = 160, 66.1%) or in the combinational group (COMB, targeted plus Helixor® VA therapy, n = 82 patients, 33.9%). Patients in the COMB group received Helixor® VA therapy in addition to newer therapies including monoclonal antibodies, immune checkpoint inhibitors, tyrosine kinase inhibitors; PARP inhibitors and/or CDK 4/6 inhibitors. The addition of Helixor® VA did not hamper the safety profile (χ2 = 0.107, p‐value = 0.99) of targeted therapy. Furthermore, no adverse events and a trend towards an improved targeted therapy adherence were observed in the COMB group.
Conclusions: The present study highlights the applicability of Helixor® VA in combination with targeted therapies. The results indicate that the additional use of Helixor® VA does not negatively modify the safety profile of targeted therapies in patients with breast cancer and gynecological diseases. Data analysis is currently ongoing and will be presented.
24. Abnobaviscum® Significantly Lowers the Recurrence Rate in Patients with Relatively Early Pancreatic Cancer
Hong Seung Soo1,2, Sung Hyun Kim1,2, Ho Kyoung Hwnag1,2, Chang Moo Kang1,2
1Division of HBP Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul, Korea, 2Pancreatobiliary Cancer Center, Yonsei Cancer Center, Severance Hospital, Seoul, Korea
E‐mail address: [email protected]
Background: Abnobaviscum® F has anti‐cancer property, derived from Viscum album, parasitic to ash trees. It is known to normalize the immune response, suppressing the proliferation of cancer cells. We retrospectively investigated the anticancer effect of the Abnobaviscum® F in patients with resected pancreatic cancer.
Methods: We retrospectively reviewed total 604 patients who underwent radical resection for pancreatic cancer from January 2005 to December 2019 in Severance hospital, Seoul, Korea. The patients were divided into two groups according to postoperative Abnobaviscum® administered (Viscum group vs Control group). Clinicopathologic characteristics, disease‐free, and overall survival were compared between two groups after propensity score matching.
Results: Of 604 patients, 113 patients received postoperative Abnobaviscum® F therapy and 1:1 propensity score matching (PSM) was performed (113 vs 113). Clinicopathologic characteristics and short‐term oncologic outcomes were not different between two groups after PSM. Viscum group showed superior results in 1 year disease free survival compared with control group (Viscum 66.4% vs Control 55.2%, p = 0.015), however overall survival did not differ statistically (Viscum 93.2% vs Control 89.6%, p = 0.292). In subgroup analysis, Viscum group showed superior disease‐free survival especially in node negative group (Viscum 75.8% vs Control 66.8%, p = 0.014), no adjuvant chemotherapy (Viscum 100.0% vs Control 61.5%, p = 0.003), R0 resection (Viscum 68.3% vs Control 55.2%, p = 0.007) and stage I, II disease (Viscum 65.1% vs Control 37.4%, p = 0.011). However, it failed to prove superior overall survival. In multivariate analysis, Viscum therapy (HR = 0.683 [95% CI: 0.474‐0.985], p = 0.041), positive lymph node metastasis (HR = 1.147 [95% CI: 1.050‐1.253], p = 0.002), and lympho‐vascular invasion (HR = 1.501 [95% CI: 1.007‐2.237], p = 0.046) were significant risk factor for disease‐free survival.
Conclusions: Viscum treatment significantly lowered the recurrence rate in patients with relatively early pancreatic cancer. This effect based on the immune enhancement should be further analyzed, and large scale randomized controlled study is warranted.
25. Therapy Response of Equine Sarcoid‐Bearing Horses When Treated with Orally Administered Mistletoe Extract Compared to Administration by Subcutaneous Injection or Placebo, Respectively
Anke Beermann1, Ulrike Biegel1, Marcus Reif2, Lucia Unger3, Ophélie Clottu1, Christoph Koch3
1Research Institute of Organic Agriculture (FiBL) Frick, Switzerland, 2Society for Clinical Research (GKF e.V.), Berlin, Germany, 3Swiss Institute of Equine Medicine, ISME, Vetsuisse Faculty, University of Bern, Bern, Switzerland
E‐mail address: [email protected]
Background: Equine sarcoids are the most common equine skin tumors. Their treatment can be challenging. Repeated subcutaneous injections of mistletoe extract (Iscador P®, manufacturer and marketing authorization holder Iscador AG, Arlesheim, Switzerland, fermented pine mistletoe available in ampoules with concentrations ranging from 0.1mg/ml to 20mg/ml) have already been successfully used in the therapy of sarcoids. However, repeated injections are inconvenient for the majority of horse owners, resulting in less frequent use of this therapy in practice.
Hypothesis: Oral administration of Iscador P® is as effective as subcutaneous injection and more effective than placebo. Furthermore, extending the duration of therapy from 15 to 28 weeks will shorten the time until remission and lead to a higher remission rate.
Animals: 45 privately owned horses with equine sarcoids (aged 5‐12 years), in Switzerland.
Methods: A three‐arm, randomized, prospective, parallel, placebo‐controlled, double‐blinded study in a double‐dummy design was conducted. Horses were treated with Iscador P® (1ml, concentrations from 0.1 to 20mg/ml) and/or placebo (1ml sterile NaCl solution) for a duration of 28 weeks.
Results: The results of this study are anticipated to be available by summer 2023.
26. Oral Administration of Viscum album Extracts: First Results of Intestinal Uptake, Safety and Effectiveness
Jürgen‐Johannes Kuehn1, Uwe Pfüller2
1Lukas Klinik Arlesheim, new name: Klinik Arlesheim, Switzerland, 2Institute of Anatomy and Experimental Morphology, University Cancer Center Hamburg, Germany
E‐mail address: [email protected]
Background: In worldwide opinion intestinal uptake of orally administered Viscum album extract is denied supposing a breakdown of the mistletoe lectins by digestion. Therefore, in humans no oral treatment has been examined, even though in animals tumor regression is documented after oral administration.
Methods: 10 healthy volunteers were treated orally with 200 – 400mg oak tree Viscum album extract (Viscum album Qu 200mg, Institute for Cancer Research, Arlesheim) daily. Specific antibodies against mistletoe lectins I‐III before intake and 21 and 34 days after intake was measured as well as immune phenotyping in peripheral blood was performed. Also, a group of mice bearing inoculated T‐cell lymphoma was treated orally with oak tree Viscum album and compared with a subcutaneous injection control group. Clinical effects are presented for two patients with chronic lymphatic leukemia, one of them treated with pine tree Viscum album (100mg Helixor), the other with oak tree Viscum album (200mg) and for one patient with T‐LGL leukemia, treated with pine tree Viscum album (100mg Helixor).
Results: All 10 healthy volunteers produced specific antibodies against mistletoe lectins I‐III. One single person developed strong diarrhea; in the other 9 persons no side effects were documented. In immune phenotyping absolute lymphocyte count increased. Complete remission was seen in the patient with T‐LGL leukemia, not complete remission in the two patients with chronic lymphatic leukemia. In the orally treated group of mice regression of the T cell lymphoma was seen, but no regression in the subcutaneously treated group.
Conclusion: In humans orally administered Viscum album extract is working by intestinal uptake. It is well tolerated and may cause immune stimulation. Clinical effects in B and T cell lymphomas are existing. Further investigations concerning clinical effectiveness in lymphomas and other malignancies should be realized.
27. Systematic Retrospective Evaluation of Patients with Sarcoidosis Treated with the “Havelhoehe Sarcoidosis Therapy Protocol” (HSP)
Annika Marzok3, David Martin3, Marcus Reif4, Irina Gatov4, Timo Weiß2, Katarzyna Blazejczyk2, Hannah Wüstefeld1,2, Christian Grah1,2
1Fachabteilung Pneumologie, Gemeinschaftskrankenhaus Havelhöhe (GKH), Berlin, Germany, 2FIH, Forschungsinstitut Havelhöhe, Berlin, Germany, 3University Witten/Herdecke, Germany, 4Gesellschaft für klinische Forschung e.V., Berlin, Germany
E‐mail addresses: annika.marzok@uni‐wh.de, [email protected]
Introduction: Chronic sarcoidosis is a granulomatous systemic disease of unknown etiology with a heterogeneous course. The sites of manifestation of granulomatous organ infiltration, in rare cases with scarring‐fibrosing remodeling, are usually the lymph nodes and their drainage pathways, as well as the parenchyma of the lungs or other organs. If untreated mortality is reported to be 5%1. A causal therapy for sarcoidosis is not yet available. In progressive and systematic courses, immunosuppression is performed.
In the Havelhoehe Community Hospital (GKH), in continuation of previous treatment experience2,3, a standardized therapy has been developed4 aiming to stimulate autoregulation in the acquired immune system, in particular the CD4/CD8 imbalance. The treatment protocol includes cyclic application of the immunomodulator Viscum album L. (Iscucin Salicis, FA Wala) accompanied by Ferrum, Graphite, Stibium, and Phosphorus. One treatment cycle regularly takes three months.
Methods: In the years 2003‐2022 n = 956 patients with chronic sarcoidosis were treated at the Hospital GKH. From 301 of these patients, we received the consent to evaluate the pseudonymized treatment courses, which had been performed in the period from May 2003 to April 2022 in the Department of Pneumology at the GKH. According to defined inclusion and exclusion criteria of a retrospective observation protocol, a cohort of 136 patients was identified who could be submitted to a systematic evaluation. The aim of this analysis was, besides safety and tolerability, the effects of the treatments in order to provide a basis for prospective and randomized.
Results: In addition to a stabilization of the disease process, HSP was observed to be very safe. First results show only 10 of the 136 affected patients to suffer from side effects, all of which can be classified as mild. In addition, the dose of glucocorticoids could be reduced or discontinued in 43 of 70 cases. Symptoms of the disease improved or regressed, e.g., fatigue in 46 of 89 cases.
Discussion: This cohort of 136 cases allows us for the first time to make a systematic statement on the safety, tolerability, and effects of an innovative treatment approach for sarcoidosis and, given the heterogeneous nature of the disease, creates the basis for prospective RCTs for HSP. The evaluation is still ongoing.
References
1. Bokhari SRA, Zulfigar H, Mansur A. Sarcoidosis. 2022, Dec. 24. In: StatPearls (Internet). Treasure Island (FL): STatPearls Publishing; 2023 Jan‐. PMID: 28613460
2. Kümmell HC, Buchner C, Marx C. Zur Frage der Therapiebeurteilung bei Sarkoidose. Rheuma Medizin 1983, 5:120‐124
3. Kümmell HC, Fricke L, Engelke P, Büssing A: Langzeitbeobachtung bei nicht‐steroidaler Sarkoidosetherapie, Bericht der Abteilung für Innere Medizin, Gemeinschaftskrankenhaus Herdecke, www.rhythmen.de/downloads/sark_nonsteroid.pdf 2003 (website last accessed 21.06.2023
4. Grah C, Happel H, Vogt J: Die Behandlung der pulmonalen Sarkoidose nach dem Havelhöher Sarkoidose‐Therapieprotokoll. Merkurstab 2008, 4: 343‐353
28. Pharmacokinetics and Safety of Intravenous Helixor® P: Results of a Clinical Trial in Healthy Subjects
Roman Huber1, Sabine Rieger2, Michael Schink2, Imma Fischer3, Michael Adler4, Ann‐Kathrin Lederer1,5
1Uni‐Zentrum Naturheilkunde, Department Innere Medizin II, Universitätsklinikum Freiburg, Germany, 2Helixor Heilmittel GmbH, Rosenfeld, Germany, 3Biostatistik – Tübingen, Tübingen, Germany, 4chimera biotec GmbH, Dortmund, Germany, 5Klinik für Allgemein‐, Viszeral‐ und Transplantationschirurgie, Universitätsmedizin Mainz, Germany
E‐mail address: roman.huber@uniklinik‐freiburg.de
Background: Intravenous infusions of mistletoe preparations are used off label to increase dosages and efficacy in comparison to subcutaneous injections in cancer patients.
Methods: We studied pharmacokinetics of natural mistletoe lectin (ML) as relevant active ingredient in Helixor® P (Pini). Eight healthy subjects received a single infusion of 2.000 mg Helixor® P within 2.5 h intravenously and were followed for 72 h for pharmacokinetic studies. ML was detected with a validated ELISA specific for the A‐chain.
Results: In all subjects, ML concentration was below detection threshold before the infusion and peaked immediately after end of infusion. After 10 h, ML was still detectable in all subjects, after 18 h it was below level of detection in all but two subjects. Half‐life, elimination rate, maximum plasma concentration and area under the curve will be calculated from the data. In all eight subjects, liver enzymes ALT and AST raised substantially within two days after infusion, which we classified as mild (ALT n = 1, AST n = 2), moderate (ALT n = 2, AST n = 1) or severe (ALT n = 5, AST n = 5) adverse events according to CTCAEv4.03 criteria. In none of the cases the reactions were serious. The study, which had been designed to treat 12 subjects, was terminated prematurely due to these adverse events. During follow up of 2‐8 weeks, liver enzymes returned to normal in all subjects.
Summary: We were able to determine pharmacokinetics after a single infusion of 2.000 mg Helixor® P but found this dose to cause hepatitis in healthy subjects.
29. The Mistletoe and Breast Cancer (MAB) Study: A UK Pilot Randomised Controlled Trial
Lorna J. Duncan, Susan Bryant, Gene Feder, Alyson Huntley on behalf of the MAB team
Centre for Academic Primary Care, Bristol Medical School, Bristol BS8 2PS, UK
E‐mail address: [email protected]
Objective: To test the feasibility of a pilot, randomised controlled trial of mistletoe therapy with an embedded qualitative study in the UK National Health Service (NHS) setting.
Methods: The aim was to recruit 45 patients via an NHS oncology centre who had a diagnosis of early/locally advanced breast cancer and whose standard treatment included chemotherapy. Participants were allocated to: Iscador® Malus, Iscador® Pinus or physiological saline (placebo), and used a diary to record their therapy. Questionnaires EORTC QLQ‐C30, EORTC QLQ‐BR23, FACT‐N, CFS, ARS‐State, and the CompleMentary and Alternative Beliefs Inventory (CAMBI) were administered at three time‐points. Qualitative interviews were undertaken with participants, oncologists, and nurses. Feasibility was assessed by recruitment, retention, attrition, blinding and acceptability.
Results: Sixty‐seven patients were approached between August 2019 and March 2020 and 15 gave consent. One participant dropped out prior to randomisation. Of the 14 participants randomised, two withdrew during the trial. Ten participants and five staff were interviewed. These interviews showed there was a naivety around mistletoe therapy by participants and staff.
Barriers to recruitment cited by participants were extra treatment and time, extra injections, and the possibility of placebo allocation. COVID‐19 had a negative impact on recruitment and caused extra stress for some participants.
Adherence to the MAB therapy was very good measured by diaries and questionnaires. However, diaries and interviews indicated that participants struggled with injections, and in some cases, the skin reactions. The interviews highlight a positive approach by participants; devising ways to cope with self‐injection. Adverse events were low and all related to injections and skin reactions.
7/14 participants stated they did not know their therapy allocation; with all participants describing their decision on how they felt, and not on the therapy appearance. This study was not powered to test efficacy (e.g., differences in QoL between groups). The CAMBI showed participants liked interventions which encourage personal control, and perceived as natural, immune‐boosting and promoting self‐healing.
Conclusion: This pilot shows that it is feasible in the UK to recruit breast cancer patients into a randomised controlled trial of mistletoe versus placebo, for them to adhere to treatment and provide follow‐up data.
30. Clinical Regression of Chondrosarcoma and Measured an Extended Safe High‐Dose of Viscum album Lectin (VAL) Under Intratumoral Injection: Case Report
Joon Beom (John) Park1, Inmyung Oh2, Sunjoo Chung2, Taek Joon Yoon3, JongBae Kim1
1Mistletoe Research Center, New Breath Hospital, Seoul, South Korea, 2Mistletoe Cancer Clinic, New Breath Hospital, Seoul, South Korea, 3DoGenBio, Independent Researcher & Consultant, Seoul, South Korea.
E‐mail address: [email protected]
Background: Mistletoe Lectin (ML/VAL) is vital as the primary relevant inducer of apoptotic cell death. Intratumoral applications of Viscum album extract (VAE) have induced local tumor response in various cancer entities for variant carcinomas. This report is the first to show regression of chondrosarcoma by intratumoral injection with Viscum album extract. From this regressed case of treatment for large‐sized chondrosarcoma by intratumoral VAE injections, the authors define more extended the maximum high‐dose Abnoba F® and its dependent dose of mistletoe lectin can be applied in intratumoral treatment for other cases in the future.
Methods: The apoptotic cell death effect appeared in the following week of the beginning. As a total VAE, the dose of Abnoba F was incrementally increased. To research the maximum safe high dose of VAL intratumoral usage. The authors measured the lectin amount in Abnoba F (fraxini)® 20mg/1 ampoule and Helixor A (abietis)® 100 mg/1 ampoule used for this case. The concentration of VAL was analyzed using the sandwich ELISA method in a blind test. The standard substance mistletoe lectin was separated using an immunoaffinity column with lectin‐specific monoclonal antibodies.
Results: A 46‐year‐old male patient with chondrosarcoma had two large‐sized masses (40cm x 25cm x 17cm) and a satellite tumor (8cm x 14cm x 3cm). For 32 weeks, the tumoral parenchyma showed a significant regression (>70% of the tumor size) by 24 Abnoba F intratumoral injections and concurrently 19 times Helixor A 100mg IV infusions weekly. Retrospectively, on average, the lectin amount in one ampoule of Abnoba F 20mg commercially supplied was measured as 205.2 ng/ml. As eight ampules of Abnoba 20 mg (total 160mg) were injected into the patient a day by intratumoral application, up to 1,642 ng/ml of mistletoe lectin (ML) was injected as the extending maximum high‐dose in safety.
Conclusion: Chondrosarcoma, a tumor otherwise very resistant to conventional therapies, was observed to cause significant regression due to the dose‐dependent cytotoxic, apoptogenic effects of VAE with up to 1,642 ng/ml of VAL at once for intratumoral injection. The quantified lectin content of Abnoba F is to contribute to setting the standard for maximum usage of intratumoral injection for achieving tumoral regression by apoptosis‐induced cell death and clinical safety.
31. Developed Based on Reported Complete Remission of High‐Grade Bladder CIS in a Non‐Smoking Female as a Sentinel Environmental Cancer Refractory to Bacillus Calmette‐Guerin and Mitomycin C: A Novel Low‐Cost Combined Therapy with Mistletoe and Ascorbate
Devra Davis1, Dugald Seely2, Chris Morash3, Mikhail Kogan4, Nasha Winters5
1Environmental Health Trust, Teton Village, WY, USA, 2The Centre for Health Innovation, Ottawa, Ontario, Canada, 3The Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada, 4George Washington University Medical Center, Washington, DC, USA, 5Metabolic Terrain Institute, Tucson, AZ, USA
E‐mail address: [email protected]
Background: The state‐of‐the‐art treatment for bladder cancer remains intravesical instillation of Bacillus Calmette‐Guerin (BCG), an agent in short supply globally. We have previously reported complete remission (CR) in a patient with high‐grade carcinoma in situ on the bladder, refractory to BCG, who incurred childhood and early adult life exposures to several environmental carcinogens. Combined treatment for this patient included applications of 50 mg subcutaneous mistletoe, pini (Uriel pharmacy, USA), 900 mg intravenous and 1200 mg intravesical mistletoe, mali (Uriel pharmacy, USA), and high dose (>50 gms) of intravenously applied ascorbate (IVAA) along with a number of natural health products. These therapies to be described in presentation are known to activate NK cells, induce dose‐dependent apoptotic cell death, and enhance growth and maturation of T‐cells, with potentially additive and synergistic mechanisms.
Aim: Within a decade of diagnosis, about three‐fourths of patients with high‐risk bladder cancer will recur, progress, or die. Though most do not die from the disease, the vast majority experience recurrence and progression. Given the demonstrated CR in this case, a case series should be devised to provide intravesical mistletoe and IVAA in order to reduce recurrence risk.
Discussion: With a worldwide shortage of BCG, the high rate of recurrence for high‐grade CIS, the proportion of cases refractory to BCG and MIT‐C, the unproven use of off‐label pharmaceuticals such as gemcitabine or highly toxic checkpoint inhibitors previously reserved for metastatic disease, and the relative cost‐effectiveness of mistletoe and IVAA, it is important to employ these combined functional medicine treatments for refractory cases of high‐grade NMIBC. We call on physicians to develop additional cases that can advance our understanding, including standardization of methods for systematically evaluating combined therapies (blinded and non‐blinded), nomenclature regarding mistletoe preparation, dose, concentration, regime of administration, length of treatment, targeted cancer type, and other aspects.
32. Classification and Minimum Clinically Important Difference of the German Version of the Cancer Fatigue Scale (CFS‐D)
Marcus Reif1, Roland Zerm2,3, Christoph Gutenbrunner4, Matthias Kröz2,5,6
1Gesellschaft für Klinische Forschung (GKF), Berlin, 2Forschungsinstitut Havelhöhe (FIH), Berlin, Germany; 3Geriatrische Abteilung, Gemeinschaftskrankenhaus Havelhöhe, Berlin, Germany, 4Klinik für Rehabilitationsmedizin, Medizinische Hochschule Hannover, Hannover, Germany, 5Institut für Integrative Medizin der Universität Witten/Herdecke, 6Forschungsabteilung der Klinik Arlesheim, Arlesheim, Switzerland
E‐mail address: marcus.reif@gkf‐berlin.de
Objective: Cancer‐related fatigue (CRF) is a major factor of quality of life in cancer patients. The Cancer Fatigue Scale (CFS‐D) is a robust 15‐item inventory covering physical, cognitive, and affective fatigue. We conducted a classification procedure for best separating no/minor from moderate/clinically relevant fatigue and estimated minimum‐clinically‐ important‐differences (MCID).
Method: Data came from 3 studies: a) 21 breast (BC) and 7 colorectal (CRC) out of 57 cancer patients, and 57 matched healthy controls; b) 41 BC‐ and 25 CRC‐patients with chemotherapy; and c) 105 BC‐patients assessed 4 times during a CRF‐ intervention study.
For a) and b), 4 groups with increasing mean CFS‐D could be distinguished (N ♀/♂): C 65/27, CRC with mistletoe 27/34, BC with mistletoe 110/0, BC without mistletoe 30/0; various mistletoe extracts were used in different dosages. In cut‐off analyses we iteratively categorized the CFS‐D sub‐/scales into 2 × 2‐, 3 × 4‐ and 4 × 4‐tables using moving thresholds, each time calculating the respective χ2‐values for between‐class differences. We selected those categories that resulted in maximum χ2‐values. ROC‐curves were assessed for concordance. We conducted anchor analyses by orthogonal regression of FNS and EORTC QLQ‐C30 Fatigue scales on CFS‐D. With c), we estimated MCIDs of CFS‐D‐sub‐/scales based on published FNS‐ and EORTC‐Fatigue MCIDs and compared them with patient gradings of therapy satisfaction and well‐being 4 years later.
Results: CFS‐D total‐score cut‐off values of 22, 22/29 and 22/29/32 in 2‐, 3‐ and 4‐class categorisations were selected, respectively. ROC‐analyses corroborated to a threshold of 23 between no/minor and moderate fatigue. Anchor analyses revealed ranges of 21‐23 for thresholds between no/minor and moderate fatigue, of 31‐34 between moderate and strong fatigue, and a MCID of 6. Subscale analyses yielded ambiguous results, yet ‘no’, ‘minor/moderate’ or ‘strong’ fatigue might be stated below/above physical fatigue: 9/15, cognitive fatigue: 9/11, and affective fatigue: 6/8. Furthermore, in b) CFS‐D sum‐score and cognitive fatigue yielded chemotherapy and mistletoe sensitivity.
Conclusion: The CFS‐D is a reliable inventory indicating moderate or clinically relevant CRF at least for ≥23 and with a conservative MCID‐estimation of 6 (10%), indicating CFS‐D to capture individual dimensions of fatigue clinically relevant including chemotherapy‐ and mistletoe sensitivity. Thresholds for strong fatigue and CFS‐D‐subscales need further evaluation.
33. The Introspective Patient Experience of Mistletoe Therapy in Cancer: A Qualitative Study
Annika Mascher1,2,3, Florian Pelzer1,2, Lorna J. Duncan4, David Martin1,5, Stephan Baumgartner1,2, Bettina Berger1
1University Witten/Herdecke, Witten, Germany, 2Society for Cancer Research, Arlesheim, Switzerland, 3Klinik Arlesheim, Arlesheim, Switzerland, 4University of Bristol, Bristol, United Kingdom, 5University of Tübingen, Tübingen, Germany
E‐mail address: [email protected]
Introduction: The patients' perspective on mistletoe therapy in cancer treatment has received little scientific interest, although it contributes highly relevant aspects to facilitate a holistic understanding of this therapy. This study contributes to patient‐centered research and treatment by documenting the subjective experiences of individuals undergoing mistletoe therapy.
Methods: This qualitative, explorative study included 20 outpatients recruited from Arlesheim Hospital (Arlesheim, Switzerland) with a history of various cancer types. All patients received subcutaneous mistletoe therapy with Iscador from the five available host trees, in different concentrations, for at least two years (median 7.5 years). Data was collected through two semi‐structured, in‐depth interviews per patient. Qualitative content analysis was applied to examine the data. The individual experience of mistletoe therapy was analyzed with regard to six predefined levels of human experience: physical, vital, emotional, mental, spiritual and social. Three additional aspects emerged out of the interviews: warmth, immune strengthening and general wellbeing, considered as cross‐dimensional perspectives.
Results: Data analysis revealed considerable heterogeneity among patients' experiences with mistletoe therapy. The importance of particular aspects became apparent, such as increased vitality to manage daily life, increased warmth within the body, sensations of a deeper awareness of one's body, greater emotional stability, feelings of safety and protection through mistletoe therapy, mental strengthening and resilience, heightened self‐awareness and improved self‐care, as well as sensations of spiritual connectedness and improved well‐being generally.
Conclusion: Prior to this study it had not been shown that cancer patients using mistletoe therapy can have observations at different levels of experience. These results are only a first step towards a deeper insight into patients' experiences with mistletoe therapy. Further investigations into the impact of mistletoe therapy on the emotional, mental, and spiritual levels are warranted. Indeed, this seems essential in order to support cancer patients in a holistic manner during their mistletoe treatment.
POSTER PRESENTATIONS
Biology, Pharmacy, Immunology, In Vitro Testing
34. “Few Can Imagine that Mistletoe is One of the Most Interesting Plants.” 100 Years of Karl von Tubeuf's Monograph on Mistletoe
Hartmut Ramm, Konrad Urech
Society for Cancer Research, Hiscia Institute, Arlesheim, Switzerland
E‐mail address: [email protected]
Background: In 1923, the Monograph on Mistletoe, comprising well over 800 pages, was published. The botanist Karl von Tubeuf had thus created a standard work through the breadth of topics and his precise descriptions, which has remained the basis for research on white‐berried mistletoe Viscum album L. to this day. Interestingly, V. album was introduced into medicine as an injectable around the same time and became the most widely used remedy in complementary cancer treatment in the 20th century. Tubeuf's accurate documentation of French locations of the exceptionally rare oak mistletoe made even possible in 1928 to produce an oak mistletoe preparation (Iscador® Qu).
Tubeuf's investigations into the occurrence of V. album on various tree species in Europe were also intended as a means of regulating the rampant spread of mistletoe, which is currently once again in the critical focus of public attention due to climate change. Tubeuf's detailed studies of chorology, morphology and physiology led him to the conclusion that mistletoe differs from botanical normality in almost all respects. Current research has deepened this exceptional position, for example by revealing a lack of complex I in the respiratory chain of the mitochondria and correspondingly in photosystem I of the chloroplasts.
Aim: In the meantime, several monographs have been published describing the entirety of parasitic flowering plants, including well over thousand species of mistletoe distributed all over the globe. However, the diversity of the literature on mistletoe research, which has increased exponentially in recent decades, is hardly reflected in these monographs. True to Tubeuf's statement that “such a work is actually never finished”, it seems timely to respond to the currently growing worldwide interest in research on V. album with a new monograph that is as comprehensive as it is in‐depth.
35. The Photosynthesis Apparatus of European Mistletoe
Lucie Schröder, Jennifer Senkler, Hans‐Peter Braun
Institute of Plant Genetics, Leibniz Universität Hannover, Hannover, Germany
E‐mail address: [email protected]‐hannover.de
Background: The photosynthesis of plants can be divided into two sub‐processes: (i) the light reaction, through which the energy‐rich compounds ATP and NADPH are produced, and (ii) anabolic metabolic pathways such as the Calvin‐Benson cycle, through which the formation of organic compounds takes place by the use of ATP and NADPH. Two operation modes are known for the light reaction, which are based on either linear or cyclic electron transport pathways (LET and CET). LET allows formation of ATP and NADPH, whereas CET only leads to ATP formation. Since the energy metabolism of the mitochondria of Viscum album is organized in a very unique way (Senkler et al. 2018), we here present an investigation on its chloroplast energy system at the molecular level.
Methods: V. album leaves were harvested in spring. Thylakoid preparations were performed for V. album and the model plant Arabidopsis thaliana as reference. The preparations were carried out using a combination of differential and density gradient centrifugations. Membrane bound protein complexes of the thylakoids were solubilized by a mild detergent. Photosystems and other protein complexes involved in the light reaction were separated via one‐dimensional (1D) blue native (BN) polyacrylamide gel electrophoresis (PAGE) and two‐dimensional (2D) BN / sodium dodecyl sulfate (SDS) PAGE. Protein complexes and proteins of the 1D and 2D separations were identified via mass spectrometry.
Results and conclusions: The photosynthesis apparatus of V. album shows several distinct features (Schröder et al. 2022): (1) The NDH complex (chloroplast NADH dehydrogenase‐like complex), which is involved in CET, is absent. (2) Two proteins, PGR5 (proton gradient regulation 5) and PGRL1 (PGR5 like phenotype 1), which also contribute to CET, are present in reduced amounts. (3) The amount of photosystem I, which is involved in both, LET and CET, is low in V. album compared to A. thaliana. (4) The photosystem II and the ATP synthase complexes are present in comparable amounts in V. album and A. thaliana. (5) The ATP synthase of V. album was found to be especially stable. We conclude that the capacity for LET and especially for CET is reduced in V. album. Reduced photosynthetic metabolism can possibly be compensated for by the provision of energy‐rich compounds by the host trees, which should be further investigated.
References
Senkler J, Rugen N, Eubel H, Hegermann J, Braun HP (2018) Absence of complex I implicates rearrangement of the respiratory chain in European Mistletoe. Curr. Biol. 28, 1606‐1613.
Schröder L, Hegermann J, Pille P, Braun HP (2022) The photosynthesis apparatus of European mistletoe (Viscum album). Plant Physiol. 190, 1896‐1914.
36. Distribution and Abundance of Viscum album ssp. album in France
Konrad Urech, Alejandro Casteller, Stephan Baumgartner
Society for Cancer Research, Hiscia Institute, Arlesheim, Switzerland
E‐mail address: [email protected]
Background: France is considered the most important area of mistletoe (Viscum album ssp. album) incidence in Europe. Yet little is known about the patterns of abundance within the country. The assessment of the geographic range and abundance of V. album ssp. album in the highly heterogenous environment of France was the objective of the present work.
Methods: The distribution and abundance of Viscum album ssp. album were visually assessed from the running car along the roads passed through during February and March (1980‐2001). The presence of the well visible mistletoe plants on the defoliated host trees was classified in each case within a distance of about 7‐9 km by means of six abundance classes: absent (0); rare (1); occasional (2); frequent (3); common (4); abundant (5). The survey points were plotted on IGN (Institut Géographique National) maps and analysed using GIS (Geographic Information System).
Results: Nearly 11900 survey points were assessed covering most parts of France except some peripheral northern regions. North of 46th parallel area‐wide presence of V. album ssp. album was registered with the exception of a few areas devoid of mistletoe (e.g., the Beauce). High mistletoe densities were recorded in the central regions of Franche‐Comté, Bourgogne, Centre, and Pays de la Loire and along rivers often lined with poplars. South of the 46th parallel consisted in a coherent mistletoe‐free area with interspersed conspicuous mistletoe centers (e.g., in the Périgord, the area around Saintes, near Bordeaux and near Toulouse). Mistletoe abundance increased towards the northern slope of the Pyrenees.
Conclusions: Visual assessment was used to estimate the relative abundance of V. album ssp. album in France. Distribution centers, gradients of population densities and areas devoid of mistletoe could be identified, mapped, and further spatially analysed. The spatial patterns of mistletoe distribution explored in the present work can be the basis for the identification of physical and biotic factors crucial for the presence and prospering of V. album ssp. album.
37. Liposomal Encapsulation of Mistletoe Extracts for the Therapy of Glioblastoma
Josanna Kaufmann, Harden Rieger, Gero Leneweit
ABNOBA GmbH, Niefern‐Öschelbronn, Germany
E‐mail address: [email protected]
Background: Glioblastoma multiforme (GBM) is the most common malignant and lethal form of brain cancer which is currently considered incurable. With a median survival of 12‐15 months after diagnosis, the 5‐year survival rate is less than 5%. Specific and selective tumour targeting to cross the blood‐brain tumour barrier (BBTB) are the main challenges in GBM treatment.
Methods: Compounds of mistletoe extracts are encapsulated in liposomes by first producing nano‐emulsions in a hydrophobic phase. The processing conditions of emulsification, the transformation of nano‐emulsion droplets into liposomes and the novel drug delivery system are thoroughly characterized. Different phospholipids are used to study for their effects on liposomal size distribution, encapsulation of active pharmaceutical ingredients and colloidal stability.
Results: Using suitable phospholipid compositions, mistletoe lectins positively contribute to achieve small, monodisperse and monomodal liposomal size distributions of 100‐150 nm with good stability characteristics. In vitro tests on different GBM cell lines show high anti‐tumoural activity of mistletoe compounds.
Conclusions: In vitro results on anti‐tumoural activity of mistletoe compounds are applied in a rat glioblastoma model to test the efficiency of the drug delivery system under a variety of formulation conditions.
38. Influence of Pharmaceutical Manufacture Processes on the Quality of Viscum album L. Mother Tinctures
João Vitor da Costa Batista1, Bettina Leonhard1, Johanna Zeise1,4, Michelle Nonato de Oliveira Melo2, Paul Doesburg1,4, Claudia Scherr1,4, Maria Olga Kokornaczyk1,5, Mirio Grazi1, Jakob Maier1, Sibylle Kienle3, Matthias Plath3, Carla Holandino1,2, Christoph Kalbermatten3, Stephan Baumgartner1,4,5
1Society for Cancer Research, Hiscia Institute, 4144 Arlesheim, Switzerland, 2Laboratório Multidisciplinar de Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, 21941‐902 Rio de Janeiro, Brazil, 3Department of Research and Development, Ceres Heilmittel AG, 8593 Kesswil, Switzerland, 4Institute of Integrative Medicine, University of Witten/Herdecke, 58313 Herdecke, Germany, 5Institute of Complementary and Integrative Medicine, University of Bern, 3010 Bern, Switzerland
E‐mail address: [email protected]
Background: Safety and efficacy of herbal medicines, which account for the quality control, ensure their reproducibility and medicinal uses. Several aspects influence their properties, such as the manufacturing process, the plant harvest season, the site of collection, and the herbal organs used. In the present work, the influence of two standardized manufacturing processes in the production of Viscum album mother tinctures (MTs) was evaluated.
Methods: V. album stems, leaves and berries growing on Quercus sp. and Malus domestica harvested in November 2022 were produced following two manufacturing processes. From each harvest, two batches were produced: one according to the monography described in the Brazilian (BHP) and the other in the German (GHP) Homoeopathic Pharmacopoeias, the latter provided by Ceres Heilmittel AG. The four MTs were submitted to: high‐performance thin‐layer chromatography (HPTLC), picture‐forming methods (Pfeiffer's circular chromatography – PCC and copper chloride crystallization – CCC).
Results: The final EtOH content and dry residues of the MTs were respectively: 47% v/v and 8.7% w/w (GHP) and 65% v/v and 3.5% w/w (BHP). All 4 MTs showed similar HPTLC profile, with more intense bands for the GHP MTs and for the ones from Quercus sp. A reddish band was observed on the upper part (Rf 0.98) for the BHP MTs and in counterpart, a yellow‐blueish band for the GHP ones. PCC patterns clearly distinguished the mistletoe growing on Malus domestica from Quercus sp, since the pictures' radial features (e.g., channels and spikes) as well as their colour intensities were specific for each MT. In addition to visual evaluation, computer‐based image analysis using grey‐level co‐occurrence matrix provided statistical differences for PCC. Structure analysis of CCC patterns of different regions of interest (ROIs) showed differences between pharmaceutical manufacturing processes as well as between the mistletoe host trees.
Conclusion: This study provides preliminary evidence about the use of picture‐forming methods to evaluate the mistletoe preparations. The maturation of MTs will be evaluated using the same procedures at three additional time points. Besides, further experiments should be conducted with in vitro and in vivo models in order to better understand the overall differences of the manufacturing processes.
39. A Fermented Mistletoe Extract Elicits Endoplasmic Reticulum Stress Driven Immunogenic Cell Death in Breast Cancer and Melanoma Cells
Ulrike Weissenstein1, Bettina Leonhard1, Stephan Baumgartner1,2,3
1Society for Cancer Research, Arlesheim, Switzerland, 2Institute of Integrative Medicine, Witten/Herdecke University, Herdecke, Germany, 3Institute for Complementary and Integrative Medicine, Bern University, Switzerland
E‐mail address: [email protected]
Introduction and objective: Tumors prevent a patient's immune system from recognizing and eliminating them through various escape mechanisms. Immunogenic cancer cell death (ICD) is an important step for the initiation of a specific anti‐cancer T‐cell response. Triggering ICD can make an existing tumor recognizable and attackable for the immune system. An ideal ICD inducer activates different pathways such as apoptotic cell death, endoplasmic reticulum (ER) stress response and the induction of reactive oxygen species (ROS). An activation of these pathways leads to the cellular expression of damage‐associated molecular patterns (DAMPs).
Cancer patients often get extracts from European mistletoe (Viscum album L.) as supportive therapy, frequently together with classical oncological treatment procedures. The aim of our in vitro study was to investigate whether mistletoe extracts are able to induce immunogenic tumor cell death.
Methods: Three human breast carcinoma and one murine melanoma cell line (SKBR3, MDA‐MB‐231, MCF‐7 and B16F10) were treated with an aqueous, fermented Viscum album extract (VAE: Iscador Q spez.), Paclitaxel and Tunicamycin (ICD/ER stress inducer positive controls), respectively. Cell surface exposure of DAMPs (Calreticulin, heat shock proteins hsp70 and hsp90) and apoptosis were assessed by flow cytometry. To investigate whether VAE induces ribotoxic stress, we measured the ER stress regulators p‐eIF2a, ATF4, and CHOP in breast cancer cells by Western blot.
Results: Treatment with either VAE, paclitaxel or tunicamycin induced a cell line and concentration dependent cell surface exposition of DAMPs, which significantly correlated with early apoptosis in all cell lines except MCF‐7. VAE and paclitaxel induced an incomplete ER stress response in breast cancer cells. Phosphorylation of EIF2α was induced by VAE, paclitaxel and tunicamycin. The ER stress inducer tunicamycin also stimulated the expression of ATF4 and CHOP.
Conclusion: In this in vitro study, we demonstrated the potential of mistletoe extracts to induce immunogenic cell death for the first time. This could be of clinical interest especially for a potential application of intratumorally applied mistletoe extracts in combination with systemic cancer immunotherapy.
40. Effect of Mistletoe Extract on the Activity of Natural Killer Cells in Combination with Checkpoint‐Inhibitor Therapy Against Breast Cancer Spheroids
Michael Schink1, Eugenia Violeta Díez García de Olalla2, Alexander Sebastian Franzén2, Martin J. Raftery2, Sabine Rieger1, Gabriele Pecher2
1Helixor Heilmittel GmbH, Rosenfeld, Germany, 2Kompetenzzentrum Immunonkologie und Translationale Zelltherapie (KITZ), Medizinische Klinik m.S. Hämatologie, Onkologie und Tumorimmunologie, CCM, Charité‐Universitätsmedizin Berlin, Germany
E‐mail address: [email protected]
Background: Helixor® A is a mistletoe extract widely used in integrative medicine as supplementary medication, e.g., in breast cancer patients with aggressive tumors. Since checkpoint inhibitors, like atezolizumab (PD‐L1 blocker) and pembrolizumab (PD‐1 blocker), are becoming more widely used to treat such patients, it is important to research the interactions of Helixor® A, and these antibodies.
Methods: 2D cell culture experiments were carried out with the cell lines HCC1937 and T47D. These cell lines were also used to form spheroids for further experiments. The BC cell lines and K562 cells were used as target cells for testing of NK cell activity. For this, all three cell lines were modified to express NanoLuciferase in a stable manner to be used to carry out NK cell activity assays. The NK cells were isolated from healthy human donor blood/buffy coats according to standard procedures. The effect of Helixor® A, pembrolizumab and atezolizumab were tested alone and in combination at concentrations of 1 μg/ml and 10 μg/ml, respectively on NK cell activity. Surface marker expression (CD63, EpCAM, PD‐L1, and CEACAM5) on BC cells was analyzed by the use of a flow cytometer.
Results: There was no effect of Helixor® A on NK cell activity under the conditions tested. It seems that Helixor® A doesn't hinder nor aid the target cell lysis with PD‐1 negative or PD‐1 low expressing NK cells from healthy donors. Moreover, Helixor® A doesn't significantly affect the effect of atezolizumab or pembrolizumab on NK cell activity. On the other hand, it was found that in BC spheroids, Helixor® A significantly reduces PD‐L1 expression.
Conclusion: These findings highlight the importance of studying potential cancer therapies in spheroid models rather than in a 2D cell culture model. Not only were PD‐L1 expression levels different, but also the effect of Helixor® A on this marker was only significant under 3D conditions. Furthermore, in regard to the cytotoxicity assays and the effect of Helixor® A on NK cell activity, a different effect on NK cell‐mediated cytotoxicity was also seen when comparing the two culture conditions.
41. Inhibition of Colorectal Cancer Cell Line Growth by Mistletoe Extracts
Sebastian Wolfshöfer1, Martina Gast1, Friedemann Schad2, Hedwig Lammert3, Michael Hummel3, Sebastian Stintzing1, Patricia Grabowski1,2
1Charité – University Medicine Department of Hematology, Oncology and Cancer Immunology | CCM, Germany, 2Gemeinschaftskrankenhaus Havelhöhe, Interdisciplinary Oncology and Palliative Care, Berlin, Germany, 3Charité ‐ Universitätsmedizin Berlin ‐ Institute of Pathology | CCM, Germany
E‐mail address: [email protected]
Introduction: Colorectal carcinomas are among the most frequent malignant tumors diagnosed in Germany. As metastasis is common after surgical removal of primary tumors, adjuvant chemotherapy is considered standard treatment for patients. However, many patients develop resistance to chemotherapy or progress during the course of the disease. Extracts produced of mistletoe (Viscum album) are often administered in combination with chemotherapeutic agents to improve quality of life for patients, by reducing side effects. Mistletoe extracts can differ substantially in their composition, depending on the host tree species and the harvesting time. Mistletoe extracts show immunomodulating properties that may improve effectivity of tumor therapy. Moreover, in vitro experiments suggest a direct effect on growth and proliferation of colorectal cancer cell lines. However, the involved intracellular pathways and the capacity of the anti‐tumorigenic potential are not well characterized, yet.
Methods: We used the MTT‐assay to analyze the effects of two mistletoe extracts, Helixor A® (host: fir) and Helixor M® (host: apple tree), on cell viability in different colorectal cancer cell lines (Caco2, HT‐29, SW48, SW480, HCT116, p53 deficient HCT116) and determined the half inhibitory concentration after 72 h of treatment. Cell cycle was analyzed by flow cytometry. In addition, we performed multiplex gene expression analyses to assess involved signaling pathways.
Results: Both mistletoe extracts reduced cell viability in a dose‐dependent manner. Helixor A® extract was more potent than Helixor M® in all six cell lines. SW480 and Caco2 cells were most susceptible to both extracts. Compared to 5‐FU treated controls, the addition of mistletoe extract to 5‐FU therapy reduced cell viability by approximately 50% in SW480 cells and by 30% in Caco2 cells, indicating an additive effect. Gene expression analysis revealed the involvement of mitochondrial signaling and Myc signaling. These results were validated by Western blot analysis.
Conclusions: These experiments demonstrate that mistletoe extracts can inhibit proliferation in colorectal cancer cells alone and in combination with 5‐FU in vitro. Further validation of gene expression analysis results and additional combinatory treatment experiments may contribute to provide a rationale for investigation of mistletoe extracts as therapeutic agents in vivo and in clinical trials.
42. In Vitro Mutagenicity Assessment of Aqueous Viscum album L. Preparations
Ilona Zilkowski, Claudia Turek, Nora Mörbt, Peter Vögele, Florian C. Stintzing
WALA Heilmittel GmbH, Bad Boll/Eckwälden, Germany
E‐mail address: [email protected]
Background: Viscum album L. preparations obtained from different host trees, conifers as well as deciduous trees are frequently used in complementary therapy to treat cancer patients. Genotoxic potential of herbal substances and preparations therefrom can be assessed in vitro [1], complementing already existing preclinical and clinical safety data [e.g. 2]. Here we present test results of eight different Viscum album L. preparations produced according to the official method 38 of the German Homeopathic Pharmacopeia.
Methods: Viscum album L. preparations were produced according to current pharmaceutical standards using mistletoe from eight different host trees. The preparations Iscucin® Abietis (fir), Crataegi (hawthorn), Mali (apple), Pini (pine), Populi (poplar), Salicis (willow) and Tiliae (lime) (all strength H, dilution 1:20, 50 mg/ml) and Iscucin® Quercus (oak) (strength F, dilution 1:8000, 0.125 mg/ml) (WALA Heilmittel GmbH, Bad Boll, Germany) were tested for their mutagenic potential in an in vitro bacterial reverse mutation assay, with and without exogenic metabolic activation, following OECD standards [3].
Results: Under the experimental conditions reported, none of the preparations induced gene mutations by base pair changes or frameshifts in the genome of the bacterial strains used.
Conclusion: None of the tested Viscum album L. preparations caused gene mutations. Thus, all were considered non‐mutagenic in this official OECD assay. These new data contribute to a more differentiated preclinical safety assessment of the tested aqueous mistletoe extracts derived from different host trees.
References
[1] HMPC. Guideline on the assessment of genotoxicity of herbal substances/preparations. EMEA/HMPC/107079/2007. London: European Medicines Agency (EMA); 2008.
[2] Huber et al. Safety and effects of two mistletoe preparations on production of interleukin‐6 and other immune parameters ‐ a placebo controlled clinical trial in healthy subjects. BMC Complementary and Alternative Medicine 2011, 11:116.
[3] OECD. Test No. 471: Bacterial Reverse Mutation Test, OECD Guidelines for the Testing of Chemicals. Section 4. Paris: OECD Publishing; 2020. p. 1‐11.
Clinical Practice and Clinical Research
43. Case Series on the Oral Use of a Mistletoe Extract in Equine Sarcoid
Ophélie Clottu1, Ulrike Biegel1, Marcus Reif2
1Forschungsinstitut für biologischen Landbau (FiBL) Frick, Switzerland, 2Gesellschaft für klinische Forschung e.V., Berlin, Germany
E‐mail address: [email protected]
Background: Equine sarcoid is the most common skin tumor in horses and despite a large number of available therapies, treatment of this disease continues to be a challenge for the practitioner. In an RCT study (Christen‐Clottu et al. 2010) subcutaneous mistletoe injections showed a significantly higher rate of sarcoid regression than placebo treatment.
Hypothesis: Oral application of mistletoe treatment would also be effective in the treatment of sarcoid.
Purpose: Proof‐of‐Concept of the oral application of mistletoe extract (MEoral) (Iscador® P Iscador AG, Arlesheim, Switzerland) in practice and comparison with the placebo group of the RCT study (PLRCT).
Method: 9 horses and one donkey, aged 3‐10 years, with 1‐10 sarcoids each were treated orally with mistletoe extract (Iscador® P, 0.1‐20mg aqueous extract of pine mistletoe) in a manner similar to the RCT protocol (3 doses/week for 15 weeks +1‐year follow‐up). The treatment was administered directly into the mouth or mixed with some food.
Results: Five horses and one donkey showed complete regression of all sarcoids (60%). Three horses showed a decrease in the number of sarcoids, one horse an increase. In comparison, of the 20 PLRCT horses, only 3 showed complete regression of sarcoids (15%). Although the two groups of horses were comparable before treatment regarding the number of sarcoids (number of ES, mean ± SD: PLRCT 5.3 ± 3.2, MEoral 5.0 ± 3.1) and lesion area (area: PLRCT 3.8 ± 2.1, MEoral 4.7 ± 2.6), significant differences were found between the two groups in the evolution of sarcoids during the treatment period until the end of the observation period (change in number of ES: PLRCT +0.2 ± 2.5; MEoral ‐2.3 ± 2.1; decrease in area/month: PLRCT +0.015 ± 0.248; MEoral ‐0.234 ± 0.220).
Conclusion: These encouraging results are a first indication of the use of oral mistletoe extracts as a viable and effective method of treatment of equine sarcoid. A randomized double‐blind study of 45 horses is currently underway to verify these results.
Literature:
Christen‐Clottu O, Klocke P, Burger D, Straub R, Gerber V: Treatment of clinically diagnosed equine sarcoid with a mistletoe extract (Viscum album austriacus). J Vet Intern Med. 2010; 24(6): 1483–9.
44. Misteltherapie.de: The New Website for Mistletoe Therapy in Oncology
Friedemann Schad1,2, Anja Thronicke1, Marion Debus3, Georg Soldner4
1Research Institute Havelhoehe at the Hospital Gemeinschaftskrankenhaus Havelhöhe, Berlin, Germany, 2Interdiscplinary Oncology and Palliative Care, Hospital Gemeinschaftskrankenhaus Havelhöhe, Berlin, Germany, 3Clinic Arlesheim, Arlesheim, Switzerland, 4Medical Section at the Goetheanum, School of Spiritual Science, Dornach, Switzerland
E‐mail‐address: [email protected]
Purpose: The number of scientific‐clinical publications on the European mistletoe (Viscum album L., VA) in oncology is steadily growing. The communication of the scientific findings to the patients and the professional public plays a crucial role. The aim of the present project was to create a clearly arranged website being continuously updated to reflect the current state of knowledge on mistletoe therapy and, at the same time, to meet the demands of interested clinicians, experts, cancer patients and regulatory authorities.
Methods: The www.mistletoe‐therapy.de website was launched in September 2019 by an expert panel of practicing clinicians, researchers, and IT specialists. Within the last 3.5 years, all current clinical studies on anthroposophic mistletoe therapy in oncology were scientifically and informatively prepared for the different target groups and presented on the website.
Results: The website www.mistletoe‐therapy.de provides physicians, scientists, patients, and the professional public with an up‐to‐date overview of the mechanisms of anthroposophic mistletoe therapy, details of its research and a sound overview of its clinical evidence in oncology. It continues to provide information on the use and safety of mistletoe preparations, taking into account current guidelines, systematic reviews and meta‐analyses, randomized controlled trials, and real‐world data studies. In a recent publication of the website team, add‐on mistletoe therapy was found to have good evidence in improving health‐related quality of life (HRQL) in breast cancer and prolonging survival in advanced pancreatic cancer. The manuscript also recommends that new or updated guidelines in the field of gastrointestinal tumors, gynecologic tumors, and lung cancer should include clearer recommendations on integrative therapies, including mistletoe therapy. The website information is also available in English and Spanish. As of May 2023, the current user base was over 10.000 per month and has quintupled since launch.
Conclusions: For three and a half years, the current medical and scientific state of knowledge on the mistletoe therapy in oncology has been made available via the website www.mistel‐therapie.de. Additional analyses of the literature revealed good evidence for add‐on mistletoe therapy of improving HRQL of breast cancer patients and prolonging survival in pancreatic cancer. The increasing numbers of national and international users of the website show the acceptance of this online information source.
45. Efficacy of Tango Argentino on Cancer‐Associated Fatigue in Breast Cancer Patients
Shiao Li Oei1, Anja Thronicke1, Thomas Rieser1,2, Sarah Becker3, Jessica Groß3, Harald Matthes1,2, Friedemann Schad1,4
1Research Institute Havelhoehe at the Hospital Gemeinschaftskrankenhaus Havelhöhe, Berlin, Germany, 2Institute for Social Medicine, Epidemiology and Health Economics, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt‐Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany, 3Breast Cancer Centre, Hospital Gemeinschaftskrankenhaus Havelhöhe, Berlin, Germany, 4Interdiscplinary Oncology and Palliative Care, Hospital Gemeinschaftskrankenhaus Havelhöhe, Berlin, Germany
E‐mail address: [email protected]
Purpose: Persistent impairments of quality of life, in particular cancer‐associated fatigue, are major limitations for breast cancer patients and survivors. The objective of this study was to investigate the effectiveness of a six‐week Argentine tango program on self‐reported fatigue and further quality of life outcomes of breast cancer patients.
Methods: In a randomized controlled TANGO trial 60 eligible participants diagnosed with stage I‐III breast cancer 12‐48 months prior to study enrollment, and having increased symptoms of fatigue were included and randomized 1:1 into a tango or waiting group. The tango program consisted of six weekly one‐hour tango group sessions. Self‐reported quality of life (QoL) and fatigue were assessed by the evaluation of the European Organization of Research and Treatment Health‐Related Quality of Life Core Questionnaire scale (EORTC QLQ‐C30) and the German Cancer Fatigue Scale (CFS‐D). Pre‐post analysis of changes in QoL and also 6 and 12 months thereafter for the entire tango cohort were performed and compared with a of historical control cohort of breast cancer survivors having increased fatigue levels 12 months after their primary diagnosis.
Results: A total of 52 participants of the TANGO trial completed the tango and waiting assessments. Significant and clinically meaningful between‐group differences with superiority for the tango group in fatigue (d = ‐0.64; 95%CI, ‐1.2 to ‐0.08; P = .03) were observed. Additionally, superiority for the tango group was detected for symptoms of diarrhea (d = ‐0.69; 95% CI, ‐1.3 to ‐0.1; P = .02). Pre‐post analyses of 50 participants who completed the 6‐week tango program revealed significant improvements in several QoL outcomes, particularly a 10% improvement in fatigue, social functioning (P = .02), insomnia (P = .008), and diarrhea (P = .01). At six‐month follow‐up, significant and substantial improvement in fatigue (P = .006) and diarrhea (P = .04) was still detectable for the 50 tango participants, whereas no significant improvement in symptoms of fatigue or diarrhea was observed over the consecutive 12 months in the historical control cohort of 108 breast cancer survivors.
Conclusions: This TANGO randomized controlled trial revealed that a six‐week Argentine tango program significantly reduced fatigue symptoms in breast cancer patients and that this improvement in fatigue persisted for at least six months.
46. European‐US Collaboration to Put Iscador in the Pediatric Oncology Pipeline: Lessons Learned
Katharine Offer1, Marcus Reif2, Karen Moody3
1Joseph M. Sanzari Children's Hospital, Hackensack Meridian Health (HUMC), Hackensack, NJ, USA, 2Iscador AG, Berlin, Germany, 3M.D. Anderson Children's Cancer Hospital (MDACC), Houston, TX, USA
E‐mail address: [email protected]
Background: Many cancers affecting children are rare and often lack standard treatment guidelines for relapse/recurrence. Pediatric oncology urgently needs novel, in particular safe, therapies. Although Viscum album is a well‐established complementary cancer therapy in Europe, in the United States (US), most oncologists are still unaware of its use. Viscum album can be obtained there through integrative medicine centers, yet it is not regulated and not generally used in conventional medical practice. Currently, there has only been one clinical trial in the US using Viscum album (NCT03051477) but none in children.
Aim: In an effort to broaden access to one promising cancer therapy for pediatric patients, European scientists and clinicians in the US from two pediatric oncology programs have designed a clinical trial to study subcutaneous Iscador P (Viscum album Pini, 0.01‐20mg) for improving the event‐free survival of pediatric patients with relapsed osteosarcoma after complete resection of pulmonary metastases (NCT05726383). This trial is near to actively enrolling. During this development, we have learned several important lessons, and by sharing these we may make the goal of opening clinical trials of such therapies in the US more attainable.
Conclusions: 1. The success of introducing a naturally derived agent into the US pediatric oncology pipeline depends on the strength of published preclinical and clinical data, to which we fortunately had access for Iscador P. This included a small study by Longhi et al. of 9 patients from a similar population with promising results even during long‐term follow up. There was also plentiful safety data even in the pediatric population, which allowed us to forgo a phase 1 and move directly to a phase 2 study.
2. The manufacturing process of these plant‐derived therapeutics needs to be very clearly described in order to gain both regulatory and institutional approval. The strict GMP and QA/QC procedures used in Iscador P manufacturing were beneficial in obtaining approval of a Food and Drug Administration (FDA) Investigational New Drug application as well as approval through the pharmacy departments of HUMC and MDACC. The FDA accepted a European IMPD in place of a Drug Master File.
3. As with any collaboration, one challenge in opening this study was navigating multiple IRBs and contract offices at separate institutions, each with different processes. This process was not found to be complicated by the international nature of the collaboration.
47. Mistletoe Therapy in Context of a Multimodal Treatment in a Patient with Severe Cancer Survivorship Fatigue Syndrome with Comorbid Sleep Disorder: A Case Report
Timotheus Haeck1, Ana Paula Simões‐Wüst1, Sibylle Creutz von Essen2, Florian Strasser3, Matthias Kröz1,4,5,6
1Department of Research, Klinik Arlesheim, Switzerland, 2Oncology, Klinik Arlesheim, Switzerland, 3Cancer Fatigue Clinic, Schaffhausen, Switzerland, 4Sleep medicine, Klinik Arlesheim, Switzerland, 5Institute for Integrative medicine, University Witten/Herdecke, Germany, 6Research Institute Havelhöhe, Berlin, Germany
E‐mail address: timotheus.haeck@klinik‐arlesheim.ch
Background: Cancer‐related fatigue (CRF) is a frequent and burdensome syndrome in cancer patients related to disturbed sleep. We report the case of a female patient suffering from severe chronic CRF triggered by a carcinoma in situ of the vocal cord – diagnosed 2017 – and the consecutive surgery and radiotherapy. The CRF accompanied by cognitive fatigue and hypersomnia was aggravated by a post‐traumatic‐stress‐disorder.
Treatment & Results: The patient was treated with a multimodal therapy (MT) from 08.2018‐10.2022 to tackle the complex dysregulation. The MT consisted of three mainstays: 1) subcutaneous (sc.) and intravenous (iv.) mistletoe applications, 2) cancer‐fatigue rehabilitative interventions (aerobic‐, strength‐training, relaxation‐, mindfulness‐, nutrition and psychotherapy) and 3) sleep‐therapy based on sleep hygiene and restriction, stimulus control (CBTI), and Zincum valerianicum D3 and Bryophyllum 50% chewable tablets to treat the Restless‐Legs‐Syndrome (RLS)/Periodic‐leg‐movements and hindering supine sleep‐position due to borderline sleep apnoea in supine positions (OSA). The mistletoe therapy started in August 2018 and consisted mainly of sc.‐injection with Iscador P (1.1mg/week‐20mg/week), infusions of Helixor P (50mg/week‐550mg/week), Abnobaviscum Fraxini D30 (1ml/application) and endothermic infusions with Iscador M (12mg‐24mg/infusion). In June 2020 the rehabilitation intervention and in February 2022 the sleep therapy started. With the mistletoe therapy and the rehabilitation therapy the CRF was slowly reduced. Upon inducing fever until 39.5°C, the patient reported short‐term reduction of the severe fatigue (Fatigue‐Numerical Scale (FNS) values reduced from 6/10 (morning) and 9/10 (afternoon) to 3/10 (morning) and 5‐6/10 (afternoon) up to 2‐3 days). Beginning with sleep therapy and additional lavender oil applications on the legs before going to bed in 02.2022, the patient reduced RLS‐symptoms and improved clinically relevantly daytime sleepiness and hypersomnia (from 12.5 h to 8‐10h) and sleep quality (from 6.9/10 to 8.1/10 in the timeframe from 2/22‐ 8/22). The fatigue reduced in the Cancer Fatigue Scale (CFS‐D) from 44 to 42 in that timeframe. However, cognitive fatigue persisted (CFS‐D: 15/20), consistent with no change in moderate neuropsychological dysfunction.
Conclusion: Mistletoe therapy can contribute in CRF‐treatment. However, fatigue and sleep quality improved sustainably under multimodal therapy. Further research on multimodal approaches to treat severe CRF is highly needed.
48. Viscum album Lipophilic Extract in Actinic Keratosis, Cutaneous Squamous Cell Carcinoma and Basal Cell Carcinoma: A Multinational Retrospective Case Series
Karolina Königsberger1,2, Florian Pelzer1,2, Wilfried Tröger2, Marcus Reif3, David Martin1, Stephan Baumgartner1,2
1Institute for Integrative Medicine, Witten/Herdecke University, Germany, 2Society for Cancer Research, 4144 Arlesheim, Switzerland, 3Society for Clinical Research, 10623 Berlin, Germany
E‐mail address: [email protected]
Background: Cutaneous squamous cell carcinoma (CSCC) and basal cell carcinoma (BCC) belong to the group of non‐melanoma skin cancers (NMSC), actinic keratosis is a precursor lesion of CSCC. The incidences of CSCC, BCC and AK are currently strongly increasing (1).
Hydrophilic mistletoe extracts have been used in anthroposophic cancer therapy since 1917. Viscum album Lipophilic extract (VALE) is a new approach that has been developed at the Society for Cancer Research in Arlesheim, Switzerland (1). This retrospective case series assessed the safety, tolerability and clinical effects of the topical application of VALE in AK, CSCC and BCC.
Methods: The main target parameters were the clinical response to treatment with VALE (following the RECIST classification (2)) and adverse drug reactions (ADR). Risk factors, concomitant therapies and diseases, further diagnostic and therapeutic information were documented where available. Data analysis was performed both on the level of individual cases and of the whole population.
Results: The study population consisted of 55 patients with 74 skin lesions. The analysis of clinical response of all treated lesions showed a complete remission rate of 24% and a clinical response rate (complete + partial remission) of 71%. Separately for diagnoses, there was a remarkable difference in complete remission rates between AK (15%), CSCC (56%) and BCC (35%) whereas clinical response rates were similar among the three diagnoses (71%, 78% and 70%). ADR were observed in 5 patients. These were erythema and inflammatory reactions of mostly moderate severity that resolved completely. In one case, therapy was temporarily paused, in four cases it was continued without interruption. (3)
Conclusion: The results of this study suggest that VALE is a safe and tolerable drug under whose application complete and partial remissions of AK, CSCC and BCC could be observed. To assess the efficacy of VALE, prospective investigations are necessary and under current preparation.
References
1. Urech K. Entdeckung von pharmakologischen Wirkungen des Mistelleims Viscin. Arlesheim: Verein für Krebsforschung; 2004.
2. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228‐47.
3. Königsberger K: Anwendung eines Harz‐Extraktes aus Viscum album bei aktinischer Keratose, kutanem Plattenepithelkarzinom und Basalzellkarzinom. Dissertation. Universität Witten/Herdecke; 2022.
49. Mistletoe Therapy During Pregnancy: A Historical Review
Ana Paula Simões‐Wüst1,2 Daniel Krüerke1,3
1Klinik Arlesheim, Research Department, Arlesheim, Switzerland, 2Department of Obstetrics, University Hospital Zurich, University of Zurich, Zurich, Switzerland, 3Society for Cancer Research, Hiscia Research Institute, Arlesheim, Switzerland,
E‐mail address: anapaula.simoes‐wuest@klinik‐arlesheim.ch
Background: Medications prescribed during pregnancy can significantly affect the mother and the unborn child, making their use a sensitive issue. The safety of mistletoe therapy during pregnancy has long been a concern for physicians and expectant mothers alike. However, to date, no clinical studies have been conducted on this topic.
Methods: We present a historical overview of the limited research on the use of mistletoe therapy during pregnancy. These include the results of a physician survey initiated by Dr. Rita Leroi in the 1980s and completed by Dr. Maria Fornalski in the 1990s, as well as the cases reported in the publication of Dr. Weidemann and Ralf Aden [1]. Additionally, literature searches were performed in Pubmed and Google Scholar.
Results: In the 1980s, Dr. Leroi contacted numerous anthroposophical gynecologists in the Federal Republic of Germany, requesting that they complete a questionnaire on mistletoe treatment in pregnancy and potential side effects on mother and child. The survey documented 27 pregnancies between 1965 and 1995, with an average mistletoe therapy duration of 8 months. Twenty‐seven healthy children, including one set of twins, were born without malformations. One child was born with a cardiac anomaly, classified as an unlikely consequence of mistletoe therapy. No information was available on additional medication, risk factors and the total number of physicians contacted. A later cover letter suggests a possibly low response rate. The 2017 edition of the “Vademecum Anthroposophical Medicines” reports 50 cases in which mistletoe therapy was used during pregnancy. Literature searches as of March 2023 confirmed the absence of clinical studies on the safety of mistletoe therapy during pregnancy.
Conclusion: While the collected information provides some encouraging feedback, our understanding of the prevalence and safety of mistletoe therapy in pregnancy is still extremely limited. Assuming its safety merely due to the lack of reported adverse effects is insufficient and requires further investigation. Retrospective analyses of clinical data and relevant preclinical studies, such as ex vivo placental perfusion experiments, are warranted.
References
1. Angelika Weidemann and Ralf Aden, Auswertungen des Tumor‐Krankengeschichten‐Archives der Praxis Emme, (1992) Der Merkurstab 45(3) 199‐216.
50. Safety, Tolerability, Therapeutic Efficacy and Quality of Life (QoL) Assessment of Patients with Malignant Urogenital Tumors Upon Treatment with Iscucin® Populi: Results of a Non‐Interventional Study (NIS)
Jennifer E. Felenda, Claudia Turek, Florian C. Stintzing
WALA Heilmittel GmbH, Bad Boll/Eckwälden, Germany
E‐mail address: [email protected]
Introduction and Background: Mistletoe preparations are frequently applied in complementary medical tumour therapy [1]. Iscucin® Populi (Isc. pop.; WALA Heilmittel GmbH, Bad Boll, Germany) is a preparation made of mistletoe from poplar trees. In anthroposophical medicine, its potential is assigned to the metabolic‐limb system. On this basis, the preparation is often used in treatment of bladder and prostate cancers [2].
Methods: Eight physicians in Germany included 72 patients treated with Isc. pop. strength A (1:1.024x1013) to H (1:20), suffering from malignant urogenital tumors (MUT) under routine conditions into this NIS. All patients were observed for a period of approximately 1 year.
Results: In the intention‐to‐treat analysis, 69 patients (96 % males, mean age 71 years) suffered from prostate (87 %) and/or bladder (15 %) carcinoma, from less than 6 months to more than 5 years before Isc. pop treatment. Conventional tumor therapies were in line with existing clinical practice guidelines [3, 4, 5, 6]. Physicians prescribed Isc. pop. mostly in addition to current therapies. Treatment regimens were determined individually. 64 % of the patients received an effective dose of strength H (50 mg/ml aqueous mistletoe extract) and 20 % strength G (2.5 mg/ml), respectively.
During the study, the number of patients with progression decreased, while more patients went in remission. At baseline, 29 patients already had an event regarding recurrence, second malignancy or/and metastases. During treatment, ten patients developed at least one event or died (n = 7). The physicians reported that general condition and QoL was mostly very good until decease. Regarding QoL, all functional and symptom scales improved and patients' sensitivity to cold decreased. Stated reasons for evaluating a good global efficacy were improvement/stabilisation of general conditions, stable tumor status (decreased tumor marker prostate specific antigen), reduced pain, increased vitality, and improved mood. Global tolerability was rated very good. 91 % of the patients would decide for treatment with Isc. pop. again.
Summary and Conclusion: Isc. pop. is prescribed as a curative, adjuvant, or palliative treatment across all degrees of severity of MUT. In this NIS, patients' tumor status mostly stabilised, which was reflected by improvement of remission status and decreased tumor marker. QoL of patients improved during the treatment with Isc. pop.
References
1. Kienle GS, Berrino F, Büssing A, Portalupi E, Rosenzweig S, Kiene H: Mistletoe in cancer ‐ a systematic review on controlled clinical trials. Eur J Med Res. 2003 Mar 27;8(3):109‐19. PMID: 12730032.
2. Wilkens J: Misteltherapie. Differenzierte Anwendung der Mistel nach Wirtsbäumen. 1. Auflage. Stuttgart: Sonntag Verlag, 2006: 79‐84
3. Wolff JM et al.: Leitlinie F1 Prostatakarzinom. Arbeitsgemeinschaft urologische Onkologie e.V. (AUO): 2008.
4. Wirth M et al.: Interdisziplinäre Leitlinie der Qualität S3 zur Früherkennung, Diagnose und Therapie der verschiedenen Stadien des Prostatakarzinoms. Deutschen Gesellschaft für Urologie (DGU): 2009.
5. Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF): Interdisziplinäre Leitlinie der Qualität S3 zur Früherkennung, Diagnose und Therapie der verschiedenen Stadien des Prostatakarzinoms, Langversion 5.1, 2019, AWMF‐Registernummer: 043/022OL, http://www.leitlinienprogramm-onkologie.de/leitlinien/prostatakarzinom (website last accessed 21.06.2023).
6. Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF): S3‐Leitlinie Früherkennung, Diagnose, Therapie und Nachsorge des Harnblasenkarzinoms, Langversion 1.1, 2016, AWMF‐Registrierungsnummer 032/038OL, http://leitlinienprogramm-onkologie.de/Harnblasenkarzinom.92.0.html (website last accessed 21.06.2023).
51. Improvement of Quality of Life in Lung Cancer Patients Receiving Targeted Oncological Treatment in Combination with Viscum album L.
Shiao Li Oei1, Anja Thronicke1, Patricia Grabowski2,3, Hannah Wüstefeld4, Christian Grah4, Friedemann Schad1,2
1Research Institute Havelhoehe at the Hospital Gemeinschaftskrankenhaus Havelhöhe, Berlin, Germany, 2Interdisciplinary Oncology and Palliative Care, Hospital Gemeinschaftskrankenhaus Havelhöhe, Berlin, Germany, 3Institute for Medical Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt‐Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany, 4Lung Cancer Centre, Hospital Gemeinschaftskrankenhaus Havelhöhe, Berlin, Germany
E‐mail address: [email protected]
Purpose: Lung cancer (LC) is associated with high mortality and a poor quality of life (QoL) but due to diagnostic and treatment advances, the prognosis and survival of LC patients are increasingly improving. Add‐on Viscum album L. extracts (VA) are frequently used in integrative oncology to enhance QoL. The aim of this study was to analyze the self‐reported QoL of LC patients in a real‐world setting.
Methods: The real‐world‐data (RWD) study was conducted using data from an oncological registry accredited by the German Cancer Society. The study received positive ethics approval and was registered (DRKS00013335 on 27/11/2017). Self‐reported QoL of LC patients was assessed by evaluation of the European Organization of Research and Treatment Health‐Related Quality of Life Core Questionnaire scale (EORTC QLQ‐C30). Association factors of QoL were analyzed by adjusted multivariate linear regression analyses, using the software R.
Results: A total of 112 primary LC patients (all stages, median age 70 years) answered QoL questionnaires at diagnosis and 12 months later. In addition to guideline‐oriented standard systemic oncological treatments 53 (47%) patients received VA applications. Targeted treatments including immune checkpoint inhibitors were given to 47 (42%) patients, 36 of them in combination with VA applications. Twelve months after diagnosis significant and clinical improvements in global health by 14‐points (p = 0.01), symptoms of fatigue 12‐points (p = 0.05), and constipation 19‐point (p = 0.01) were observed in patients receiving combined targeted/VA treatment.
Conclusions: Add‐on VA therapy seems to be associated with an improved self‐reported QoL in LC patients 12 months after diagnosis. Beneficial associations were observed with the combined targeted/VA treatment.
52. Combined Targeted and Helixor® Viscum album L. Therapy in Breast and Gynecologic Cancer Patients: A Real‐World Data Study
Anja Thronicke1, Shiao Li Oei1, Patricia Grabowski2,3, Friedemann Schad1,2
1Research Institute Havelhoehe at the Hospital Gemeinschaftskrankenhaus Havelhöhe, Berlin, Germany, 2Interdiscplinary Oncology and Palliative Care, Hospital Gemeinschaftskrankenhaus Havelhöhe, Berlin, Germany, 3Institute for Medical Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt‐Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
E‐mail address: [email protected]
Purpose: Targeted therapy, the foundation of precision medicine, consists of monoclonal antibodies or small molecules that control cancer cell survival, growth and mobility. Targeted therapies have been shown to prolong survival in breast and gynecologic cancers. Clinical studies suggest that the add‐on administration of mistletoe (Viscum album L., VA) improves the health‐related quality of life of cancer patients and contributes to the attenuation of adverse effects of standard oncological therapy. The primary objective of the present real‐world data study was to evaluate the safety profile of combined targeted and Helixor® VA therapy in breast and gynecologic cancers.
Methods: The present real‐world data study included patients with all stages of breast or gynecologic cancer being registered at the accredited Network Oncology Registry and who received therapies with monoclonal antibodies, immune checkpoint inhibitors, tyrosine kinase inhibitors, PARP(poly‐ADP‐ribose polymer) inhibitors, or CDK (cyclin‐dependent kinase) 4/6 inhibitors with or without Helixor® VA. Demographic, clinical and safety data documented in the registry were analyzed. R software, version 4.1.3, was utilized for the univariate and adjusted multivariable regression analyses on the safety profile.
Results: A total of 242 patients were included, 160 patients (66.1%) with targeted therapy without additional Helixor® VA therapy (CTRL) and 82 patients (33.9%) with targeted and additional Helixor® VA therapy (COMB). Patients were on average 54.5 ± 14.2 years old. Helixor® A (68.3%) and Helixor® M (25.6%) were the most commonly used Helixor® VA extracts. The most common combination of targeted and Helixor mistletoe therapy was with monoclonal antibodies (81.7%). The safety profile of targeted therapy was not affected by the addition of Helixor® VA (χ2 = 0.107, p‐value = 0.99). In addition, a trend towards a reduction in adverse effects, including adverse events, dose reductions or treatment discontinuations was observed.
Conclusions: The present study provides a first insight into the safety aspects of combinatorial treatment with targeted therapies and Helixor® VA in patients with breast cancer and gynecological diseases. The results show that additional treatment with Helixor® VA does not negatively alter the safety profile of all five targeted therapy groups studied. Further clinical studies with a larger cohort and the inclusion of additional cancer types are in preparation.
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Journal of Integrative and Complementary Medicine
Volume 29 • Issue Number S1 • September 2023
Pages: A-1 - A-24
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Copyright 2023, Mary Ann Liebert, Inc., publishers.
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Published online: 20 October 2023
Published ahead of print: 15 September 2023
Published in print: September 2023
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