Mistletoe Therapy

For thousands of years, mistletoe has been viewed as one of the most magical, mysterious, and sacred plants in nature. Mistletoe, or Viscum, was used by the Druids and the ancient Greeks, and appears in legend and folklore as a panacea. The modern tradition of kissing under the mistletoe can be traced back to ancient mistletoe lore. Mistletoe is a parasitic plant that attaches to and penetrates the branches of a tree or shrub by a structure called the haustorium, through which mistletoe absorbs water and nutrients from the host plant. Though there are hundreds of species of mistletoe worldwide, only Viscum Album is used to treat cancer. In the scientific community, mistletoe has been studied as an anticancer agent since the 1920s because its extracts have exhibited both cytotoxic and immunomodulatory properties. Currently, mistletoe extracts are used to treat a variety of conditions including cancer, HIV, hepatitis, and degenerative joint disease. In this article, I focus on the proven benefits, research, and application of injectable mistletoe extract in breast cancer treatment. Injectable mistletoe extract was first used for cancer therapy in the 1920s by Rudolf Steiner, Ph.D., and Dr. Ita Wegman based on anthroposophical medicine principles.1, 2, 3, 4 In Europe, mistletoe therapy is no longer controversial, and oncologists have continued to prescribe mistletoe extracts for the past 90 years. By some estimates, 40% of French5 and up to 60% of German cancer patients6 receive this botanical extract. The U.S. FDA, however, has not approved mistletoe as a treatment for cancer or any other medical condition. Accordingly, the FDA does not allow injectable mistletoe to be imported, sold, or used except for clinical research. Fortunately for patients in the U.S. there are still ways to obtain injectable mistletoe extracts from Europe, despite these government restrictions. Every year, Germans alone spend more than $30 million on mistletoe preparations as cancer treatment. Results of a national survey conducted in Germany in l995 by the Society for Biologic Cancer Defense found that mistletoe preparations were the most frequently prescribed botanical drug (80%) followed by trace elements, vitamins, enzymes, and xenogenic peptides like thymus preparations. In Germany, Switzerland, and Austria, mistletoe preparations are licensed medicines that are partly reimbursable through the official healthcare system. Actress, author, and breast cancer survivor Suzanne Somers revealed in her 2009 book Knockout that she opted to use mistletoe extracts in her breast cancer treatment. Despite its popularity and long usage in Europe, for many people in North America this was the first time that they had heard of mistletoe therapy. The U.S. medical media rarely covers ongoing evidence-based mistletoe research. Commercial Mistletoe Extracts

Mistletoe extracts are primarily manufactured in Europe and sold under brand names including:

• Iscador (also called Iscar)

• Helixor

• Eurixor

• Isorel (also called Vysorel)

• Iscucin

• Lektinol (also called Plenosol)

• abnobaVISCUM

Though there are several types of mistletoe extracts available in Europe, the most commonly prescribed is Iscador, which is distributed by Weleda AG in Schwäbisch Gmünd, Germany. The manufacture and quality assurance of Iscador is regulated by European law. Iscador is prepared by fermenting an aqueous extract of the whole mistletoe plant with Lactobacillus plantarum. The product is filtered to remove bacteria before standardization and packaging for injection. Formulations are labeled based on the tree from which the mistletoe was harvested. For example, Iscador M for malus (apple); Iscador P for pinus (pine); Iscador A for abies (fir); Iscador Qu for quercus (oak); and Iscador U for ulmus (elm), with different effects attributed to each type. Tree varieties of mistletoe are selected for different types of cancer, with Iscador M used most often in breast cancer.7 Apple tree mistletoe extracts have also proven beneficial for tumors of the lower abdomen (colon, bladder, uterus, and ovaries), and upper abdomen (stomach, liver, and pancreas). It is also important to understand that not all mistletoe preparations are similar. Some are made from whole plant extract (Iscador, Helixor) while others contain only mistletoe Lectin I, a single chemical from the mistletoe plant (Eurixor). Many of the Iscador preparations are also available with additional homeopathic dosages (D8) of certain metal salts — for example, malachite (copper carbonite), mercury sulphate and silver carbonite. These compositions are based on anthroposophical principles of treatment and augment the specific mistletoe treatment. Mistletoe Constituents and their Effects

Constituents of mistletoe with tumor-reducing components include specific lectins such as viscumin and viscotoxins, alkaloids, polysaccharides, and polyphenolic substances. Other components include carbohydrates, phenolic compounds, sterols, triterpenes, and amines.8 Isolation of lectin and alkaloid components of mistletoe extracts has yielded reproducible tumor-reducing properties. Mistletoe lectins are the most investigated single component of mistletoe extracts, with cytotoxic effects attributed in part to ribosome-inactivating properties and apoptotic induction.9 Lectins are proteins or glycoproteins with specific binding sites for sugars which are not antibodies or enzymes. Mistletoe lectins have been shown to induce macrophage and natural killer cell cytotoxicity10, stimulate phagocytosis of immune cells, increase TNFα, IL-1, IL-2, and IL-6 cytokine secretion, and enhance cytotoxicity effects on various cell lines in vitro.11 Mistletoe lectins also react with red blood cells and certain immunoglobulins, and have experimentally induced cytotoxicity by inhibiting protein synthesis on the ribosomal level. Their “A-chain properties” exhibit mitogenicity and inhibit synthesis in cell-free systems. A-chain properties are also candidates for construction of immuotoxins. Their “B-chain properties” activate macrophages and release lymphokines from lymphocytes, as well as inhibit allergen-induced histamine release from leukocytes and collagen-induced serotonin release from platelets.12 Hence, mistletoe lectins activate the immune system in several ways to reduce tumor growth. Specifically, three different mistletoe lectins have been isolated, and of these, viscumin and viscotoxins are the most researched. Viscumin has been shown to interfere with intracellular protein synthesis13, 14, stimulate the production of tumor necrosis factor15, 16, and activate leukocytes.17 Viscumin may also affect the processes of metastasis and apoptosis.18 Viscotoxins, or thionins, are cytotoxic, small molecular weight proteins that have a molecular structure similar to that of viscumin, but are more cytotoxic and able to induce cellular necrosis of tumors. Mistletoe viscotoxins are responsible for immunostimulant and tumor-inhibiting activities.19 Mistletoe alkaloids are also toxic for tumor cells, but have not been as extensively researched as the lectins. Mistletoe polysaccharides may have an immune boosting effect, by the stimulation of the neutrophil granulocytes.20 Mistletoe Extract Research

Mistletoe extracts have been extensively researched over the last 70 years. Numerous in vivo, in vitro and human studies have confirmed that mistletoe extracts can boost the immune system which enhances tumor destruction or shrinkage.21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 Most of the clinical studies on the efficacy of mistletoe extract on health-related quality of life and survival time have been conducted in Germany and Switzerland, with some in Russia, Serbia, and the Ukraine. Of the commercial mistletoe extracts, Iscador and Helixor are the most thoroughly researched. Iscador has produced the following results in breast cancer patients after one intravenous infusion: enhancement of phagocytic activity of white blood cells; significant increase in natural killer cell and antibody-dependent cell mediated cytotoxicity; and augmented levels of large granular lymphocytes.38 In 2007, in vitro research with Iscador Q, Iscador M, and Iscador P indicated that different Iscador preparations can induce cell cycle inhibition and tumor cell regression. Researchers observed complete inhibition of S-phase progression in MCF7 breast cancer cell line.39 Several human studies support the use of mistletoe extracts for cancer care. Most have shown mistletoe to reduce side effects of cytotoxic chemotherapy and radiotherapy, and to prolong survival.40, 41, 42 In human studies, mistletoe improved cancer-treatment related toxicities in patients with advanced non-small cell lung cancer43 and colorectal cancer44, and reduced symptoms and improved quality of life in patients with pancreatic45 and breast cancers.46 Mistletoe administered in conjunction with gemcitabine in patients with advanced solid tumors allowed higher gemcitabine doses to be used without apparent effects from mistletoe on gemcitabine pharmacokinetics.47 Epidemiological data also suggests a survival advantage following mistletoe treatment. In 2001, German researchers performed a multi-cancer prospective long-term epidemiological cohort study on the efficacy and effectiveness of Iscador on survival times including 10,226 patients with different types of malignancy. The survival times of the patient group treated with Iscador were superior to those of the control group. The authors found sufficient evidence to recommend Iscador for treatment of cancer in breast cancer patients with or without axillary metastases.48, 49 Another German study also reported benefits of mistletoe therapy in survival and tumor reduction in women with metastasized breast cancer.50 The above research confirms that mistletoe extracts, which contain a complex of oncologically relevant active substances and exert a variety of anticancer effects, appear to prolong survival times and promote tumor reduction in patients with various tumor types, especially breast cancer. Application and Dosages

Unfortunately, mistletoe extracts are often given in stage 3 or 4 cancer as a last resort after chemotherapy and radiation has failed, and after recurrences. So, data reflects this. When mistletoe extracts, like Iscador, is started earlier, metastasis and overall survival rates are more impressive. For many U.S. patients, the duration of Iscador treatment is also frequently too short. In European clinics, a typical treatment course of mistletoe can last several months to several years. The doses are gradually increased and adjusted depending on the patient's general condition, sex, age, and type of cancer. Mistletoe extract is typically given by subcutaneous injection, usually 1-3 times per week. The injection site is most often in the abdomen or thigh. Less commonly, mistletoe is given intravenously or directly into the tumor. Various Iscador preparations are available with uniform concentrations per package ranging from 0.0001 to 20 milligrams as well as in series (series 0, I, and II) with differing concentrations in one package. These figures do not refer to the content of the active agent in the ampoule but to the amount of plant material used to produce the fermented watery extract, measured in milligrams. IscadorM is the most commonly used type of injectable mistletoe for breast cancer and is available in different dosages as “serie 0, serie 1 and serie 2.” All dosages are individualized, starting lower (0.01 mg) and gradually increasing depending on patient reaction. In some cases, reaction to the first dosage can be very strong, even though it may be a homoeopathic dosage. Hence, the first injection should always be administered under a physician’s supervision. Later on, it is also possible for the patient, her partner, or another caretaker to administer the injection. Mistletoe extracts should never be injected into any of the following:

• The chest or arm where you had breast surgery – however, some physicians inject mistletoe directly into tumor sites

• Inflamed skin areas

• Radiation fields (areas that have received radiation therapy)

• Near recent surgical scars

Generally, there are two phases: an induction phase and a maintenance phase. It is necessary to estimate the reaction of the patient to mistletoe (Iscador) in the induction phase to avoid an initial reaction. One thus begins with a weak preparation. The course of events during the maintenance phase depends on the condition of the patient, what other therapies are being administered (e.g. chemotherapy or radiation therapy) and to what degree the cancer has spread. During the induction phase, one always begins with the dosage 0.01 mg and increases this very gradually until the individual dosage has been achieved. One should always begin with series 0, if possible, without metal additives. In the case of a definite reaction in the patient, series 0 should also be administered in the maintenance phase. Patients who show no reaction to series 0 should go on to series I. Series I is usually the recommended dose. The administration of series II or series III should only be attempted by experienced therapists and then only if there is no reaction in the patient. The question often arises if mistletoe extracts can be administered during cytotoxic chemotherapy or with hormone chemotherapy. Absolutely, yes. During cytotoxic chemotherapy, there is a decrease in white blood cells due to bone marrow suppression and mistletoe extracts have a stabilizing effect on this situation. One might, however, need to increase dosages during chemotherapy. There must, in other words, be stronger stimulation, but the need and dosage for this must be determined individually. Generally, the tolerance to chemotherapy is improved by the simultaneous treatment with mistletoe extracts like Iscador. Desired Reaction

After injection, there will be a reddening and slight swelling at the injection site. This so-called local reaction usually reaches a peak 2 - 3 days after the injection was given, then quickly disappears. This is considered neither an allergy nor a side effect, but rather the immunological reaction or body’s response to the mistletoe extract. Sometimes the injection site will itch a little. Dosage should be given to keep the diameter of the local reaction under 5 cm (2 in). If there is no reddening or swelling at the injection site, the dosage will need to be increased. If the local reaction is smaller than 5 cm (2 in), it is advisable to keep the dosage constant and not to increase it. If the local reaction is about 5 cm (2 in), the dosage will need to be reduced one step, whereas, if the local reaction is larger than 5 cm (2 in), the dosage will need to be reduced two dosage steps. If there is absolutely no reaction, even with series III, the type of mistletoe extract should be changed. The individual reaction dosage can also be assessed by:

• The improvement of general well-being and lessening of tumor-related pain.

• Temperature reactions, in the sense of a slight increase in body temperature.

• Improvement of immunological status, which can be documented as an increase in the T helper cells and a reduction in the T suppressor cells, as well as an increase in the eosinophils and the absolute lymphocyte count.

• The treating physician should be notified if a fever above 38 °C (100.4 °F) develops.

Length of Treatment

With most tumors, like breast tumors, one must consider that 80% of the recurrences and metastases appear during the first two years after primary therapy. It is therefore necessary that mistletoe be administered for at least two years. After two years of therapy, the treating doctor should decide whether it is possible to introduce longer pauses between the series. This depends on the individual risk, on the tumor size, and on the risk of possible metastasis. Mistletoe extracts are manufactured exclusively as ampules and must always be stored at room temperature (maximum 25 °C) or in a fridge (2 - 8 °C) in the closed package (protected from light). Mistletoe Extract Side Effects

Although mistletoe plants and berries are considered poisonous to humans, few serious side effects have been associated with mistletoe extract use. While hundreds of thousands of patients safely utilize mistletoe preparations each year, certain mild side effects can occur:

1. Local inflammation at the injection site. Redness and swelling may occur. This is a normal, harmless reaction, and indicates that the patient’s immune system is responding to the injection. If the area of redness is larger than 2 inches across, there may need to be an adjustment made in the dose or schedule of injections.

2. Rise in body temperature, which indicates stimulation of the immune system. It may be helpful to keep a daily log of morning and evening body temperatures, to document a temperature response. If the body temperature rises above 100.4°F then injections should be discontinued and the prescribing physician should be contacted. This degree of fever may indicate a new infection unrelated to the use of mistletoe.

3. Allergic reactions. Systemic allergic reactions have been reported, but are rare. This may include itching, rash, or swelling and should be reported immediately. Mistletoe therapy always begins with a very low dose, but the first injection should be done in the physician’s office so that any allergic reactions can be treated immediately. Politics and Legalities

Like so many inexpensive plant-based cancer remedies, mistletoe extracts do not reap high profits for any of the big pharmaceutical companies. For example, Iscador treatment costs in Europe range around 50-100 euros per month, compared to interferon treatment that can cost over $4000 per month. Despite growing international medical literature in support of Iscador, Heloxor, and other mistletoe extracts’ anticancer properties, it continues to be blacklisted by the American Cancer Society. The ACS has not changed its position on Iscador since it presented the following in 1982:51 “After careful study of the literature and other information available to it, the American Cancer Society does not have evidence that treatment with Iscador, an extract of mistletoe, results in objective benefit in the treatment of cancer in human beings. Lacking such evidence, the American Cancer Society would strongly urge individuals afflicted with cancer not to participate in treatment with Iscador.” The legalities of mistletoe extracts in the U.S. is confusing and ever-changing. The FDA has not approved the use of any mistletoe extracts as a treatment for cancer or any other medical condition, and does not allow injectable mistletoe extracts to be imported or used except for clinical research. The FDA still identifies mistletoe in its “review of some lethal herbal and related products commonly used in cancer patients.”52 Iscador is the only injectable mistletoe product approved for distribution by the FDA in accordance with its requirements for research use only. Although mistletoe extracts are not commercially available in the U.S., Iscador, Heloxor, and other mistletoe extracts are available from many European pharmacies. Physicians in the U.S. can order Iscador, Heloxor or others directly from European manufacturers, and Canadian and German apothekes may also be contacted online and by facsimile. Fortunately, individuals still report that mistletoe extract can be imported to the U.S. for personal use. Finding a local physician versed in mistletoe extract usage may be more problematic than acquiring it. In summary, mistletoe extracts, such as Iscador, are a popular cancer therapy in Europe, particularly Germany, Switzerland, Great Britain, France, and the Netherlands. Mistletoe extracts are inexpensive and can be easily self-administered. The cytotoxic efficacy of mistletoe extracts against cancer cells has been evaluated in numerous evidence-based studies, as well as in vitro and in vivo laboratory experiments, and mainly positive antitumor activities have been reported. It is well established that mechanisms underlying the anticancer activity of mistletoe involved apoptosis and immunomodulation/stimulation of pro-inflammatory cytokines. This points to an improved balance of the innate immune system. Mistletoe extract is generally not claimed to result in dramatic destruction of tumors. Instead, it is believed to slow the growth of tumors or even stop tumor growth altogether, and then lead to gradual tumor regression. Research shows that tumor cells regress and undergo a transformation from malignant forms to semi-malignant forms, then to chronic inflammation, and finally to normal forms. Studies confirm that mistletoe extracts prolong survival, improve quality of life, and can be tremendously useful in preventing recurrence, rendering them more relevant today than ever before. The following books are excellent resources for more information on mistletoe therapy: Mistletoe: From Mythology to Evidence-Based Medicine by K.S. Zänker and S.V. Kaveri, Mistletoe by Arndt Bussing, Iscador: Mistletoe in Cancer Therapy by Christine Murphy, and Mistletoe Therapy for Cancer: Prevention, Treatment and Healing by Johannes Wilkens and Gert Böhm.

Notes ______________________ 1. Rudolf Steiner PhD, an Austrian scientist and philosopher, was the founder of Anthroposophy. The word anthroposophy is derived from the Greek words Anthropos = man and Sophia = wisdom. Anthroposophy refers to a method of dealing with science and general life in a holistic way. It incorporates all fields of modern science into a spiritual and comprehensible approach. Steiner in association with the Dutch physician Dr. Ita Wegman founded the Medical Section at the Goetheanum (in Dornach, Switzerland (1876 – 1943). Dr. Ita Wegman in the 1920’s introduced the mistletoe preparation Iscador into clinical cancer treatments. Steiner theorized that the human body is subject to various forces, some of which result in cell growth and multiplication (“lower organizing forces”) and some of which control and organize cell growth to form tissues and organs (“higher organizing forces”). Steiner believed that the balance between these forces determined an individual’s susceptibility to cancer, with a serious imbalance promoting the development of cancer. 2. Steiner, R., Die Rätsel der Philosophie in ihrer Geschichte als Umriß dargestellt. (1914), pp. 1-696, Rudolf Steiner Verlag, Dornach 1985. 3. Steiner R, “Vortrag vom 2.4,” in (1920); Geisteswissenschaft und Medizin GA 312, vol. 312, pp. 242–262, Verlag der Rudolf Steiner-NachlaBverwaltung, Dornach, Switzerland, 1961. 4. Steiner, R., Grundlegendes für eine Erweiterung der Heilkunst nach geisteswissenschaftlichen Erkenntnissen. (1925), pp. 1-144, Rudolf Steiner Verlag, Dornach 1991. 5. Simon L, Prebay D, Beretz A, et al. Complementary and alternative medicines taken by cancer patients. Bull Cancer.2007; 94(5):483-488. 6. Schonekaes K, Micke O, Mucke R, et al. Use of complementary/alternative therapy methods by patients with breast cancer. Forsch Komplementarmed Klass Naturheilkd. 2003; 10(6):304-308. 7. Many of the Iscador preparations are also available with additional homeopathic dosages of certain metal salts - for example, malachite (copper carbonite), mercury sulphate and silver carbonite. These compositions are based on anthroposophical principles of treatment and augment the specific mistletoe treatment. 8. Jordan E, Wagner H (1986), Structure and Properties of Polysaccharides from Viscum album (L.); Oncology 43: suppl. 1, pp. 8-15. 9. Melzer J, Iten F, Hostanska K, et al. Efficacy and safety of mistletoe preparations (Viscum album) for patients with cancer diseases. A systematic review. Forsch Komplementmed. Aug 2009;16(4): 217-226. doi: 10.1159/000226249. 10. Klett CY, Anderer FA, “Activation of natural killer cell cytotoxicity of human blood monocytes by a low molecular weight component from viscum album extract,” Arzneimittelforschung, vol. 39, no. 12, pp. 1580–1585, 1989. 11. Goebell PJ, Otto T, Suhr J, et al. Evaluation of an unconventional treatment modality with mistletoe lectin to prevent recurrence of superficial bladder cancer: a randomized phase II trial. J Urol. Jul 2002;168(1):72-75. 12. Franz H (1986) Mistletoe Lectins and Their A and B Chains. Oncology 43: suppl. 1, pp. 23-24. 13. Stirpe F, Sandvig K, Olsnes S, Pihl A. Action of viscumin, a toxic lectin from mistletoe, on cells in culture. J Biol Chem 1982;257(22):13271-7. 14. Walzel H, Jonas L, Rosin T, Brock J. Relationship between internalization kinetics and cytotoxicity of mistletoe lectin I to L1210 leukaemia cells. Folia Biol (Praha) 1990;36:181-8 15. Locock RA. Mistletoe. Can Pharm J 1986;(Mar):125-7. 16. Mannel DN, Becker H, Gundt A, Kist A, Franz H. Induction of tumor necrosis factor expression by a lectin from Viscum album. Cancer Immunol Immunother 1991;33:177-82. 17. Timoshenko AV, Gabius HJ. Efficient induction of superoxide release from human neutrophils by the galactoside-specific lectin from Viscum album. 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Randomised and non-randomised prospective controlled cohort studies in matched-pair design for the long-term therapy of breast cancer patients with a mistletoe preparation (Iscador): a re-analysis. Eur J Med Res. Nov 30, 2006;11(11):485-495. 50. Kröz M, Schad F, Matthes B, Pickartz H, and Girke M, “Blut- und gewebseosinophilie, mistellektin-antikörper und lebensqualität bei einer mammakarzinom-patientin unter intratumoraler und subkutaner misteltherapie,” Forsch Komplementärmed Kl. Naturheilkd, vol. 9, pp. 160–167, 2002. 51.ACS. CA Cancer J Clin. 1983 May-Jun;33(3):186-8. 52. http://www.accessdata.fda.gov/scripts/Plantox/Detail.CFM?ID=14012