National Cancer Institute - Mistletoe Extracts

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Table of Contents

Overview
General Information
History
Laboratory/Animal/Preclinical Studies
Human/Clinical Studies
Adverse Effects
Overall Level of Evidence for Mistletoe Extracts
Changes to This Summary (08/20/2004)
More Information

Overview

This complementary and alternative medicine (CAM) information summary provides an overview of the use of mistletoe as a treatment for cancer. The summary includes a brief history of mistletoe research, the results of clinical trials, and possible side effects of mistletoe use.

This summary contains the following key information:

Mistletoe is a semiparasitic plant that has been used for centuries to treat numerous human ailments.
Extracts of mistletoe have been shown to kill cancer cells in the laboratory and to stimulate the immune system.
Mistletoe is used mainly in Europe, where a variety of different extracts are manufactured and marketed as injectable prescription drugs. These extracts are not available commercially in the United States.
Although mistletoe plants and berries are considered poisonous to humans, few serious side effects have been associated with mistletoe extract use.
The use of mistletoe as a treatment for cancer has been investigated in more than 30 clinical studies. Reports of improved survival and/or quality of life have been common, but nearly all of the studies had major weaknesses that raise doubts about the reliability of the findings.
At present, the use of mistletoe cannot be recommended outside the context of well-designed clinical trials. Such trials will be valuable to determine more clearly whether mistletoe can be useful in the treatment of specific subsets of cancer patients.

Many of the medical and scientific terms used in this summary are hypertext linked (at first use in each section) to the Cancer.gov Dictionary, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window. All linked terms and their corresponding definitions will appear in a glossary in the printable version of the summary.

Reference citations in some PDQ CAM information summaries may include links to external Web sites that are operated by individuals or organizations for the purpose of marketing or advocating the use of specific treatments or products. These reference citations are included for informational purposes only. Their inclusion should not be viewed as an endorsement of the content of the Web sites or of any treatment or product by the PDQ Cancer CAM Editorial Board or the National Cancer Institute (NCI).

General Information

Mistletoe, a semiparasitic plant, holds interest as a potential anticancer agent because extracts derived from it have been shown to kill cancer cells in vitro [1-15] Reviewed in [16,17] and to stimulate immune system cells both in vitro and in vivo. [18-48] Reviewed in [17,49-60] Two components of mistletoe, namely viscotoxins and lectins, may be responsible for these effects.[1,4,7,9-11,13,24,26-28,30-33,35,36,38-42,46-48,61-63] Reviewed in [16,17,43,49-52,54-59,64-67] Viscotoxins are small proteins that exhibit cell-killing activity and possible immune-system–stimulating activity.[7,13,47,48] Reviewed in [50,64] Lectins are complex molecules made of both protein and carbohydrates that are capable of binding to the outside of cells (for example, immune system cells) and inducing biochemical changes in them. Reviewed in [17,51,56,68-71] In view of mistletoe’s ability to stimulate the immune system, it has been classified as a type of biological response modifier. Reviewed in [51] Biological response modifiers constitute a diverse group of biological molecules that have been used individually, or in combination with other agents, to treat cancer or to lessen the side effects of anticancer drugs.

Mistletoe is used mainly in Europe, where commercially available extracts are marketed under a variety of brand names, including Iscador, Eurixor, Helixor, Isorel, Iscucin, Plenosol, and ABNOBAviscum. Some extracts are marketed under more than one name. For example, Iscador, Isorel, and Plenosol are also sold as Iscar, Vysorel, and Lektinol, respectively. All of these products are prepared from Viscum album Loranthacea (Viscum album L. or European mistletoe). They are not available commercially in the United States. (See below for more information concerning U.S. availability of these extracts.)

Mistletoe grows on several types of trees, and the chemical composition of extracts derived from it depends on the species of the host tree (e.g., apple, elm, oak, pine, poplar, and spruce), the time of year harvested, how the extracts are prepared, and the commercial producer.[4,72] Reviewed in [15,49,51,52,54-56]

Mistletoe extracts are prepared as aqueous solutions or solutions of water and alcohol, and they can be fermented or unfermented.[4,13] Reviewed in [8,11,20,37,52,53,72-74] Some extracts are prepared according to homeopathic principles, and others are not. Reviewed in [17,75] In addition, the commercial products can be subdivided according to the species of host tree. For example, Iscador, a fermented aqueous extract of Viscum album L. that is prepared as a homeopathic drug, is marketed as IscadorM (from apple trees), IscadorP (from pine trees), IscadorQ (from oak trees), and IscadorU (from elm trees). Helixor, an unfermented aqueous extract of Viscum album L. that is standardized by its biological effect on human leukemia cells in vitro, is marketed as HelixorA (from spruce trees), HelixorM (from apple trees), and HelixorP (from pine trees). Reviewed in [52] Eurixor, an unfermented aqueous extract of Viscum album L. harvested from poplar trees, is reportedly standardized to contain a specific amount of one of mistletoe’s lectins (i.e., the lectin ML-I; see History section). Reviewed in [52] Some proponents contend the choice of extract should depend on the type of tumor and the gender of the patient.[76] Reviewed in [52,55,77]

Mistletoe extracts are usually given by subcutaneous injection, although administration by other routes (i.e., oral and intrapleural) has been described.[27,36,42,45,46,51,57-59,65,66,76-94] Reviewed in [52,53,55,56,60,75] In most reported studies, subcutaneous injections were given 2 to 3 times a week, but the overall duration of treatment varied considerably.

Viscum album is listed in the Homeopathic Pharmacopoeia of the United States (HPUS), which is the officially recognized compendium for homeopathic drugs in this country.[95] Although the Food and Drug Administration (FDA) has regulatory authority over homeopathic drugs, this authority is usually not exercised unless the drugs are formulated for injection or there is evidence of severe toxicity. At present, the FDA does not allow the importation or distribution of injectable preparations of mistletoe, including homeopathic formulations, except for the purpose of clinical research. The FDA has not approved the use of mistletoe as a cancer treatment.

Before researchers can conduct clinical drug research in the United States, they must file an Investigational New Drug (IND) application with the FDA. IND approval is also required for clinical investigation of homeopathic drugs. The FDA does not disclose information about IND applications or approvals; this information can be released only by the applicants. At present, at least 2 U.S. investigators have IND approval to study mistletoe as a treatment for cancer.[96,97]

In this summary, the mistletoe extract or product used in each study will be specified wherever possible.

References

Stirpe F, Sandvig K, Olsnes S, et al.: Action of viscumin, a toxic lectin from mistletoe, on cells in culture. J Biol Chem 257 (22): 13271-7, 1982. [PUBMED Abstract]
Khwaja TA, Dias CB, Pentecost S: Recent studies on the anticancer activities of mistletoe (Viscum album) and its alkaloids. Oncology 43 (Suppl 1): 42-50, 1986. [PUBMED Abstract]
Ribéreau-Gayon G, Jung ML, Baudino S, et al.: Effects of mistletoe (Viscum album L.) extracts on cultured tumor cells. Experientia 42 (6): 594-9, 1986. [PUBMED Abstract]
Ribéreau-Gayon G, Jung ML, Di Scala D, et al.: Comparison of the effects of fermented and unfermented mistletoe preparations on cultured tumor cells. Oncology 43 (Suppl 1): 35-41, 1986. [PUBMED Abstract]
Hülsen H, Mechelke F: In vitro effectiveness of a mistletoe preparation on cytostatic-drug-resistant human leukemia cells. Naturwissenschaften 74 (3): 144-5, 1987. [PUBMED Abstract]
Kuttan G, Vasudevan DM, Kuttan R: Isolation and identification of a tumour reducing component from mistletoe extract (Iscador). Cancer Lett 41 (3): 307-14, 1988. [PUBMED Abstract]
Jung ML, Baudino S, Ribéreau-Gayon G, et al.: Characterization of cytotoxic proteins from mistletoe (Viscum album L.). Cancer Lett 51 (2): 103-8, 1990. [PUBMED Abstract]
Kuttan G, Vasudevan DM, Kuttan R: Effect of a preparation from Viscum album on tumor development in vitro and in mice. J Ethnopharmacol 29 (1): 35-41, 1990. [PUBMED Abstract]
Walzel H, Jonas L, Rosin T, et al.: Relationship between internalization kinetics and cytotoxicity of mistletoe lectin I to L1210 leukaemia cells. Folia Biol (Praha) 36 (3-4): 181-8, 1990. [PUBMED Abstract]
Gawlik C, Versteeg R, Engel E, et al.: Antiproliferative effect of mistleotoe-extracts in melanoma cell lines. [Abstract] Anticancer Res 12 (6A): A-364, 1882, 1992.
Janssen O, Scheffler A, Kabelitz D: In vitro effects of mistletoe extracts and mistletoe lectins. Cytotoxicity towards tumor cells due to the induction of programmed cell death (apoptosis). Arzneimittelforschung 43 (11): 1221-7, 1993. [PUBMED Abstract]
Jurin M, Zarković N, Hrzenjak M, et al.: Antitumorous and immunomodulatory effects of the Viscum album L. preparation Isorel. Oncology 50 (6): 393-8, 1993 Nov-Dec. [PUBMED Abstract]
Schaller G, Urech K, Giannattasio M: Cytotoxicity of different viscotoxins and extracts from the European subspecies Viscum album L. Phytother Res 10 (6): 473-7, 1996.
Gabius HJ, Darro F, Remmelink M, et al.: Evidence for stimulation of tumor proliferation in cell lines and histotypic cultures by clinically relevant low doses of the galactoside-binding mistletoe lectin, a component of proprietary extracts. Cancer Invest 19 (2): 114-26, 2001. [PUBMED Abstract]
Maier G, Fiebig HH: Absence of tumor growth stimulation in a panel of 16 human tumor cell lines by mistletoe extracts in vitro. Anticancer Drugs 13 (4): 373-9, 2002. [PUBMED Abstract]
Franz H: Mistletoe lectins and their A and B chains. Oncology 43 (Suppl 1): 23-34, 1986. [PUBMED Abstract]
Mengs U, Göthel D, Leng-Peschlow E: Mistletoe extracts standardized to mistletoe lectins in oncology: review on current status of preclinical research. Anticancer Res 22 (3): 1399-407, 2002 May-Jun. [PUBMED Abstract]
Nienhaus J, Stoll M, Vester F: Thymus stimulation and cancer prophylaxis by Viscum proteins. Experientia 26 (5): 523-5, 1970. [PUBMED Abstract]
Rentea R, Lyon E, Hunter R: Biologic properties of iscador: a Viscum album preparation I. Hyperplasia of the thymic cortex and accelerated regeneration of hematopoietic cells following X-irradiation. Lab Invest 44 (1): 43-8, 1981. [PUBMED Abstract]
Bloksma N, Schmiermann P, de Reuver M, et al.: Stimulation of humoral and cellular immunity by Viscum preparations. Planta Med 46 (4): 221-7, 1982. [PUBMED Abstract]
Hajto T: Immunomodulatory effects of iscador: a Viscum album preparation. Oncology 43 (Suppl 1): 51-65, 1986. [PUBMED Abstract]
Hajto T, Lanzrein C: Natural killer and antibody-dependent cell-mediated cytotoxicity activities and large granular lymphocyte frequencies in Viscum album-treated breast cancer patients. Oncology 43 (2): 93-7, 1986. [PUBMED Abstract]
Hamprecht K, Handgretinger R, Voetsch W, et al.: Mediation of human NK-activity by components in extracts of Viscum album. Int J Immunopharmacol 9 (2): 199-209, 1987. [PUBMED Abstract]
Hajto T, Hostanska K, Gabius HJ: Modulatory potency of the beta-galactoside-specific lectin from mistletoe extract (Iscador) on the host defense system in vivo in rabbits and patients. Cancer Res 49 (17): 4803-8, 1989. [PUBMED Abstract]
Mueller EA, Hamprecht K, Anderer FA: Biochemical characterization of a component in extracts of Viscum album enhancing human NK cytotoxicity. Immunopharmacology 17 (1): 11-8, 1989 Jan-Feb. [PUBMED Abstract]
Hajto T, Hostanska K, Frei K, et al.: Increased secretion of tumor necrosis factors alpha, interleukin 1, and interleukin 6 by human mononuclear cells exposed to beta-galactoside-specific lectin from clinically applied mistletoe extract. Cancer Res 50 (11): 3322-6, 1990. [PUBMED Abstract]
Beuth J, Ko HL, Gabius HJ, et al.: Behavior of lymphocyte subsets and expression of activation markers in response to immunotherapy with galactoside-specific lectin from mistletoe in breast cancer patients. Clin Investig 70 (8): 658-61, 1992. [PUBMED Abstract]
Kuttan G, Kuttan R: Immunological mechanism of action of the tumor reducing peptide from mistletoe extract (NSC 635089) cellular proliferation. Cancer Lett 66 (2): 123-30, 1992. [PUBMED Abstract]
Kuttan G, Kuttan R: Immunomodulatory activity of a peptide isolated from Viscum album extract (NSC 635 089). Immunol Invest 21 (4): 285-96, 1992. [PUBMED Abstract]
Gabius HJ, Walzel H, Joshi SS, et al.: The immunomodulatory beta-galactoside-specific lectin from mistletoe: partial sequence analysis, cell and tissue binding, and impact on intracellular biosignalling of monocytic leukemia cells. Anticancer Res 12 (3): 669-75, 1992 May-Jun. [PUBMED Abstract]
Beuth J, Ko HL, Tunggal L, et al.: Thymocyte proliferation and maturation in response to galactoside-specific mistletoe lectin-1. In Vivo 7 (5): 407-10, 1993 Sep-Oct. [PUBMED Abstract]
Timoshenko AV, Gabius HJ: Efficient induction of superoxide release from human neutrophils by the galactoside-specific lectin from Viscum album. Biol Chem Hoppe Seyler 374 (4): 237-43, 1993. [PUBMED Abstract]
Timoshenko AV, Kayser K, Drings P, et al.: Modulation of lectin-triggered superoxide release from neutrophils of tumor patients with and without chemotherapy. Anticancer Res 13 (5C): 1789-92, 1993 Sep-Oct. [PUBMED Abstract]
Kuttan G: Tumoricidal activity of mouse peritoneal macrophages treated with Viscum album extract. Immunol Invest 22 (6-7): 431-40, 1993 Aug-Oct. [PUBMED Abstract]
Beuth J, Ko HL, Tunggal L, et al.: Immunoprotective activity of the galactoside-specific mistletoe lectin in cortisone-treated BALB/c-mice. In Vivo 8 (6): 989-92, 1994 Nov-Dec. [PUBMED Abstract]
Heiny BM, Beuth J: Mistletoe extract standardized for the galactoside-specific lectin (ML-1) induces beta-endorphin release and immunopotentiation in breast cancer patients. Anticancer Res 14 (3B): 1339-42, 1994 May-Jun. [PUBMED Abstract]
Stein G, Berg PA: Non-lectin component in a fermented extract from Viscum album L. grown on pines induces proliferation of lymphocytes from healthy and allergic individuals in vitro. Eur J Clin Pharmacol 47 (1): 33-8, 1994. [PUBMED Abstract]
Timoshenko AV, Gabius HJ: Influence of the galactoside-specific lectin from Viscum album and its subunits on cell aggregation and selected intracellular parameters of rat thymocytes. Planta Med 61 (2): 130-3, 1995. [PUBMED Abstract]
Timoshenko AV, Cherenkevich SN, Gabius HJ: Viscum album agglutinin-induced aggregation of blood cells and the lectin effects on neutrophil function. Biomed Pharmacother 49 (3): 153-8, 1995. [PUBMED Abstract]
Hostanska K, Hajto T, Spagnoli GC, et al.: A plant lectin derived from Viscum album induces cytokine gene expression and protein production in cultures of human peripheral blood mononuclear cells. Nat Immun 14 (5-6): 295-304, 1995. [PUBMED Abstract]
Beuth J, Stoffel B, Ko HL, et al.: Immunomodulating ability of galactoside-specific lectin standardized and depleted mistletoe extract. Arzneimittelforschung 45 (11): 1240-2, 1995. [PUBMED Abstract]
Lenartz D, Stoffel B, Menzel J, et al.: Immunoprotective activity of the galactoside-specific lectin from mistletoe after tumor destructive therapy in glioma patients. Anticancer Res 16 (6B): 3799-802, 1996 Nov-Dec. [PUBMED Abstract]
Fischer S, Scheffler A, Kabelitz D: Oligoclonal in vitro response of CD4 T cells to vesicles of mistletoe extracts in mistletoe-treated cancer patients. Cancer Immunol Immunother 44 (3): 150-6, 1997. [PUBMED Abstract]
Preisfeld A: Influence of aqueous mistletoe preparations on humoral immune parameters with emphasis on the cytotoxicity of human complement in breast cancer patients. Forsch Komplementarmed 4: 224-8, 1997.
Chernyshov VP, Omelchenko LI, Heusser P, et al.: Immunomodulatory actions of Viscum album (Iscador) in children with recurrent respiratory disease as a result of the Chernobyl nuclear accident. Complementary Therapy and Medicine 5 (3): 141-6, 1997.
Heiny BM, Albrecht V, Beuth J: Correlation of immune cell activities and beta-endorphin release in breast carcinoma patients treated with galactose-specific lectin standardized mistletoe extract. Anticancer Res 18 (1B): 583-6, 1998 Jan-Feb. [PUBMED Abstract]
Stein GM, Schaller G, Pfüller U, et al.: Characterisation of granulocyte stimulation by thionins from European mistletoe and from wheat. Biochim Biophys Acta 1426 (1): 80-90, 1999. [PUBMED Abstract]
Stein GM, Schaller G, Pfüller U, et al.: Thionins from Viscum album L: influence of the viscotoxins on the activation of granulocytes. Anticancer Res 19 (2A): 1037-42, 1999 Mar-Apr. [PUBMED Abstract]
Bocci V: Mistletoe (viscum album) lectins as cytokine inducers and immunoadjuvant in tumor therapy. A review. J Biol Regul Homeost Agents 7 (1): 1-6, 1993 Jan-Mar. [PUBMED Abstract]
Capernaros Z: The golden bough: the case for mistletoe. Eur J Herbal Med 1 (1):19-24, 1994.
Gabius HJ, Gabius S, Joshi SS, et al.: From ill-defined extracts to the immunomodulatory lectin: will there be a reason for oncological application of mistletoe? Planta Med 60 (1): 2-7, 1994. [PUBMED Abstract]
Kleijnen J, Knipschild P: Mistletoe treatment for cancer: review of controlled trials in humans. Phytomedicine 1: 255-60, 1994.
Mistletoe. In: Murray MT: The Healing Power of Herbs. Roseville, Calif: Prima Publishing, 1995, pp 253-9.
Zee-Cheng RK: Anticancer research on Loranthaceae plants. Drugs of the Future 22 (5): 519-30, 1997.
Kaegi E: Unconventional therapies for cancer: 3. Iscador. Task Force on Alternative Therapies of the Canadian Breast Cancer Research Initiative. CMAJ 158 (9): 1157-9, 1998. [PUBMED Abstract]
Samtleben R, Hajto T, Hostanska K, et al.: Mistletoe lectins as immunostimulants (chemistry, pharmacology and clinic). In: Wagner H, ed.: Immunomodulatory Agents from Plants. Basel, Switzerland: Birkhauser Verlag, 1999, pp 223-41.
Lenartz D, Dott U, Menzel J, et al.: Survival of glioma patients after complementary treatment with galactoside-specific lectin from mistletoe. Anticancer Res 20 (3B): 2073-6, 2000 May-Jun. [PUBMED Abstract]
Steuer-Vogt MK, Bonkowsky V, Ambrosch P, et al.: The effect of an adjuvant mistletoe treatment programme in resected head and neck cancer patients: a randomised controlled clinical trial. Eur J Cancer 37 (1): 23-31, 2001. [PUBMED Abstract]
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 168 (1): 72-5, 2002. [PUBMED Abstract]
Stauder H, Kreuser ED: Mistletoe extracts standardised in terms of mistletoe lectins (ML I) in oncology: current state of clinical research. Onkologie 25 (4): 374-80, 2002. [PUBMED Abstract]
Olsnes S, Stirpe F, Sandvig K, et al.: Isolation and characterization of viscumin, a toxic lectin from Viscum album L. (mistletoe). J Biol Chem 257 (22): 13263-70, 1982. [PUBMED Abstract]
Holtskog R, Sandvig K, Olsnes S: Characterization of a toxic lectin in Iscador, a mistletoe preparation with alleged cancerostatic properties. Oncology 45 (3): 172-9, 1988. [PUBMED Abstract]
Dietrich JB, Ribéreau-Gayon G, Jung ML, et al.: Identity of the N-terminal sequences of the three A chains of mistletoe (Viscum album L.) lectins: homology with ricin-like plant toxins and single-chain ribosome-inhibiting proteins. Anticancer Drugs 3 (5): 507-11, 1992. [PUBMED Abstract]
Schrader G, Apel K: Isolation and characterization of cDNAs encoding viscotoxins of mistletoe (Viscum album). Eur J Biochem 198 (3): 549-53, 1991. [PUBMED Abstract]
Friess H, Beger HG, Kunz J, et al.: Treatment of advanced pancreatic cancer with mistletoe: results of a pilot trial. Anticancer Res 16 (2): 915-20, 1996 Mar-Apr. [PUBMED Abstract]
Grossarth-Maticek R, Kiene H, Baumgartner SM, et al.: Use of Iscador, an extract of European mistletoe (Viscum album), in cancer treatment: prospective nonrandomized and randomized matched-pair studies nested within a cohort study. Altern Ther Health Med 7 (3): 57-66, 68-72, 74-6 passim, 2001 May-Jun. [PUBMED Abstract]
Sweeney EC, Palmer RA, Pfüller U: Crystallization of the ribosome inactivating protein ML1 from Viscum album (mistletoe) complexed with beta-D-galactose. J Mol Biol 234 (4): 1279-81, 1993. [PUBMED Abstract]
Nicolson GL: The interactions of lectins with animal cell surfaces. Int Rev Cytol 39: 89-190, 1974. [PUBMED Abstract]
Barondes SH: Lectins: their multiple endogenous cellular functions. Annu Rev Biochem 50: 207-31, 1981. [PUBMED Abstract]
Abdullaev FI, de Mejia EG: Antitumor effect of plant lectins. Nat Toxins 5 (4): 157-63, 1997. [PUBMED Abstract]
Kilpatrick DC: Mechanisms and assessment of lectin-mediated mitogenesis. Mol Biotechnol 11 (1): 55-65, 1999. [PUBMED Abstract]
Jäggy C, Musielski H, Urech K, et al.: Quantitative determination of lectins in mistletoe preparations. Arzneimittelforschung 45 (8): 905-9, 1995. [PUBMED Abstract]
Wagner H, Jordan E, Feil B: Studies on the standardization of mistletoe preparations. Oncology 43 (Suppl 1): 16-22, 1986. [PUBMED Abstract]
Zarkovic N, Vukovic T, Loncaric I, et al.: An overview on anticancer activities of the Viscum album extract Isorel. Cancer Biother Radiopharm 16 (1): 55-62, 2001. [PUBMED Abstract]
Mellor D: Mistletoe in homoeopathic cancer treatment. Prof Nurse 4 (12): 605-7, 1989. [PUBMED Abstract]
Fellmer KE: A clinical trial of Iscador: follow-up treatment of irradiated genital carcinomata for the prevention of recurrences. Br Homeopath J 57: 43-7, 1968.
Kjaer M: Misteltoe (Iscador) therapy in stage IV renal adenocarcinoma. A phase II study in patients with measurable lung metastases. Acta Oncol 28 (4): 489-94, 1989. [PUBMED Abstract]
Majewski A, Bentele W: [Adjunct treatment in female genital carcinoma]. Zentralbl Gynakol 20: 696-700, 1963.
Fellmer Ch, Fellmer KE: [Follow-up treatment of irradiated genital carcinoma with the Viscum album preparation "Iscador"]. Krebsarzt 2: 175-85, 1966.
Leroi R: [Studies on additional Iscador therapy in the management of women with surgically and radiotherapeutically treated genital carcinoma] Gynaecologia 167 (3): 158-70, 1969. [PUBMED Abstract]
Leroi R: [Postoperative Viscum album therapy after surgery of breast neoplasms] Helv Chir Acta 44 (3): 403-14, 1977. [PUBMED Abstract]
Salzer G, Havelec L: [Prevention of recurrence of bronchial carcinomas after surgery by means of the mistletoe extract Iscador. Results of a clinical study from 1969-1971] Onkologie 1 (6): 264-7, 1978. [PUBMED Abstract]
Salzer G, Denck H: [Randomized study on medicamentous recurrence prophylaxis with 5-fluorouracil and Iscador in resectioned stomach cancer. Results of an intermediate assessment]. Dtsch Z Onkol 11 (5): 130-1, 1979.
Salzer G: Pleura carcinosis. Cytomorphological findings with the mistletoe preparation iscador and other pharmaceuticals. Oncology 43 (Suppl 1): 66-70, 1986. [PUBMED Abstract]
Douwes FR, Wolfrum DI, Migeod F: [Results of a prospective randomized study: chemotherapy versus chemotherapy plus "biological response modifier" in metastasizing colorectal carcinoma]. Dtsch Z Onkol 18 (6): 155-64, 1986.
Dowes FR, Kalden M, Frank G, et al.: [Treatment of advanced colorectal carcinoma: efficacy test of the combination of 5-fluorouracil and tetrahydrofolic acid versus 5-fluorouracil and tetrahydrofolic acid in combination with an optimized Helixor treatment]. Dtsch Z Onkol 21 (3): 63-7, 1988.
Gutsch J, Berger H, Scholz G, et al.: [Prospective study in radically operated breast cancer with polychemotherapy, Helixor® and untreated controls]. Dtsch Z Onkol 21: 94-101, 1988.
Bradley GW, Clover A: Apparent response of small cell lung cancer to an extract of mistletoe and homoeopathic treatment. Thorax 44 (12): 1047-8, 1989. [PUBMED Abstract]
Dold U, Edler L, Mäurer HCh, et al., eds.: [Adjuvant Cancer Therapy in Advanced Non-Small Cell Bronchial Cancer: Multicentric Controlled Studies To Test the Efficacy of Iscador and Polyerga]. Stuttgart, Germany: Georg Thieme Verlag, 1991.
Heiny BM: [Adjuvant therapy with standardized mistletoe extract reduces leukopenia and improves the quality of life of patients with advanced breast cancer under palliative chemotherapy (VEC regimen)]. Krebsmedizin 12: 1-14, 1991.
Schaefermeyer G, Schaefermeyer H: Treatment of pancreatic cancer with Viscum album (Iscador): a retrospective study of 292 patients 1986-1996. Complementary Therapy and Medicine 6: 172-7, 1998.
Kleeberg UR, Brocker EB, Lejeune F, et al.: Adjuvant trial in melanoma patients comparing rlFN-alpha to rlFN-gamma to Iscador to a control group after curative resection of high risk primary (>=3mm) or regional lymphnode metastasis (EORTC 18871). [Abstract] Eur J Cancer 35 (Suppl 4): A-264, s82, 1999.
Heiny BM, Albrecht V, Beuth J: Stabilization of quality of life with mistletoe lectin-1-standardized extract in advanced colorectal carcinoma. Onkologe 4 (Suppl 1): S35-9, 1998.
Wetzel D, Schäfer M: Results of a randomised placebo-controlled multicentre study with PS76A2 (standardised mistletoe preparation) in patients with breast cancer receiving adjuvant chemotherapy. [Abstract] Phytomedicine 7 (Suppl 2): A-SL-66, 2000.
Viscum album. In: Homoeopathic Pharmacopoeia Convention of the United States.: Homoeopathic Pharmacopoeia of the United States. Washington, DC: 2002, Monograph 9444 Visc.
Mansky PJ, National Center for Complementary and Alternative Medicine: Phase I Study of Gemcitabine and Mistletoe in Patients With Advanced Solid Tumors, NCCAM-02-AT-260, Clinical trial, Active. [PDQ Clinical Trial]
Rosenzweig S, Kimmel Cancer Center at Thomas Jefferson University - Philadelphia: Phase II Study of Supplemental Treatment With Mistletoe in Patients With Stage IIIB or IV Non-Small Cell Lung Cancer Receiving Palliative Chemotherapy, TJUH-01F.45, Clinical trial, Active. [PDQ Clinical Trial]

History

Mistletoe has been used for centuries for its medicinal properties. Reviewed in [1-6] It was reportedly used by the Druids and the ancient Greeks, and it appears in legend and folklore as a panacea. It has been used in various forms to treat cancer, epilepsy, infertility, menopausal symptoms, nervous tension, asthma, hypertension, headache, and dermatitis. Modern interest in mistletoe as an anticancer treatment began in the 1920s. Reports of more than 30 clinical studies of mistletoe as a treatment for cancer have been published since the early 1960s.[7-36] Reviewed in [37,3,38] Most of the results of these studies were published exclusively in German. (See Human/Clinical Studies section.)

As indicated previously (General Information section), proposed mechanisms of action for mistletoe that are relevant to cancer include stimulation of the immune system [39-62,7,63-68] Reviewed in [69,70,1,8,37,2,71,72,3,9-11,38] and a direct toxic effect on tumor cells.[73-89] Reviewed in [1,69,71,90] Another reported activity that may be relevant to optimum functioning of the immune system in individuals with cancer is stabilization of the DNA in white blood cells, including white blood cells that have been exposed to DNA-damaging chemotherapy drugs.[91-94] Reviewed in [95]

Mistletoe has been shown to stimulate increases in the number and the activity of various types of white blood cells.[40-62,7,63-68] Reviewed in [69,70,8,2,71,72,3,9,11,29,93,95-98,38] Immune-system–enhancing cytokines, such as interleukin-1, interleukin-6, and tumor necrosis factor-alpha, are released by white blood cells after exposure to mistletoe extracts.[42,47,57,61,64] Reviewed in [69,70,1,8,37,71,3,72,11,29,91,93-96,98,38] Other evidence suggests that mistletoe exerts its cytotoxic effects by interfering with protein synthesis in target cells [73,81,90,4,99] Reviewed in [79,86,69,61,8,70-72,3,89,100,92,95,98,101] and by inducing apoptosis.[83,95,102] Reviewed in [87,69,63,72,3,98] Mistletoe may also serve a bridging function, bringing together immune system effector cells and tumor cells.[46,103]

Although viscotoxins and lectins have both been investigated as active components in mistletoe, most research has focused on the lectins.[73-76,81-83,86,90,45,47,48,51-54,56,57,59-62,99,7,66,9-11,4,88,89,95-98,101] Reviewed in [69,8,70,37,3,12] Purified mistletoe lectins have demonstrated cytotoxic and immune-system–stimulating activities. Four different lectins—ML-I, ML-II, ML-III, and Viscum album chitin-binding agglutinin—have been identified in mistletoe extracts to date. ML-I (or viscumin) may be responsible for many of mistletoe’s biological effects. When a laboratory method was used to selectively deplete ML-I from Viscum album extracts, their cytotoxic and immune-system–stimulating properties were markedly reduced.[83,62] It should be noted that fermentation eliminates most of the ML-I in mistletoe extracts.[104] Reviewed in [2,100]

ML-I consists of an alpha chain and a beta chain, which can be separated from one another.[86,90,53,4,89] Reviewed in [79,81,86,59,69,61,70,2,8,71,3,88,99,12,100,95,98,101] Each chain type appears to mediate a subset of the activities described for the intact lectin. Cytotoxicity is associated mainly with the alpha chain. In laboratory studies, the ML-I alpha chain has been coupled to monoclonal antibodies to produce "immunotoxins" that target and kill specific cell types.[105,106] Reviewed in [70]

More Information about the immune system and how it works.

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Stirpe F, Sandvig K, Olsnes S, et al.: Action of viscumin, a toxic lectin from mistletoe, on cells in culture. J Biol Chem 257 (22): 13271-7, 1982. [PUBMED Abstract]
Khwaja TA, Dias CB, Pentecost S: Recent studies on the anticancer activities of mistletoe (Viscum album) and its alkaloids. Oncology 43 (Suppl 1): 42-50, 1986. [PUBMED Abstract]
Ribéreau-Gayon G, Jung ML, Baudino S, et al.: Effects of mistletoe (Viscum album L.) extracts on cultured tumor cells. Experientia 42 (6): 594-9, 1986. [PUBMED Abstract]
Ribéreau-Gayon G, Jung ML, Di Scala D, et al.: Comparison of the effects of fermented and unfermented mistletoe preparations on cultured tumor cells. Oncology 43 (Suppl 1): 35-41, 1986. [PUBMED Abstract]
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Schaller G, Urech K, Giannattasio M: Cytotoxicity of different viscotoxins and extracts from the European subspecies Viscum album L. Phytother Res 10 (6): 473-7, 1996.
Gabius HJ, Darro F, Remmelink M, et al.: Evidence for stimulation of tumor proliferation in cell lines and histotypic cultures by clinically relevant low doses of the galactoside-binding mistletoe lectin, a component of proprietary extracts. Cancer Invest 19 (2): 114-26, 2001. [PUBMED Abstract]
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Dietrich JB, Ribéreau-Gayon G, Jung ML, et al.: Identity of the N-terminal sequences of the three A chains of mistletoe (Viscum album L.) lectins: homology with ricin-like plant toxins and single-chain ribosome-inhibiting proteins. Anticancer Drugs 3 (5): 507-11, 1992. [PUBMED Abstract]
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Büssing A, Azhari T, Ostendorp H, et al.: Viscum album L. extracts reduce sister chromatid exchanges in cultured peripheral blood mononuclear cells. Eur J Cancer 30A (12): 1836-41, 1994. [PUBMED Abstract]
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Bussing A, Jungmann H, Suzart K, et al.: Suppression of sister chromatid exchange-inducing DNA lesions in cultured peripheral blood mononuclear cells by Viscum album L. J Exp Clin Cancer Res 15 (2): 107-14, 1996.
Büssing A, Suzart K, Bergmann J, et al.: Induction of apoptosis in human lymphocytes treated with Viscum album L. is mediated by the mistletoe lectins. Cancer Lett 99 (1): 59-72, 1996. [PUBMED Abstract]
Kunze E, Schulz H, Gabius HJ: Inability of galactoside-specific mistletoe lectin to inhibit N-methyl-N-nitrosourea-induced tumor development in the urinary bladder of rats and to mediate a local cellular immune response after long-term administration. J Cancer Res Clin Oncol 124 (2): 73-87, 1998. [PUBMED Abstract]
Kunze E, Schulz H, Adamek M, et al.: Long-term administration of galactoside-specific mistletoe lectin in an animal model: no protection against N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced urinary bladder carcinogenesis in rats and no induction of a relevant local cellular immune response. J Cancer Res Clin Oncol 126 (3): 125-38, 2000. [PUBMED Abstract]
Mengs U, Schwarz T, Bulitta M, et al.: Antitumoral effects of an intravesically applied aqueous mistletoe extract on urinary bladder carcinoma MB49 in mice. Anticancer Res 20 (5B): 3565-8, 2000 Sep- Oct. [PUBMED Abstract]
Sweeney EC, Palmer RA, Pfüller U: Crystallization of the ribosome inactivating protein ML1 from Viscum album (mistletoe) complexed with beta-D-galactose. J Mol Biol 234 (4): 1279-81, 1993. [PUBMED Abstract]
Jäggy C, Musielski H, Urech K, et al.: Quantitative determination of lectins in mistletoe preparations. Arzneimittelforschung 45 (8): 905-9, 1995. [PUBMED Abstract]
Burger AM, Mengs U, Schüler JB, et al.: Anticancer activity of an aqueous mistletoe extract (AME) in syngeneic murine tumor models. Anticancer Res 21 (3B): 1965-8, 2001 May-Jun. [PUBMED Abstract]
Zarkovic N, Vukovic T, Loncaric I, et al.: An overview on anticancer activities of the Viscum album extract Isorel. Cancer Biother Radiopharm 16 (1): 55-62, 2001. [PUBMED Abstract]
Mueller EA, Anderer FA: Chemical specificity of effector cell/tumor cell bridging by a Viscum album rhamnogalacturonan enhancing cytotoxicity of human NK cells. Immunopharmacology 19 (1): 69-77, 1990 Jan-Feb. [PUBMED Abstract]
Wagner H, Jordan E, Feil B: Studies on the standardization of mistletoe preparations. Oncology 43 (Suppl 1): 16-22, 1986. [PUBMED Abstract]
Wiedłocha A, Sandvig K, Walzel H, et al.: Internalization and action of an immunotoxin containing mistletoe lectin A-chain. Cancer Res 51 (3): 916-20, 1991. [PUBMED Abstract]
Tonevitsky AG, Toptygin AYu, Pfuller U, et al.: Immunotoxin with mistletoe lectin I A-chain and ricin A-chain directed against CD5 antigen of human T-lymphocytes; comparison of efficiency and specificity. Int J Immunopharmacol 13 (7): 1037-41, 1991. [PUBMED Abstract]

Laboratory/Animal/Preclinical Studies

The immune-system–stimulating and cytotoxic properties of mistletoe have both been investigated in laboratory and animal studies.

Laboratory studies have shown that mistletoe extracts can stimulate the activity of white blood cells in vitro and cause them to release molecules thought to be important for anticancer immune responses.[1-10] Reviewed in [11-18] In addition, mistletoe extracts have demonstrated cytotoxic activity against a variety of mouse, rat, and human cancer cells in vitro.[19-36] Reviewed in [12,37,38] In one study, however, the in vitro growth of several types of human cancer cells was stimulated by treatment with low doses of the purified lectin ML-I.[32]

Studies of the ability of mistletoe to inhibit cancer cell growth in animals have yielded mixed and inconsistent results.[20,24,26,30,39-42,18,43-45,36] Reviewed in [12,38,15,46] In most of these studies, mistletoe extracts were administered either by subcutaneous injection or by intraperitoneal injection.

In one animal study, treatment with IscadorM increased the survival time of mice that had been implanted with one type of mouse cancer cell (Ehrlich ascites) but not 2 others (L1210 leukemia; B16 melanoma).[20] The effect of IscadorM on the growth of tumors formed in mice by 3 additional types of mouse cancer cells (Lewis lung carcinoma; colon adenocarcinoma 38; C3H mammary adenocarcinoma) was also assessed in this study. Treatment with IscadorM substantially reduced the growth rate of all 3 types of tumors.

In another animal study, mice were given IscadorM before, during, or after injection with either of 2 types of mouse cancer cells (Dalton’s lymphoma; Ehrlich ascites).[26] In this study, all groups of mice treated with mistletoe showed substantially slower tumor growth than the control groups.

In contrast, no antitumor effect or improvement in survival was observed when IscadorM was used to treat rats bearing chemically induced mammary carcinomas or tumors formed from rat Walker 256 carcinosarcoma cells.[44] In this study, IscadorM was also not effective in treating mice that had been injected with Ehrlich ascites cells. In addition, IscadorP was found ineffective in treating rats with tumors formed from rat L5222 leukemia cells.

Treatment with the mistletoe extract Lektinol (also sold as Plenosol; see General Information section) has likewise yielded mixed results in animal experiments.[43] Treatment with Lektinol slowed the growth of tumors formed in mice from implants of 3 types of mouse cancer (colon adenocarcinoma 38; Renca renal cell carcinoma; F9 testicular carcinoma) but not 2 others (B16 melanoma; Lewis lung carcinoma).

The anticancer effects of Isorel (also sold as Vysorel; see General Information section) have been examined in at least 2 animal studies.[30,36] In one study, IsorelM was used alone or in combination with local x-ray therapy in mice bearing mouse CMC-2 fibrosarcoma tumors.[30] When IsorelM was used alone, no effect on either tumor growth or animal survival was observed. However, when IsorelM injections were combined with local x-ray therapy of tumors, substantial improvements in survival were found in comparison to the survival of mice treated with local x-ray therapy alone. With local x-ray therapy alone, 22% of mice were cured of their tumors. When local x-ray therapy was combined with IsorelM injections, given before or after the x-ray treatment, the cure rate increased to 43%. When IsorelM was given both before and after local x-ray therapy, the proportion of cured mice increased to 67%.

In another study, IsorelM showed antitumor and antimetastatic effects in mice that had been injected with mouse mammary carcinoma cells.[36] The antitumor effects appeared most pronounced when IsorelM was injected in the vicinity of tumors.

The ability of purified or recombinant lectin ML-I to inhibit the formation of chemically induced bladder tumors in rats has been evaluated in 3 studies.[41,42,45] Reviewed in [12] In 2 of the studies, purified ML-I was given by subcutaneous injection.[41,42] Reviewed in [12] Treatment with ML-I did not reduce the frequency of bladder tumor formation or increase immune system activity in the bladder wall in either study. In the third study, recombinant ML-I was introduced directly into the bladder through a process known as intravesical instillation.[45] Reviewed in [12] In this study, the frequency of bladder tumor formation was reduced by approximately 50% in ML-I-treated animals. However, as in the other 2 studies, immune system activity in the bladder wall was not increased substantially. It was concluded, therefore, that the antitumor effect observed in this study was the result of direct cytotoxic action by the recombinant lectin against malignant cells.[45]

Finally, a few animal studies have suggested that mistletoe is beneficial in decreasing the side effects of conventional anticancer therapy (e.g., chemotherapy and radiation therapy) and that it counteracts the effects of drugs used to suppress the immune system.[47-49] Reviewed in [38] In one study, IscadorM was shown to increase the number of white blood cells in mice treated with cyclophosphamide chemotherapy or radiation therapy and to decrease the amount of weight loss due to radiation, but not cyclophosphamide, treatment.[49] Recombinant mistletoe lectin has also been shown to induce increased apoptosis when combined with x-ray treatment.[50] In another study, IscadorM was shown to accelerate the recovery of hematopoietic tissue in the bone marrow and spleens of irradiated rats and mice.[47] In yet another study, the mistletoe product Eurixor was shown to counteract the immunosuppressive effects of treatment with the drug cortisone.[48]

References

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Hajto T, Hostanska K, Frei K, et al.: Increased secretion of tumor necrosis factors alpha, interleukin 1, and interleukin 6 by human mononuclear cells exposed to beta-galactoside-specific lectin from clinically applied mistletoe extract. Cancer Res 50 (11): 3322-6, 1990. [PUBMED Abstract]
Timoshenko AV, Gabius HJ: Efficient induction of superoxide release from human neutrophils by the galactoside-specific lectin from Viscum album. Biol Chem Hoppe Seyler 374 (4): 237-43, 1993. [PUBMED Abstract]
Timoshenko AV, Kayser K, Drings P, et al.: Modulation of lectin-triggered superoxide release from neutrophils of tumor patients with and without chemotherapy. Anticancer Res 13 (5C): 1789-92, 1993 Sep-Oct. [PUBMED Abstract]
Timoshenko AV, Gabius HJ: Influence of the galactoside-specific lectin from Viscum album and its subunits on cell aggregation and selected intracellular parameters of rat thymocytes. Planta Med 61 (2): 130-3, 1995. [PUBMED Abstract]
Timoshenko AV, Cherenkevich SN, Gabius HJ: Viscum album agglutinin-induced aggregation of blood cells and the lectin effects on neutrophil function. Biomed Pharmacother 49 (3): 153-8, 1995. [PUBMED Abstract]
Hostanska K, Hajto T, Spagnoli GC, et al.: A plant lectin derived from Viscum album induces cytokine gene expression and protein production in cultures of human peripheral blood mononuclear cells. Nat Immun 14 (5-6): 295-304, 1995. [PUBMED Abstract]
Fischer S, Scheffler A, Kabelitz D: Oligoclonal in vitro response of CD4 T cells to vesicles of mistletoe extracts in mistletoe-treated cancer patients. Cancer Immunol Immunother 44 (3): 150-6, 1997. [PUBMED Abstract]
Stein GM, Schaller G, Pfüller U, et al.: Characterisation of granulocyte stimulation by thionins from European mistletoe and from wheat. Biochim Biophys Acta 1426 (1): 80-90, 1999. [PUBMED Abstract]
Stein GM, Schaller G, Pfüller U, et al.: Thionins from Viscum album L: influence of the viscotoxins on the activation of granulocytes. Anticancer Res 19 (2A): 1037-42, 1999 Mar-Apr. [PUBMED Abstract]
Franz H: Mistletoe lectins and their A and B chains. Oncology 43 (Suppl 1): 23-34, 1986. [PUBMED Abstract]
Mengs U, Göthel D, Leng-Peschlow E: Mistletoe extracts standardized to mistletoe lectins in oncology: review on current status of preclinical research. Anticancer Res 22 (3): 1399-407, 2002 May-Jun. [PUBMED Abstract]
Chernyshov VP, Omelchenko LI, Heusser P, et al.: Immunomodulatory actions of Viscum album (Iscador) in children with recurrent respiratory disease as a result of the Chernobyl nuclear accident. Complementary Therapy and Medicine 5 (3): 141-6, 1997.
Bocci V: Mistletoe (viscum album) lectins as cytokine inducers and immunoadjuvant in tumor therapy. A review. J Biol Regul Homeost Agents 7 (1): 1-6, 1993 Jan-Mar. [PUBMED Abstract]
Samtleben R, Hajto T, Hostanska K, et al.: Mistletoe lectins as immunostimulants (chemistry, pharmacology and clinic). In: Wagner H, ed.: Immunomodulatory Agents from Plants. Basel, Switzerland: Birkhauser Verlag, 1999, pp 223-41.
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 168 (1): 72-5, 2002. [PUBMED Abstract]
Schaefermeyer G, Schaefermeyer H: Treatment of pancreatic cancer with Viscum album (Iscador): a retrospective study of 292 patients 1986-1996. Complementary Therapy and Medicine 6: 172-7, 1998.
Mengs U, Schwarz T, Bulitta M, et al.: Antitumoral effects of an intravesically applied aqueous mistletoe extract on urinary bladder carcinoma MB49 in mice. Anticancer Res 20 (5B): 3565-8, 2000 Sep- Oct. [PUBMED Abstract]
Stirpe F, Sandvig K, Olsnes S, et al.: Action of viscumin, a toxic lectin from mistletoe, on cells in culture. J Biol Chem 257 (22): 13271-7, 1982. [PUBMED Abstract]
Khwaja TA, Dias CB, Pentecost S: Recent studies on the anticancer activities of mistletoe (Viscum album) and its alkaloids. Oncology 43 (Suppl 1): 42-50, 1986. [PUBMED Abstract]
Ribéreau-Gayon G, Jung ML, Baudino S, et al.: Effects of mistletoe (Viscum album L.) extracts on cultured tumor cells. Experientia 42 (6): 594-9, 1986. [PUBMED Abstract]
Ribéreau-Gayon G, Jung ML, Di Scala D, et al.: Comparison of the effects of fermented and unfermented mistletoe preparations on cultured tumor cells. Oncology 43 (Suppl 1): 35-41, 1986. [PUBMED Abstract]
Hülsen H, Mechelke F: In vitro effectiveness of a mistletoe preparation on cytostatic-drug-resistant human leukemia cells. Naturwissenschaften 74 (3): 144-5, 1987. [PUBMED Abstract]
Kuttan G, Vasudevan DM, Kuttan R: Isolation and identification of a tumour reducing component from mistletoe extract (Iscador). Cancer Lett 41 (3): 307-14, 1988. [PUBMED Abstract]
Jung ML, Baudino S, Ribéreau-Gayon G, et al.: Characterization of cytotoxic proteins from mistletoe (Viscum album L.). Cancer Lett 51 (2): 103-8, 1990. [PUBMED Abstract]
Kuttan G, Vasudevan DM, Kuttan R: Effect of a preparation from Viscum album on tumor development in vitro and in mice. J Ethnopharmacol 29 (1): 35-41, 1990. [PUBMED Abstract]
Walzel H, Jonas L, Rosin T, et al.: Relationship between internalization kinetics and cytotoxicity of mistletoe lectin I to L1210 leukaemia cells. Folia Biol (Praha) 36 (3-4): 181-8, 1990. [PUBMED Abstract]
Gawlik C, Versteeg R, Engel E, et al.: Antiproliferative effect of mistleotoe-extracts in melanoma cell lines. [Abstract] Anticancer Res 12 (6A): A-364, 1882, 1992.
Janssen O, Scheffler A, Kabelitz D: In vitro effects of mistletoe extracts and mistletoe lectins. Cytotoxicity towards tumor cells due to the induction of programmed cell death (apoptosis). Arzneimittelforschung 43 (11): 1221-7, 1993. [PUBMED Abstract]
Jurin M, Zarković N, Hrzenjak M, et al.: Antitumorous and immunomodulatory effects of the Viscum album L. preparation Isorel. Oncology 50 (6): 393-8, 1993 Nov-Dec. [PUBMED Abstract]
Schaller G, Urech K, Giannattasio M: Cytotoxicity of different viscotoxins and extracts from the European subspecies Viscum album L. Phytother Res 10 (6): 473-7, 1996.
Gabius HJ, Darro F, Remmelink M, et al.: Evidence for stimulation of tumor proliferation in cell lines and histotypic cultures by clinically relevant low doses of the galactoside-binding mistletoe lectin, a component of proprietary extracts. Cancer Invest 19 (2): 114-26, 2001. [PUBMED Abstract]
Maier G, Fiebig HH: Absence of tumor growth stimulation in a panel of 16 human tumor cell lines by mistletoe extracts in vitro. Anticancer Drugs 13 (4): 373-9, 2002. [PUBMED Abstract]
Holtskog R, Sandvig K, Olsnes S: Characterization of a toxic lectin in Iscador, a mistletoe preparation with alleged cancerostatic properties. Oncology 45 (3): 172-9, 1988. [PUBMED Abstract]
Dietrich JB, Ribéreau-Gayon G, Jung ML, et al.: Identity of the N-terminal sequences of the three A chains of mistletoe (Viscum album L.) lectins: homology with ricin-like plant toxins and single-chain ribosome-inhibiting proteins. Anticancer Drugs 3 (5): 507-11, 1992. [PUBMED Abstract]
Zarkovic N, Vukovic T, Loncaric I, et al.: An overview on anticancer activities of the Viscum album extract Isorel. Cancer Biother Radiopharm 16 (1): 55-62, 2001. [PUBMED Abstract]
Capernaros Z: The golden bough: the case for mistletoe. Eur J Herbal Med 1 (1):19-24, 1994.
Zee-Cheng RK: Anticancer research on Loranthaceae plants. Drugs of the Future 22 (5): 519-30, 1997.
Nienhaus J, Stoll M, Vester F: Thymus stimulation and cancer prophylaxis by Viscum proteins. Experientia 26 (5): 523-5, 1970. [PUBMED Abstract]
Kuttan G: Tumoricidal activity of mouse peritoneal macrophages treated with Viscum album extract. Immunol Invest 22 (6-7): 431-40, 1993 Aug-Oct. [PUBMED Abstract]
Kunze E, Schulz H, Gabius HJ: Inability of galactoside-specific mistletoe lectin to inhibit N-methyl-N-nitrosourea-induced tumor development in the urinary bladder of rats and to mediate a local cellular immune response after long-term administration. J Cancer Res Clin Oncol 124 (2): 73-87, 1998. [PUBMED Abstract]
Kunze E, Schulz H, Adamek M, et al.: Long-term administration of galactoside-specific mistletoe lectin in an animal model: no protection against N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced urinary bladder carcinogenesis in rats and no induction of a relevant local cellular immune response. J Cancer Res Clin Oncol 126 (3): 125-38, 2000. [PUBMED Abstract]
Burger AM, Mengs U, Schüler JB, et al.: Anticancer activity of an aqueous mistletoe extract (AME) in syngeneic murine tumor models. Anticancer Res 21 (3B): 1965-8, 2001 May-Jun. [PUBMED Abstract]
Berger M, Schmähl D: Studies on the tumor-inhibiting efficacy of Iscador in experimental animal tumors. J Cancer Res Clin Oncol 105 (3): 262-5, 1983. [PUBMED Abstract]
Elsässer-Beile U, Ruhnau T, Freudenberg N, et al.: Antitumoral effect of recombinant mistletoe lectin on chemically induced urinary bladder carcinogenesis in a rat model. Cancer 91 (5): 998-1004, 2001. [PUBMED Abstract]
Stauder H, Kreuser ED: Mistletoe extracts standardised in terms of mistletoe lectins (ML I) in oncology: current state of clinical research. Onkologie 25 (4): 374-80, 2002. [PUBMED Abstract]
Rentea R, Lyon E, Hunter R: Biologic properties of iscador: a Viscum album preparation I. Hyperplasia of the thymic cortex and accelerated regeneration of hematopoietic cells following X-irradiation. Lab Invest 44 (1): 43-8, 1981. [PUBMED Abstract]
Beuth J, Ko HL, Tunggal L, et al.: Immunoprotective activity of the galactoside-specific mistletoe lectin in cortisone-treated BALB/c-mice. In Vivo 8 (6): 989-92, 1994 Nov-Dec. [PUBMED Abstract]
Kuttan G, Kuttan R: Reduction of leukopenia in mice by "viscum album" administration during radiation and chemotherapy. Tumori 79 (1): 74-6, 1993. [PUBMED Abstract]
Hostanska K, Vuong V, Rocha S, et al.: Recombinant mistletoe lectin induces p53-independent apoptosis in tumour cells and cooperates with ionising radiation. Br J Cancer 88 (11): 1785-92, 2003. [PUBMED Abstract]

Human/Clinical Studies

Mistletoe has been evaluated as a treatment for cancer in numerous clinical studies.[1-32] Reviewed in [33-37] All studies reported to date were conducted in Europe, primarily in Germany and Austria. Results of most of these studies were published exclusively in German. The mistletoe extracts/products tested were Iscador, Eurixor, Helixor, Lektinol, and recombinant lectin ML-I (see the tables at the end of this section).

Approximately half of the reported studies were controlled studies, and a majority of these were randomized clinical trials. Survival was the principal endpoint measured in most reported studies; however, other endpoints included tumor response, tumor recurrence, and quality of life.

Although mistletoe was found to be therapeutically effective in most of the reported studies, almost all of the studies had one or more major weaknesses that raise doubts about the reliability of the findings. These weaknesses include registration of small numbers of patients; presence of large numbers of patients who either were not evaluable or were otherwise excluded from the analyses; failure to adequately document mistletoe use, mistletoe dose, and/or interruptions of mistletoe use; absence of control subjects or use of historical control subjects; use of inadequate randomization procedures; absence of treatment blinding; extensive use of subset analysis; and the measurement of mean, as opposed to median, survival. (Note: In studies with small numbers of patients, the mean survival time—i.e., the average survival time—can be greatly exaggerated if one or more patients exhibit unusually long survival; median survival, therefore, is a better measure.) In addition, evaluation of the studies is often hindered by incomplete descriptions of the study design and by incomplete reporting of clinical data, including data about previous and concurrent therapies received by the patients.

Seven of the most completely documented studies are discussed below.

One of the 7 studies was a 3-arm, randomized phase III trial that involved 408 patients with previously untreated, inoperable non-small cell lung cancer.[21] These patients were randomly assigned to one of the following treatments: 1) subcutaneous injection 3 times a week with IscadorU or IscadorQ (see General Information section; the concentration of mistletoe was increased during a 7-injection sequence or cycle, followed by a 3-day pause, and then the process was repeated; IscadorU was given for 2 cycles, followed by 2 cycles of IscadorQ; both mistletoe preparations contained mercury); 2) intramuscular injection once a week with Polyerga Neu, which is a sheep spleen glycopeptide that is reported to be an immunostimulant and an inhibitor of tumor cell glycolysis; and 3) intramuscular injection once a week with a vitamin B mixture, which served as a placebo. The trial was initiated at the beginning of 1978 and was completed at the end of June 1987. Complete follow-up information was available for 337 patients, and 312 patients (105 Iscador treated, 100 Polyerga Neu treated, and 107 placebo treated) were included in the survival analysis. No statistically significant differences in survival were found between the 3 groups. Median survival for the Iscador group was 9.1 months; for the Polyerga Neu group, it was 9.0 months; and, for the placebo group, it was 7.6 months. The researchers reported that 11.5% of the patients in the Iscador group survived 2 years from the time they entered the trial; the corresponding survival values for the Polyerga Neu and the placebo groups were 13.9% and 10.1%, respectively. In addition, no differences were found between the 3 groups with respect to tumor response, median body weight, blood chemistry values, Karnofsky Performance Status, and carefully measured quality of life. However, more patients in the Iscador group than in the Polyerga Neu or the placebo groups reported subjective improvement in feelings of “well-being” (59.4% versus 43.2% and 44.8%, respectively).

Another phase III trial involved 477 patients with squamous cell carcinoma of the head and neck.[4] Reviewed in [36] These patients were randomly assigned to treatment with surgery or surgery and radiation therapy, and then they were randomly assigned again to either no additional treatment or treatment with Eurixor. This double randomization produced the following 4 groups: 1) 105 patients treated with surgery alone; 2) 97 patients treated with surgery and Eurixor; 3) 137 patients treated with surgery and radiation therapy; and 4) 138 patients treated with surgery, radiation therapy, and Eurixor. Eurixor was given in 4 treatment cycles over a 60-week period. Each treatment cycle lasted 12 weeks and was followed by a 4-week break period. During each cycle, Eurixor was administered by subcutaneous injection twice a week. Each injection contained enough standardized mistletoe extract to yield a dose of 1 nanogram of ML-I lectin per kilogram of body weight. The results of this randomized trial showed that treatment with Eurixor did not improve either 5-year disease-free survival or 5-year disease-specific survival. In addition, no stimulation of the immune system or improvement in quality of life was found with Eurixor treatment.

It has been suggested that a less-than-optimum dose of mistletoe was administered to patients in this trial.[7] However, the same dose of Eurixor has been used in other clinical studies, including studies in which benefit was reported.[1,3,22] In addition, both the dose and the duration of Eurixor treatment in this trial are consistent with those recommended by the manufacturer.[4]

A third randomized phase III trial of mistletoe as a treatment for cancer involved 830 patients with high-risk melanoma (i.e., a primary tumor larger than 3 millimeters in diameter and no regional lymph nodes positive for cancer or a primary tumor of any size, 1 to 2 regional lymph nodes positive for cancer, and no distant metastases) who were randomly assigned to 1 of the following 4 groups after potentially curative surgery: 1) treatment with low-dose interferon-alfa, 2) treatment with low-dose interferon-gamma, 3) treatment with IscadorM, or 4) no further treatment. Both types of interferon and IscadorM were administered by subcutaneous injection for a period of 1 year.[24] The interferon injections were given every other day, whereas IscadorM was administered 3 times a week. After 8 years of follow-up, no increase in survival time or increase in time until melanoma recurrence was demonstrated for mistletoe treatment or treatment with either type of interferon.

Three other studies of mistletoe were described in a single published report.[7] The patients in these studies were drawn from 10,226 cancer patients who were participants in a prospective study of the influence of “self-regulation” (i.e., the ability of a person to achieve a sense of well-being, inner equilibrium, a feeling of competence, and an ability to control stressful situations) on the incidence and course of cancer. Among these individuals, 1,668 patients who had been treated with Iscador and 8,475 patients who had received no mistletoe therapy were identified.

One of the 3 studies was a retrospective matched-pair study of the effectiveness of Iscador as a treatment for cancer.[7] Among the patients who had been treated with Iscador and those who had not, 396 pairs of individuals were identified who were closely matched according to criteria of gender; year of birth ±3 years; year of cancer diagnosis ±3 years; type of cancer; stage of disease; type of metastasis, if present; and type(s) of conventional therapy received. These individuals had rectal cancer, colon cancer, breast cancer, stomach cancer, or lung cancer. It was reported that the mean survival time of the Iscador-treated patients was 39% longer than the mean survival time of the patients who had not been treated with mistletoe (mean survival times = 4.23 years and 3.05 years, respectively). This difference in survival was statistically significant. However, the retrospective nature of this study is a major weakness. Another weakness is the fact that Iscador use was incompletely ascertained. Only the actuality of mistletoe use (yes/no) and its overall duration of use were documented. No information was collected about the type of Iscador used (i.e., the host tree), the dose used, and whether there were any interruptions in use.

The second and third studies were prospective, randomized matched-pair studies (i.e., similar to randomized trials) that involved patients who were drawn from the group of 8,475 individuals who had not been treated with mistletoe.[7] From this group, 2 sets of matched pairs were created. One set contained 49 pairs of patients who had rectal cancer, colon cancer, stomach cancer, breast cancer, or lung cancer. The other set contained 17 pairs of individuals who had stage II or stage III breast cancer. These studies used the same matching criteria as the retrospective study. In the 2 sets, one member of each pair was randomly selected as a candidate for mistletoe therapy. These patients were advised to ask their doctor for Iscador treatment. Ultimately, only 39 individuals in the 49-pair set were treated with Iscador. Therefore, only 39 pairs of this 49-pair set were eligible for analysis. All 17 pairs in the second set were eligible for analysis.

The mean survival time of the Iscador-treated patients in the 39-pair set was 42% longer than the mean survival time of the patients who were not treated with mistletoe (mean survival times = 3.49 years and 2.45 years, respectively). The mean survival time of the Iscador-treated patients in the 17-pair set was approximately twice that of the patients who did not receive mistletoe therapy (mean survival times = 4.79 years and 2.41 years, respectively). Both differences in survival were statistically significant.

These 2 randomized studies, however, had major weaknesses, including the recruitment of small numbers of patients and insufficient documentation of mistletoe use. As in the case of the retrospective study, only the actuality of mistletoe use (yes/no) and the overall duration of mistletoe treatment were ascertained. No information was collected on the type of Iscador used, the dose of Iscador used, and whether there were any interruptions in Iscador therapy.

The seventh study was a prospective, randomized phase II trial that involved 45 patients who had noninvasive bladder cancer.[5] After surgery, the patients were randomly assigned to receive either 3 cycles of treatment with Eurixor or no further therapy. The goal of the study was to determine whether Eurixor treatment could reduce bladder cancer recurrence. Twenty-three patients were assigned to the treatment group, and 22 were assigned to the control group. Each cycle of Eurixor treatment consisted of 3 months of subcutaneous injections, given twice a week, followed by a 3-month break period. One milliliter of Eurixor was administered at each injection. After 18 months of follow-up, 11 recurrences were observed in the treatment group, and 8 were observed in the control group. The average time to recurrence for the treatment group was 6.3 months; for the control group, it was 6.4 months. The median disease-free interval for the treatment group was 9 months; for the control group, it was 10.5 months. None of these differences was considered substantial.

A major concern about this study, however, is that the dose of lectin ML-I delivered to patients appears to have varied with body weight. Furthermore, if different batches of Eurixor were used for individual patients, the patients may not have received uniform doses throughout the trial. Each milliliter of Eurixor has been reported to contain 50 to 70 nanograms of ML-I. Reviewed in [1,3,34] Therefore, the dose of lectin delivered to a person weighing 120 pounds (approximately 55 kilograms) could have ranged from 0.91 nanograms per kilogram body weight to 1.27 nanograms per kilogram body weight. For a person weighing 160 pounds (approximately 73 kilograms), the dose of lectin could have ranged from 0.68 nanograms per kilogram body weight to 0.96 nanograms per kilogram body weight. As indicated above, the manufacturer of Eurixor recommends a dose of 1 nanogram per kilogram body weight. Since 33 of the 45 patients in this trial were men and men tend to weigh more than women, it is conceivable that a substantial fraction of the patients were treated with lower-than-recommended doses of ML-I.

Finally, the PDQ clinical trials database contains protocol abstracts for 2 additional clinical studies of mistletoe as a treatment for cancer.[38,39] One of the studies is a phase I clinical trial,[34-36] and 1 is a phase II trial.[39] Both studies are being conducted in the United States.

Use of Iscador in cancer treatment: clinical reports describing therapeutic endpoints¹

Enlarge Table

Reference citation(s)	Type of study	Type(s) of cancer	Numbers of patients: enrolled; treated; control²	Strongest benefit reported³	Concurrent therapy⁴	Level of evidence score⁵
[28]	Randomized trial	Breast, stages I-III	Unknown; 76; 79	Improved 14-yr. survival	Unknown	1iiA
[28]	Randomized trial	Bronchial, operable	50; 12, stage I only; 14, stage I only	Improved median survival	No	1iiA
[21]	Randomized trial	Lung, non-small cell, inoperable	408; 105; 107⁶	Subjective improvement in quality of life	Yes⁷	1iiA
[30]	Randomized trial	Lung, non-small cell, stages I-IV	218; 87; 96	Improved median survival, LN+ patients only	No	1iiA
[24]	Randomized trial	Melanoma, stages II-III	830; 102; 102	None	No	None
[15,27,29]	Randomized trial	Stomach, stages I-IV	359; 62, stages II-III only; 75, stages II-III only	Improved median survival	No	1iiA
[10]	Nonrandomized controlled trial	Various types, no stage information	Unknown; 72; 52	Improved 2-yr. survival, uterus and breast cancer	Unknown	2A
[7]	Prospective randomized matched-pair study	Breast, stage III	8,475⁸; 17⁹; 17⁹	Improved mean survival	Yes	1iiA
[7]	Prospective randomized matched-pair study	Various types, stages I-IV	8,475⁸; 39⁹; 39⁹	Improved mean survival	Yes	1iiA
[9]	Phase II trial	Kidney, renal cell, stage IV	14; 14; None	None	Yes	3iiiA
[7]	Retrospective matched-pair, case-control study	Various types, stages I-IV	10,226⁸; 396⁹; 396⁹	Improved mean survival	Yes	3iiiA
[13]	Nonconsecutive case series	Breast, stages I-IV	1,314; 319, stages I-II only; 228, historical controls	Improved 10-yr. survival	Yes	3iiiA
[28]	Nonconsecutive case series	Bronchial, inoperable	36; 36; 42, chemotherapy-treated historical controls	Comparable survival	No	None
[26]	Nonconsecutive case series	Bronchial, operable	Unknown; Unknown; Unknown, historical controls	Improved 5-yr. survival	Unknown	None
[8,11]	Nonconsecutive case series	Cervical, stages I-III	81; 81; 800, historical controls	Improved 5-yr. survival	No	3iiiA
[28]	Nonconsecutive case series	Colon, stages I-IV	138; 47; 91	Improved 5-yr. survival	No	3iiiA
[14]	Nonconsecutive case series	Lung, stages I-III	77; 37; 40, historical controls	Improved 6-yr. survival	No	3iiiA
[23]	Nonconsecutive case series	Pancreas	292; 292; Various historical controls	Improved median survival	Yes	3iiiA
[28]	Nonconsecutive case series	Rectal, operable	Unknown; 37; 34, historical controls	Improved 5-yr. survival, LN+ patients only	No	None
[16,28]	Nonconsecutive case series	Unknown metastatic (pleura carcinosis)	168; 168; None	Partial tumor response (number not specified)	Yes	None
[12]	Nonconsecutive case series	Various female genital, stages I-IV	87; 87; None	Improved 5-yr. survival, stage III cervical, stages II-III vaginal, stage II ovarian	Yes	None
[20]	Case report	Lung, small cell, stage IV	1; 1; None	Partial response	Yes	None

¹See text and the Cancer.gov Dictionary for additional information and definition of terms; LN+ = lymph node-positive disease.
²Number of patients treated plus number of patients control may not equal number of patients enrolled; number of patients enrolled = number of patients initially recruited/considered by the researchers who conducted a study; number of patients treated = number of enrolled patients who were given the treatment being studied AND for whom results were reported; historical control subjects are not included in number of patients enrolled.
³Strongest evidence reported that the treatment under study has anticancer activity or otherwise improves the well-being of cancer patients.
⁴Chemotherapy, radiation therapy, hormonal therapy, or cytokine therapy given/allowed at the same time as mistletoe therapy.
⁵For information about levels of evidence analysis and an explanation of the level of evidence scores, see Levels of Evidence Analysis for Human Studies of Cancer Complementary and Alternative Medicine.
⁶Control patients were treated with a vitamin B mixture as a placebo; 100 additional evaluable patients were treated with Polyerga Neu, a sheep spleen glycopeptide reported to be an immunostimulant and an inhibitor of tumor cell glycolysis; treatment with Polyerga Neu was not found to be beneficial.
⁷Radiation therapy for metastases distant from the site of the primary tumor was permitted; radiation therapy to the primary tumor site or use of other anticancer treatment was not permitted.
⁸Among 10,226 cancer patients enrolled in a retrospective matched-pair, case-control study, 1,751 had been treated with Iscador or another mistletoe product and 8,475 had not been treated with mistletoe; from the 8,475 untreated patients, 2 sets of matched pairs were formed for prospective studies; in the prospective studies, one member of each pair was randomly invited to be treated with Iscador and the other member served as a control subject.
⁹Patients were strictly matched according to gender, year of birth ±3 years, year of diagnosis ±3 years, type of tumor, stage of disease, and conventional therapy received.

Use of Eurixor in cancer treatment: clinical reports describing therapeutic endpoints¹

Enlarge Table

Reference citation(s)	Type of study	Type(s) of cancer	Numbers of patients: enrolled; treated; control²	Strongest benefit reported³	Concurrent therapy⁴	Level of evidence score⁵
[5]	Randomized trial	Bladder, noninvasive	45; 23; 22	None	No	1iiDi
[1,3]	Randomized trial	Brain, glioma; 74% of patients, stages III-IV; 26% of patients, no stage information	47, 20; 18	Improved survival, stages III-IV patients only	Yes	1iiA
[22]	Randomized trial	Breast, metastatic	46; 21; 19⁶	Improved quality of life	Yes⁷	1iiC
[31,33]	Randomized trial	Colorectal, metastatic	107; 38; 41	Improved quality of life	Yes	1iiA
[4]	Randomized trial	Head and neck, squamous cell, stages I-IV	495; 235⁸; 242⁸	None	Yes⁸	1iiA
[6]	Phase I/II trial	Pancreas, stages III-IV	16; 16; None	Stabilized quality of life	No	3iiiC

¹See text and the Cancer.gov Dictionary for additional information and definition of terms.
²Number of patients treated plus number of patients control may not equal number of patients enrolled; number of patients enrolled = number of patients initially recruited/considered by the researchers who conducted a study; number of patients treated = number of enrolled patients who were given the treatment being studied AND for whom results were reported; historical control subjects are not included in number of patients enrolled.
³Strongest evidence reported that the treatment under study has anticancer activity or otherwise improves the well-being of cancer patients.
⁴Chemotherapy, radiation therapy, hormonal therapy, or cytokine therapy given/allowed at the same time as mistletoe therapy.
⁵For information about levels of evidence analysis and an explanation of the level of evidence scores, see Levels of Evidence Analysis for Human Studies of Cancer Complementary and Alternative Medicine.
⁶Control patients were treated with a saline solution as a placebo.
⁷All patients in this trial were treated with palliative chemotherapy (vindesine, epirubicin, and cyclophosphamide); chemotherapy and Eurixor were given concurrently.
⁸This trial was a 4-arm trial; patients were randomly assigned to surgery only or to surgery plus radiation therapy, followed by a second randomization to no mistletoe treatment or to treatment with Eurixor; the resulting treatment groups contained the following numbers of evaluable patients: surgery only = 105, surgery plus Eurixor = 97, surgery plus radiation therapy = 137, and surgery plus radiation therapy plus Eurixor = 138; radiation therapy and Eurixor treatment overlapped; no treatment approach was superior in terms of disease-free survival, disease-specific survival, improvement in quality of life, or stimulation of the immune system; in the table, mistletoe-treated and nontreated (control) patients were grouped (i.e., number treated = 97 + 138 = 235, and number control = 105 + 137 = 242).

Use of Helixor in cancer treatment: clinical reports describing therapeutic endpoints¹

Enlarge Table

Reference citation(s)	Type of study	Type(s) of cancer	Numbers of patients: enrolled; treated; control²	Strongest benefit reported³	Concurrent therapy⁴	Level of evidence score⁵
[19]	Randomized trial	Breast, stages I-III	692⁶; 192⁶; 274⁶	Improved survival	Yes⁶	1iiA
[17]	Randomized trial	Colorectal, metastatic	60⁷; 20⁷; 20⁷	Improved mean survival	Yes⁷	1iiA
[18]	Nonrandomized controlled trial⁸	Colorectal, recurrent or metastatic	40; 19; 20	Improved mean survival	Yes⁹	2A

¹See text and the Cancer.gov Dictionary for additional information and definition of terms.
²Number of patients treated plus number of patients control may not equal number of patients enrolled; number of patients enrolled = number of patients initially recruited/considered by the researchers who conducted a study; number of patients treated = number of enrolled patients who were given the treatment being studied AND for whom results were reported; historical control subjects are not included in number of patients enrolled.
³Strongest evidence reported that the treatment under study has anticancer activity or otherwise improves the well-being of cancer patients.
⁴Chemotherapy, radiation therapy, hormonal therapy, or cytokine therapy given/allowed at the same time as mistletoe therapy.
⁵For information about levels of evidence analysis and an explanation of the level of evidence scores, see Levels of Evidence Analysis for Human Studies of Cancer Complementary and Alternative Medicine.
⁶This trial was a 3-arm trial; after surgery, patients were randomly assigned to 1 of the 3 following groups: Helixor, chemotherapy, or control; some patients in each group were also treated with local radiation therapy; the number of evaluable patients in the chemotherapy group was 177; survival in the chemotherapy group was superior to that in the control group and equivalent to that in the Helixor group.
⁷This trial was a 3-arm trial; patients were randomly assigned to receive chemotherapy only (n = 20), chemotherapy plus Helixor (n = 20), or chemotherapy plus Ney-Tumorin (n = 20); Ney-Tumorin is a mixture of peptides and proteins from 15 different organs of fetal and young pigs or cows that is reported to have both antitumor and immunostimulatory properties; in the table, the control patients are those assigned to chemotherapy only; the treated patients are those assigned to receive chemotherapy plus Helixor; the mean survival time (in months) of patients treated with either Helixor or Ney-Tumorin was approximately twice that of patients treated with chemotherapy only.
⁸This trial was planned as a randomized trial; however, the randomization scheme failed.
⁹The patients in this trial were randomly assigned to receive chemotherapy only (n = 20) or chemotherapy plus Helixor (n = 20).

Use of other mistletoe products in cancer treatment: clinical reports describing therapeutic endpoints¹

Enlarge Table

Reference citation(s)	Type of study	Product tested	Type(s) of cancer	Numbers of patients: enrolled; treated; control²	Strongest benefit reported³	Concurrent therapy⁴	Level of evidence score⁵
[32]	Randomized trial	PS76A2 (Lektinol)	Breast	272; Unknown⁶; Unknown⁷	Improved quality of life⁸	Yes	None⁹
[2]	Nonconsecutive case series	Recombinant lectin ML-1	Lung or colorectal, refractory to treatment or progressive disease	9; 9; None	Subjective improvement in quality of life	No	None
[2]	Nonconsecutive case series	Recombinant lectin ML-1	Various types, refractory to treatment or progressive disease	14; 14; None	Subjective improvement in quality of life	Yes	None

¹See text and the Cancer.gov Dictionary for additional information and definition of terms.
²Number of patients treated plus number of patients control may not equal number of patients enrolled; number of patients enrolled = number of patients initially recruited/considered by the researchers who conducted a study; number of patients treated = number of enrolled patients who were given the treatment being studied AND for whom results were reported; historical control subjects are not included in number of patients enrolled.
³Strongest evidence reported that the treatment under study has anticancer activity or otherwise improves the well-being of cancer patients.
⁴Chemotherapy, radiation therapy, hormonal therapy, or cytokine therapy given/allowed at the same time as mistletoe therapy.
⁵For information about levels of evidence analysis and an explanation of the level of evidence scores, see Levels of Evidence Analysis for Human Studies of Cancer Complementary and Alternative Medicine.
⁶Patients were randomly assigned to treatment with 1 of 3 doses (high, medium, or low) of an extract standardized on the basis of mistletoe lectin concentration.
⁷Control patients were treated with an unidentified placebo.
⁸Quality of life was assessed using the GLQ-8 global quality-of-life scales (8 self-assessment scales) and the Spitzer uniscale.
⁹Results have been reported in abstract form only; level-of-evidence scoring is not possible due to limited information.

References

Lenartz D, Stoffel B, Menzel J, et al.: Immunoprotective activity of the galactoside-specific lectin from mistletoe after tumor destructive therapy in glioma patients. Anticancer Res 16 (6B): 3799-802, 1996 Nov-Dec. [PUBMED Abstract]
Gabius HJ, Gabius S, Joshi SS, et al.: From ill-defined extracts to the immunomodulatory lectin: will there be a reason for oncological application of mistletoe? Planta Med 60 (1): 2-7, 1994. [PUBMED Abstract]
Lenartz D, Dott U, Menzel J, et al.: Survival of glioma patients after complementary treatment with galactoside-specific lectin from mistletoe. Anticancer Res 20 (3B): 2073-6, 2000 May-Jun. [PUBMED Abstract]
Steuer-Vogt MK, Bonkowsky V, Ambrosch P, et al.: The effect of an adjuvant mistletoe treatment programme in resected head and neck cancer patients: a randomised controlled clinical trial. Eur J Cancer 37 (1): 23-31, 2001. [PUBMED Abstract]
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 168 (1): 72-5, 2002. [PUBMED Abstract]
Friess H, Beger HG, Kunz J, et al.: Treatment of advanced pancreatic cancer with mistletoe: results of a pilot trial. Anticancer Res 16 (2): 915-20, 1996 Mar-Apr. [PUBMED Abstract]
Grossarth-Maticek R, Kiene H, Baumgartner SM, et al.: Use of Iscador, an extract of European mistletoe (Viscum album), in cancer treatment: prospective nonrandomized and randomized matched-pair studies nested within a cohort study. Altern Ther Health Med 7 (3): 57-66, 68-72, 74-6 passim, 2001 May-Jun. [PUBMED Abstract]
Fellmer KE: A clinical trial of Iscador: follow-up treatment of irradiated genital carcinomata for the prevention of recurrences. Br Homeopath J 57: 43-7, 1968.
Kjaer M: Misteltoe (Iscador) therapy in stage IV renal adenocarcinoma. A phase II study in patients with measurable lung metastases. Acta Oncol 28 (4): 489-94, 1989. [PUBMED Abstract]
Majewski A, Bentele W: [Adjunct treatment in female genital carcinoma]. Zentralbl Gynakol 20: 696-700, 1963.
Fellmer Ch, Fellmer KE: [Follow-up treatment of irradiated genital carcinoma with the Viscum album preparation "Iscador"]. Krebsarzt 2: 175-85, 1966.
Leroi R: [Studies on additional Iscador therapy in the management of women with surgically and radiotherapeutically treated genital carcinoma] Gynaecologia 167 (3): 158-70, 1969. [PUBMED Abstract]
Leroi R: [Postoperative Viscum album therapy after surgery of breast neoplasms] Helv Chir Acta 44 (3): 403-14, 1977. [PUBMED Abstract]
Salzer G, Havelec L: [Prevention of recurrence of bronchial carcinomas after surgery by means of the mistletoe extract Iscador. Results of a clinical study from 1969-1971] Onkologie 1 (6): 264-7, 1978. [PUBMED Abstract]
Salzer G, Denck H: [Randomized study on medicamentous recurrence prophylaxis with 5-fluorouracil and Iscador in resectioned stomach cancer. Results of an intermediate assessment]. Dtsch Z Onkol 11 (5): 130-1, 1979.
Salzer G: Pleura carcinosis. Cytomorphological findings with the mistletoe preparation iscador and other pharmaceuticals. Oncology 43 (Suppl 1): 66-70, 1986. [PUBMED Abstract]
Douwes FR, Wolfrum DI, Migeod F: [Results of a prospective randomized study: chemotherapy versus chemotherapy plus "biological response modifier" in metastasizing colorectal carcinoma]. Dtsch Z Onkol 18 (6): 155-64, 1986.
Dowes FR, Kalden M, Frank G, et al.: [Treatment of advanced colorectal carcinoma: efficacy test of the combination of 5-fluorouracil and tetrahydrofolic acid versus 5-fluorouracil and tetrahydrofolic acid in combination with an optimized Helixor treatment]. Dtsch Z Onkol 21 (3): 63-7, 1988.
Gutsch J, Berger H, Scholz G, et al.: [Prospective study in radically operated breast cancer with polychemotherapy, Helixor® and untreated controls]. Dtsch Z Onkol 21: 94-101, 1988.
Bradley GW, Clover A: Apparent response of small cell lung cancer to an extract of mistletoe and homoeopathic treatment. Thorax 44 (12): 1047-8, 1989. [PUBMED Abstract]
Dold U, Edler L, Mäurer HCh, et al., eds.: [Adjuvant Cancer Therapy in Advanced Non-Small Cell Bronchial Cancer: Multicentric Controlled Studies To Test the Efficacy of Iscador and Polyerga]. Stuttgart, Germany: Georg Thieme Verlag, 1991.
Heiny BM: [Adjuvant therapy with standardized mistletoe extract reduces leukopenia and improves the quality of life of patients with advanced breast cancer under palliative chemotherapy (VEC regimen)]. Krebsmedizin 12: 1-14, 1991.
Schaefermeyer G, Schaefermeyer H: Treatment of pancreatic cancer with Viscum album (Iscador): a retrospective study of 292 patients 1986-1996. Complementary Therapy and Medicine 6: 172-7, 1998.
Kleeberg UR, Suciu S, Bröcker EB, et al.: Final results of the EORTC 18871/DKG 80-1 randomised phase III trial. rIFN-alpha2b versus rIFN-gamma versus ISCADOR M versus observation after surgery in melanoma patients with either high-risk primary (thickness >3 mm) or regional lymph node metastasis. Eur J Cancer 40 (3): 390-402, 2004. [PUBMED Abstract]
Viscum album. In: Homoeopathic Pharmacopoeia Convention of the United States.: Homoeopathic Pharmacopoeia of the United States. Washington, DC: 2002, Monograph 9444 Visc.
Krause F, Erkan F: [Adjuvant Iscador treatment of resectioned bronchial carcinomas]. [Abstract] Onkol Symp Ludwig Boltzmann Inst (6): 158, 1983.
Salzer G, Havelec L: [Adjuvant Iscador treatment after operated stomach cancer. Results of a randomized study]. Dtsch Z Onkol 15 (4): 106-10, 1983.
Salzer G: [30 years of experience with mistletoe therapy in public health facilities]. In: Leroi R, ed.: [Mistletoe Therapy: A Response to the Challenge of Cancer]. Stuttgart, Germany: Freies Geistesleben, 1987, pp. 173-215.
Salzer G: [Prospective randomized study: operated stomach cancer. Adjuvant treatment with Iscador--an unconventional consideration]. Dtsch Z Onkol 20 (4): 90-3, 1988.
Salzer G, Danmayr E, Wutzholfer F, et al.: [Adjuvant Iscador® treatment of non-small cell bronchial carcinoma. Results of a randomized study]. Dtsch Z Onkol 23 (4): 93-8, 1991.
Heiny BM, Albrecht V, Beuth J: Stabilization of quality of life with mistletoe lectin-1-standardized extract in advanced colorectal carcinoma. Onkologe 4 (Suppl 1): S35-9, 1998.
Wetzel D, Schäfer M: Results of a randomised placebo-controlled multicentre study with PS76A2 (standardised mistletoe preparation) in patients with breast cancer receiving adjuvant chemotherapy. [Abstract] Phytomedicine 7 (Suppl 2): A-SL-66, 2000.
Sauer H: Quality of life stabilization with mistletoe-1-standardized extract in advanced colorectal carcinoma [Letter]. Onkologe 4: 1180, 1998.
Kleijnen J, Knipschild P: Mistletoe treatment for cancer: review of controlled trials in humans. Phytomedicine 1: 255-60, 1994.
Samtleben R, Hajto T, Hostanska K, et al.: Mistletoe lectins as immunostimulants (chemistry, pharmacology and clinic). In: Wagner H, ed.: Immunomodulatory Agents from Plants. Basel, Switzerland: Birkhauser Verlag, 1999, pp 223-41.
Stauder H, Kreuser ED: Mistletoe extracts standardised in terms of mistletoe lectins (ML I) in oncology: current state of clinical research. Onkologie 25 (4): 374-80, 2002. [PUBMED Abstract]
Kienle GS, Berrino F, Büssing A, et al.: Mistletoe in cancer - a systematic review on controlled clinical trials. Eur J Med Res 8 (3): 109-19, 2003. [PUBMED Abstract]
Mansky PJ, National Center for Complementary and Alternative Medicine: Phase I Study of Gemcitabine and Mistletoe in Patients With Advanced Solid Tumors, NCCAM-02-AT-260, Clinical trial, Active. [PDQ Clinical Trial]
Rosenzweig S, Kimmel Cancer Center at Thomas Jefferson University - Philadelphia: Phase II Study of Supplemental Treatment With Mistletoe in Patients With Stage IIIB or IV Non-Small Cell Lung Cancer Receiving Palliative Chemotherapy, TJUH-01F.45, Clinical trial, Active. [PDQ Clinical Trial]

Adverse Effects

Although a number of different mistletoe extracts have been used in human studies, the reported side effects have generally been minimal and non–life-threatening. Common side effects include soreness and inflammation at injection sites, headache, fever, and chills. Reviewed in [1-3] A few cases of severe allergic reactions, including anaphylactic shock, have been reported.[2]

In contrast, mistletoe plants and berries are considered poisonous. Seizures, vomiting, and death have been reported following ingestion of these substances. Reviewed in [1,4] The severity of the toxic effects associated with mistletoe ingestion may depend on the amount consumed and the type of mistletoe plant. Reviewed in [4]

References

Kaegi E: Unconventional therapies for cancer: 3. Iscador. Task Force on Alternative Therapies of the Canadian Breast Cancer Research Initiative. CMAJ 158 (9): 1157-9, 1998. [PUBMED Abstract]
Hutt N, Kopferschmitt-Kubler M, Cabalion J, et al.: Anaphylactic reactions after therapeutic injection of mistletoe (Viscum album L.). Allergol Immunopathol (Madr) 29 (5): 201-3, 2001 Sep-Oct. [PUBMED Abstract]
Stauder H, Kreuser ED: Mistletoe extracts standardised in terms of mistletoe lectins (ML I) in oncology: current state of clinical research. Onkologie 25 (4): 374-80, 2002. [PUBMED Abstract]
Hall AH, Spoerke DG, Rumack BH: Assessing mistletoe toxicity. Ann Emerg Med 15 (11): 1320-3, 1986. [PUBMED Abstract]

Overall Level of Evidence for Mistletoe Extracts

Mistletoe is one of the most widely studied complementary and alternative medicine (CAM) therapies for cancer. Mistletoe extracts have been evaluated in numerous clinical studies, and improvements in survival, improvements in quality of life, and/or stimulation of the immune system have been frequently reported. However, most clinical studies conducted to date have had one or more major weaknesses that raise doubts about the reliability of the findings. In addition, no evidence exists to support the notion that stimulation of the immune system by mistletoe leads to an improved ability to fight cancer. Because all patients in the reported clinical studies appear to have been adults, no information is available about the use of mistletoe as a treatment for cancer in children. At present, there is insufficient evidence to recommend the use of mistletoe as a treatment for cancer outside the context of well-designed clinical trials. Such trials will be valuable to determine more clearly whether mistletoe can be useful in the treatment of specific subsets of cancer patients.

Changes to This Summary (08/20/2004)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Human/Clinical Studies

Revised text on the basis of study results published by Kleeberg et al. (2004) (added as reference 24). Deleted Kleeberg et al. (1999), Eggermont et al., EORTC-13001, and EORTC-16002.

More Information

Additional Information about CAM Therapies

The National Center for Complementary and Alternative Medicine (NCCAM).
The National Cancer Institute Office of Cancer Complementary and Alternative Medicine (OCCAM).
CAM on PubMed, a special subset of the PubMed scientific literature database created through a partnership between NCCAM and the National Library of Medicine.
Complementary and Alternative Medicine in Cancer Treatment: Questions and Answers. A fact sheet produced jointly by NCI and NCCAM.

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