Purpose of This Summary
Overview
General Information
History
Laboratory/Animal/Preclinical Studies
Human/Clinical Studies

Iscador Eurixor Isorel Helixor Abnoba-viscum

Adverse Effects
Overall Level of Evidence for Mistletoe Extracts
Changes to This Summary (12/05/2008)
More Information

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of mistletoe as a treatment for cancer. The summary is reviewed regularly and updated as necessary by the PDQ Cancer Complementary and Alternative Medicine Editorial Board.

Information about the following is included in this summary:

• A brief history of mistletoe research.
• The results of clinical studies of mistletoe.
• Possible side effects of mistletoe use.

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level of evidence designation. These designations are intended to help the readers assess the strength of the evidence supporting the use of specific interventions or treatment strategies. The PDQ Cancer Complementary and Alternative Medicine Editorial Board uses a formal evidence ranking system in developing its level of evidence designations. These designations should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version, which is written in less technical language.

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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.
• Mistletoe is used mainly in Europe, where a variety of different extracts are manufactured and marketed as injectable prescription drugs. These injectable drugs are not available commercially in the United States and are not approved as a cancer treatment.
• 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 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 NCI 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).

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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 (e.g., 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.

Preparations from mistletoe extracts are most frequently used in the treatment of cancer patients in German-speaking countries.[72] 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. Iscador, Isorel, and Plenosol are also sold as Iscar, Vysorel, and Lektinol, respectively. All of these products are prepared from Viscum album Loranthaceae (Viscum album L. or European mistletoe). They are not available commercially in the United States. (See below for more information concerning United States availability of these extracts.)

In addition to European mistletoe, extracts from a type of Korean mistletoe (Viscum album coloratum Kom.) have demonstrated in vitro and in vivo cytoxocity in laboratory studies.[73-77]

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.[4,78] 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 [8,11,20,37,52,53,78-80] Some extracts are prepared according to homeopathic principles, and others are not. Reviewed in [17,81] In addition, the commercial products can be subdivided according to the species of host tree. 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-1; refer to the History section of this summary for more information). Reviewed in [52] Some proponents contend the choice of extract should depend on the type of tumor and the gender of the patient.[82] Reviewed in [52,55,83]

A recombinant ML-1 from E. coli bacteria known as rViscumin or aviscumine has been studied in the laboratory and in phase I clinical trials. Since this is not an extract of mistletoe, it is out of the purview of this summary.[84]

Mistletoe extracts are usually given by subcutaneous injection, although administration by other routes (i.e., oral, intrapleural, and intravenous) has been described.[27,36,42,45,46,51,57-59,65,66,82,83,85-101] Reviewed in [52,53,55,56,60,81] 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, which is the officially recognized compendium for homeopathic drugs in this country.[102] Although the U.S. 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 extracts are not available commercially in the United States and are not approved 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 two U.S. investigators have IND approval to study mistletoe as a treatment for cancer.[103,104]

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

References

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40. 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]
    
    
41. 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]
    
    
42. 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]
    
    
43. 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]
    
    
44. 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. 
    
    
45. 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. 
    
    
46. 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]
    
    
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63. 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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86. Fellmer Ch, Fellmer KE: [Follow-up treatment of irradiated genital carcinoma with the Viscum album preparation "Iscador"]. Krebsarzt 2: 175-85, 1966. 
    
    
87. 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]
    
    
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89. 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]
    
    
90. 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. 
    
    
91. Salzer G: Pleura carcinosis. Cytomorphological findings with the mistletoe preparation iscador and other pharmaceuticals. Oncology 43 (Suppl 1): 66-70, 1986.  [PUBMED Abstract]
    
    
92. 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. 
    
    
93. Douwes 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. 
    
    
94. 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. 
    
    
95. 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]
    
    
96. 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. 
    
    
97. 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. 
    
    
98. 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. 
    
    
99. 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. 
    
    
100. 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. 
     
     
101. 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. 
     
     
102. Viscum album. In: Homoeopathic Pharmacopoeia Convention of the United States.: Homoeopathic Pharmacopoeia of the United States. Washington, DC: 2002, Monograph 9444 Visc. 
     
     
103. 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, Closed.  [PDQ Clinical Trial]
     
     
104. 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, Closed.  [PDQ Clinical Trial]
     
     

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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. (Refer to the Human/Clinical Studies section of this summary for more information.)

As indicated previously (refer to the General Information section of this summary for more information), 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]

More Information about the immune system and how it works.

References

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29. 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. 
    
    
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47. 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]
    
    
48. 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]
    
    
49. 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]
    
    
50. 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]
    
    
51. 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]
    
    
52. 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]
    
    
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75. 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]
    
    
76. 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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81. 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]
    
    
82. 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. 
    
    
83. 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]
    
    
84. 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]
    
    
85. 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. 
    
    
86. 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]
    
    
87. 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]
    
    
88. 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]
    
    
89. 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]
    
    
90. Franz H: Mistletoe lectins and their A and B chains. Oncology 43 (Suppl 1): 23-34, 1986.  [PUBMED Abstract]
    
    
91. 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]
    
    
92. Büssing A, Lehnert A, Schink M, et al.: Effect of Viscum album L. on rapidly proliferating amniotic fluid cells. Sister chromatid exchange frequency and proliferation index. Arzneimittelforschung 45 (1): 81-3, 1995.  [PUBMED Abstract]
    
    
93. Büssing A, Regnery A, Schweizer K: Effects of Viscum album L. on cyclophosphamide-treated peripheral blood mononuclear cells in vitro: sister chromatid exchanges and activation/proliferation marker expression. Cancer Lett 94 (2): 199-205, 1995.  [PUBMED Abstract]
    
    
94. 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. 
    
    
95. 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]
    
    
96. 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]
    
    
97. 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]
    
    
98. 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]
    
    
99. 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]
    
    
100. Jäggy C, Musielski H, Urech K, et al.: Quantitative determination of lectins in mistletoe preparations. Arzneimittelforschung 45 (8): 905-9, 1995.  [PUBMED Abstract]
     
     
101. 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]
     
     
102. 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]
     
     
103. 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]
     
     

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Laboratory/Animal/Preclinical Studies

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

Viscotoxins and lectins have been investigated as active components in mistletoe; however, most research has focused on the lectins.[1-36] Reviewed in [37-42] Purified mistletoe lectins have demonstrated cytotoxic and immune-system-stimulating activities. To date, four different lectins: ML-1, ML-2, ML-3, and Viscum album chitin -binding agglutinin have been identified in mistletoe extracts. ML-1 (or viscumin) may be responsible for many of mistletoe’s biological effects. When a laboratory method was used to selectively deplete ML-1 from Viscum album extracts, their cytotoxic and immune-system-stimulating properties were markedly reduced.[7,23] It should be noted that fermentation eliminates most of the ML-1 in mistletoe extracts.[43] Reviewed in [44,45]

The molecular structure of ML-1 consists of an alpha chain and a beta chain, which can be separated from one another.[8,9,15,29,31] Reviewed in [46,5,8,19,37,22,38,39,44,47,41,30,21,42,45,32,35,36] 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-1 alpha chain has been coupled to monoclonal antibodies to produce immunotoxins that target and kill specific cell types.[48,49] Reviewed in [38]

Recombinant ML-1, rML (also known as rViscunim or aviscumin) appears to have the same efficacy as plant-based ML-1 in laboratory studies.[50] Since this is not an extract of mistletoe, it is out of the purview of this summary.

The beta chain of ML-1 is responsible for binding to the surface of a target cell.[51] Studies of mistletoe lectin binding to cancer cells have examined whether the extent of cell binding can predict disease outcome or survival. Studies show that the prognostic value of ML-1 binding depends on the type of cancer.[52] For human breast cancer cells, the amount of lectin-bound cells correlates positively with disease outcome. However, for human adenocarcinoma of the lung, there is no correlation between the amount of lectin-bound cells and disease survival.[53] Though much research has looked at this particular aspect, there have not been studies that directly link the concentration of that component to any clinical activity of mistletoe.

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.[54,11,15,16,19,20,22,55-57] Reviewed in [9,28,35,37,38,41,58-60] In addition, mistletoe extracts have demonstrated cytotoxic activity against a variety of mouse, rat, and human cancer cells in vitro.[3,1,2,4,61,62,46,63,5-7,64,65,8,66,30,31,51,67,68] Reviewed in [37,69,47]

There are conflicting reports concerning the stimulation of cancer cell growth in vitro. In one study, the in vitro growth of several types of human cancer cells was stimulated by treatment with low doses of the purified lectin ML-1.[8] However, two subsequent studies found that ML-1 did not induce cell proliferation.[70,71]

A 2004 in vitro study of IscadorQu, a fermented aqueous extract from European mistletoe grown on oaks, against various cell lines demonstrated that sensitivity to this extract varies greatly among cell lines. In sensitive cell lines, a strong effect was seen in epidermal (HaCaT), lung adenocarcinoma (NCI-H125), and breast adenocarcinoma (MCF-7) cell lines whereas, little or no effect was seen in lung squamous cell carcinoma (MR65) and colon carcinoma (Cac0-2, HT-29). Some cells lines were responsive to high or low concentrations of IscadorQu. IscadorQu showed early cell cycle inhibition followed by apoptosis in a dose-dependent manner.[72]

Studies of the ability of mistletoe to inhibit cancer cell growth in animals have yielded mixed and inconsistent results.[1,62-64,73,33,34,74,35,36,75,76,67] Reviewed in [37,47,41,77] 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 Ehrlich ascites mouse cancer cells, but not L1210 leukemia or B16 melanoma cancer cells.[1] The effect of IscadorM on the growth of tumors formed in mice by three additional types of mouse cancer cells (i.e., Lewis lung carcinoma, colon adenocarcinoma 38, and C3H mammary adenocarcinoma) was also assessed in this study. Treatment with IscadorM substantially reduced the growth rate of all three types of tumors.

In another animal study, mice were administered IscadorM before, during, or after injection with either of two types of mouse cancer cells (i.e., Dalton lymphoma or Ehrlich ascites).[63] In this study, all groups of mice treated with mistletoe showed substantially slower tumor growth than the control groups.

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.[75] 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.

In another study, intratumoral injections of mistletoe extract (ABNOBAviscum Fraxini-2) demonstrated more antitumor activity than intravenous gemcitabine when injected into mouse xenografts of human pancreatic cancer.[78]

Treatment with the mistletoe extract Lektinol (also sold as Plenosol; refer to the General Information section of this summary for more information) has likewise yielded mixed results in animal experiments.[36] Treatment with Lektinol slowed the growth of tumors formed in mice from implants of three types of mouse cancer (i.e., colon adenocarcinoma 38, Renca renal cell carcinoma, and F9 testicular carcinoma) but not in two other mouse cancers (i.e., B16 melanoma and Lewis lung carcinoma).

The anticancer effects of Isorel (also sold as Vysorel; refer to the General Information section of this summary for more information) have been examined in at least two animal studies.[64,67] In one study, IsorelM was used alone or in combination with local x-ray therapy in mice bearing mouse CMC-2 fibrosarcoma tumors.[64] When IsorelM was used alone, no effect on either tumor growth or animal survival was observed. 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, administered before or after the x-ray treatment, the cure rate increased to 43%. When IsorelM was administered 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.[67] The antitumor effects appeared most pronounced when IsorelM was injected in the vicinity of tumors.

The ability of purified or recombinant lectin ML-1 to inhibit the formation of chemically induced bladder tumors in rats has been evaluated in three studies.[33,34,76] Reviewed in [37] In two of the studies, purified ML-1 was administered by subcutaneous injection.[33,34] Reviewed in [37] Treatment with ML-1 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-1 was introduced directly into the bladder through a process known as intravesical instillation.[76] Reviewed in [37] In this study, the frequency of bladder tumor formation was reduced by approximately 50% in ML-1-treated animals. As in the other two studies, immune system activity in the bladder wall was not increased substantially. It was concluded that the antitumor effect observed in this study was the result of direct cytotoxic action by the recombinant lectin against malignant cells.[76]

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.[17,79,80] Reviewed in [47] 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 during cyclophosphamide treatment.[80] Recombinant mistletoe lectin has also been shown to induce increased apoptosis when combined with x-ray treatment.[81] In another study, IscadorM was shown to accelerate the recovery of hematopoietic tissue in the bone marrow and spleens of irradiated rats and mice.[79] In another study, the mistletoe product Eurixor was shown to counteract the immunosuppressive effects of treatment with the drug cortisone.[17]

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77. 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]
    
    
78. Rostock M, Huber R, Greiner T, et al.: Anticancer activity of a lectin-rich mistletoe extract injected intratumorally into human pancreatic cancer xenografts. Anticancer Res 25 (3B): 1969-75, 2005 May-Jun.  [PUBMED Abstract]
    
    
79. 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]
    
    
80. 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]
    
    
81. 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]
    
    

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Human/Clinical Studies

Mistletoe has been evaluated as a treatment for cancer in numerous clinical studies.[1-33] Reviewed in [34-38] One ongoing phase II study in Israel involves carboplatin /gemcitabine in combination with mistletoe as a complementary treatment in patients with non-small cell lung cancer (ECOG-5597 and NCT00516022). Most studies have been conducted in Europe, primarily in Germany and Austria. However, in 2002, the National Center for Complementary and Alternative Medicine in cooperation with the National Cancer Institute (NCI) began accruing patients to a phase I trial (NCCAM-02-AT-260) of mistletoe (Helixor A) and gemcitabine in patients with advanced solid tumors. The trial is now closed and the data is being analyzed. Another United States trial (NCT00283478) of the mistletoe extract Iscar with gemcitabine versus gemcitabine alone as a second-line therapy for non-small cell lung cancer patients who have failed one prior line of chemotherapy is closed.

The mistletoe extracts and products studied in clinical trials were Iscador, Eurixor, Helixor, Lektinol, Isorel, Abnoba-viscum,[39] and recombinant lectin ML-1 (refer to 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, many of the studies had one or more major weaknesses that raised 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. A selection of studies is discussed below organized by the type of mistletoe extract used.

A three-arm, randomized phase III trial that involved 408 patients with previously untreated, inoperable non-small cell lung cancer was conducted between 1978 and 1987.[21] Patients were randomly assigned to one of the following treatments: (1) subcutaneous injection 3 times a week with IscadorU or IscadorQ (refer to the General Information section of this summary for more information); the concentration of mistletoe was increased during a seven-injection sequence or cycle, followed by a 3-day pause, and then the process was repeated; IscadorU was administered for two cycles, followed by two 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. 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 three 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 three 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% vs. 43.2% and 44.8%, respectively).

Another randomized phase III trial of mistletoe as a treatment for cancer involved 830 patients with high-risk melanoma (i.e., a primary tumor >3 mm in diameter and no regional lymph nodes positive for cancer or a primary tumor of any size, one or two regional lymph nodes positive for cancer, and no distant metastases) who were randomly assigned to one of the following four groups after potentially curative surgery: (1) treatment with low-dose interferon -alpha, (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 administered 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. A nonrandomized, case-control study of long-term mistletoe extract for patients with melanoma, however, showed a survival advantage among patients with high-risk disease.[40]

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 the 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 three studies was a retrospective, prospective 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 within 3 years; year of cancer diagnosis within 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 or 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 a group of 8,475 individuals who had not been treated with mistletoe.[7] From this group, two 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 two 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 and 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 two 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 or 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 use of Iscador as an adjuvant treatment has been examined in several studies. In the following studies, Iscador proved safe and effective and also showed a significant survival advantage over untreated controls.

A retrospective multicenter cohort study of parallel groups examined Iscador as a postoperative adjuvant using safety and efficacy as the main endpoints. A total of 1,442 patient records (710 treated patients and 732 untreated controls) were randomly selected from medical institutions that provided both standard and alternative treatments. Safety and efficacy were measured by the number and severity of adverse drug reactions. The treatment group showed significantly less adverse reactions (confidence interval = 95%; P = < .001) compared with the controls.[41,42]

In a phase l/ll trial of Iscador as an adjuvant postoperative treatment for superficial bladder cancer, mistletoe extract was found to be a safer and more effective alternative to Bacillus Calmette-Guérin (BCG). Thirty patients were administered Iscador instillations 4 weeks after surgery. Patients treated with Iscador did equally well with fewer side effects than a group of historical controls treated with BCG.[43,44]

In another retrospective multicenter cohort study to determine safety and efficacy of Iscador as an adjuvant long-term treatment following surgery for multiple myeloma, 686 patient records were examined (e.g., 357 untreated controls and 329 treated with Iscador). Safety, efficacy, and a cluster of survival endpoints (tumor-related, disease-free, brain-metastases free, and overall survival) were measured. Only mild to intermediate adverse drug reactions were seen in the treated group. Survival analyses showed no evidence of tumor enhancement and increased incidence of brain or other metastases in the Iscador group. Results suggest significant survival benefit for all survival-related endpoints in the treatment group.[40]

Five randomized controlled trials of Eurixor have been published as peer-reviewed articles. The largest of these studies involved 477 patients with squamous cell carcinoma of the head and neck.[4] Reviewed in [37] These patients were randomly assigned to treatment with surgery or surgery and radiation therapy, and they were randomly assigned again to either no additional treatment or treatment with Eurixor. This double randomization produced the following four 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 administered in four 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-1 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] The same dose of Eurixor, however, 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 prospective, randomized phase II trial involved 45 patients who had noninvasive bladder cancer.[5] After surgery, the patients were randomly assigned to receive either three 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 randomly assigned to the treatment group, and 22 were randomly assigned to the control group. Each cycle of Eurixor treatment consisted of 3 months of subcutaneous injections, administered 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 eight were observed in the control group. The average time of 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 significant.

A major concern about this study, however, is that the dose of lectin ML-1 administered to patients was not adjusted for body weight. 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-1. Reviewed in [1,3,35] Therefore, the dose of lectin administered to a person weighing 120 pounds (approximately 55 kg) 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 kg), 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-1. One other trial that used Eurixor without concurrent therapy involved 16 patients (seven women and nine men) with stage III and IV pancreatic cancer.[6]

Only two trials of Isorel have been reported in the publicly available, online indexed peer-reviewed medical literature. In one study of 64 advanced colorectal cancer patients (Dukes C and D) patients were randomly assigned to three groups: (1) surgery and chemotherapy; (2) surgery and chemotherapy plus Isorel; and (3) surgery alone. Patients receiving treatment with Isorel had a significantly better median survival advantage and a better cumulative survival advantage than patients in the other two groups. In addition there were no side effects to treatment in the Isorel group.[45]

Another study showed that perioperative use of Isorel in the digestive tract of cancer patients resulted in an increase in lymphocytes through 14 days of drug administration. In a group of 70 surgically treated patients, 40 patients were assigned to the Isorel-treated group, and 30 patients were assigned to the control group. The treatment group showed an increase in CD4/CD8 ratio (P = < .05) from the start to end of treatment and an increase in natural killer (NK) cell determinants. NK cell activity and lymphocyte levels declined in the controls. Quality-of-life measures also increased in the treatment group.[46]

In a three-arm randomized trial, patients were randomly assigned to one of the following groups after surgery: 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 with survival in the chemotherapy group superior to that in the control group and equivalent to that in the Helixor group.[19] In another three-arm randomized 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. The control patients were randomly assigned to chemotherapy only; the treated patients were randomly assigned to receive chemotherapy plus Helixor; and 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.[17]

No tumor response was seen in any of the 25 patients in a phase ll trial that examined the effect of a mistletoe extract in metastatic colorectal cancer resistant to standard treatment (5- fluorouracil and leucovorin chemotherapy), which used an extract known as Abnoba-viscum. The endpoint of the study was objective tumor response. Patients were administered a gradually increasing daily dose of 0.15 mg to 15 mg. Treatment duration ranged from 4 weeks to 66 weeks. Toxicity levels were mild. Some patients reported relief of disease symptoms.[47]

Refer to the NCI's PDQ Clinical Trials Registry for a current list of active clinical trials involving the use of mistletoe in cancer treatment.

References

1. 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]
   
   
2. 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]
   
   
3. 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]
   
   
4. 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]
   
   
5. 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]
   
   
6. 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]
   
   
7. 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]
   
   
8. 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. 
   
   
9. 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]
   
   
10. Majewski A, Bentele W: [Adjunct treatment in female genital carcinoma]. Zentralbl Gynakol 20: 696-700, 1963. 
    
    
11. Fellmer Ch, Fellmer KE: [Follow-up treatment of irradiated genital carcinoma with the Viscum album preparation "Iscador"]. Krebsarzt 2: 175-85, 1966. 
    
    
12. 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]
    
    
13. Leroi R: [Postoperative Viscum album therapy after surgery of breast neoplasms] Helv Chir Acta 44 (3): 403-14, 1977.  [PUBMED Abstract]
    
    
14. 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]
    
    
15. 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. 
    
    
16. Salzer G: Pleura carcinosis. Cytomorphological findings with the mistletoe preparation iscador and other pharmaceuticals. Oncology 43 (Suppl 1): 66-70, 1986.  [PUBMED Abstract]
    
    
17. 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. 
    
    
18. Douwes 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. 
    
    
19. 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. 
    
    
20. 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]
    
    
21. 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. 
    
    
22. 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. 
    
    
23. 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. 
    
    
24. 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]
    
    
25. Viscum album. In: Homoeopathic Pharmacopoeia Convention of the United States.: Homoeopathic Pharmacopoeia of the United States. Washington, DC: 2002, Monograph 9444 Visc. 
    
    
26. Krause F, Erkan F: [Adjuvant Iscador treatment of resectioned bronchial carcinomas]. [Abstract] Onkol Symp Ludwig Boltzmann Inst (6): 158, 1983. 
    
    
27. Salzer G, Havelec L: [Adjuvant Iscador treatment after operated stomach cancer. Results of a randomized study]. Dtsch Z Onkol 15 (4): 106-10, 1983. 
    
    
28. 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. 
    
    
29. Salzer G: [Prospective randomized study: operated stomach cancer. Adjuvant treatment with Iscador--an unconventional consideration]. Dtsch Z Onkol 20 (4): 90-3, 1988. 
    
    
30. 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. 
    
    
31. 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. 
    
    
32. 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. 
    
    
33. Schöffski P, Riggert S, Fumoleau P, et al.: Phase I trial of intravenous aviscumine (rViscumin) in patients with solid tumors: a study of the European Organization for Research and Treatment of Cancer New Drug Development Group. Ann Oncol 15 (12): 1816-24, 2004.  [PUBMED Abstract]
    
    
34. Sauer H: Quality of life stabilization with mistletoe-1-standardized extract in advanced colorectal carcinoma [Letter]. Onkologe 4: 1180, 1998. 
    
    
35. Kleijnen J, Knipschild P: Mistletoe treatment for cancer: review of controlled trials in humans. Phytomedicine 1: 255-60, 1994. 
    
    
36. 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. 
    
    
37. 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]
    
    
38. 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]
    
    
39. Mabed M, El-Helw L, Shamaa S: Phase II study of viscum fraxini-2 in patients with advanced hepatocellular carcinoma. Br J Cancer 90 (1): 65-9, 2004.  [PUBMED Abstract]
    
    
40. Augustin M, Bock PR, Hanisch J, et al.: Safety and efficacy of the long-term adjuvant treatment of primary intermediate- to high-risk malignant melanoma (UICC/AJCC stage II and III) with a standardized fermented European mistletoe (Viscum album L.) extract. Results from a multicenter, comparative, epidemiological cohort study in Germany and Switzerland. Arzneimittelforschung 55 (1): 38-49, 2005.  [PUBMED Abstract]
    
    
41. Bock PR, Friedel WE, Hanisch J, et al.: Retrolective, comparative, epidemiological cohort study with parallel groups design for evaluation of efficacy and safety of drugs with "well-established use". Forsch Komplementarmed Klass Naturheilkd 11 (Suppl 1): 23-9, 2004.  [PUBMED Abstract]
    
    
42. Bock PR, Friedel WE, Hanisch J, et al.: [Efficacy and safety of long-term complementary treatment with standardized European mistletoe extract (Viscum album L.) in addition to the conventional adjuvant oncologic therapy in patients with primary non-metastasized mammary carcinoma. Results of a multi-center, comparative, epidemiological cohort study in Germany and Switzerland] Arzneimittelforschung 54 (8): 456-66, 2004.  [PUBMED Abstract]
    
    
43. Elsässer-Beile U, Leiber C, Wetterauer U, et al.: Adjuvant intravesical treatment with a standardized mistletoe extract to prevent recurrence of superficial urinary bladder cancer. Anticancer Res 25 (6C): 4733-6, 2005 Nov-Dec.  [PUBMED Abstract]
    
    
44. Elsässer-Beile U, Leiber C, Wolf P, et al.: Adjuvant intravesical treatment of superficial bladder cancer with a standardized mistletoe extract. J Urol 174 (1): 76-9, 2005.  [PUBMED Abstract]
    
    
45. Cazacu M, Oniu T, Lungoci C, et al.: The influence of isorel on the advanced colorectal cancer. Cancer Biother Radiopharm 18 (1): 27-34, 2003.  [PUBMED Abstract]
    
    
46. Enesel MB, Acalovschi I, Grosu V, et al.: Perioperative application of the Viscum album extract Isorel in digestive tract cancer patients. Anticancer Res 25 (6C): 4583-90, 2005 Nov-Dec.  [PUBMED Abstract]
    
    
47. Bar-Sela G, Haim N: Abnoba-viscum (mistletoe extract) in metastatic colorectal carcinoma resistant to 5-fluorouracil and leucovorin-based chemotherapy. Med Oncol 21 (3): 251-4, 2004.  [PUBMED Abstract]
    
    

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Adverse Effects

Although a number of different mistletoe extracts have been used in human studies, the reported side effects have generally been minimal and not 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]

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

1. 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]
   
   
2. 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]
   
   
3. 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]
   
   
4. Hall AH, Spoerke DG, Rumack BH: Assessing mistletoe toxicity. Ann Emerg Med 15 (11): 1320-3, 1986.  [PUBMED Abstract]
   
   

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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, 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 weakness that raises 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.

Separate levels of evidence scores are assigned to qualifying human studies on the basis of statistical strength of the study design and scientific strength of the treatment outcomes (i.e., endpoints) measured. The resulting two scores are then combined to produce an overall score. For additional information about levels of evidence analysis, refer to Levels of Evidence for Human Studies of Cancer Complementary and Alternative Medicine.

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Changes to This Summary (12/05/2008)

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.

General Information

Added text to state that preparations from mistletoe extracts are most frequently used in the treatment of cancer patients in German-speaking countries (cited Horneber et al. as reference 72).

Human/Clinical Studies

Added text about a study that showed perioperative use of Isorel in the digestive tract of cancer patients, which resulted in an increase in lymphocytes through 14 days of drug administration (cited Enesel et al. as reference 46).

Added text about a nonrandomized Isorel trial to Table 4.

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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.

About PDQ

• PDQ® - NCI's Comprehensive Cancer Database

  Full description of the NCI PDQ database.

Other PDQ Summaries

• PDQ® Cancer Information Summaries: Adult Treatment

  Treatment options for adult cancers.

• PDQ® Cancer Information Summaries: Pediatric Treatment

  Treatment options for childhood cancers.

• PDQ® Cancer Information Summaries: Supportive and Palliative Care

  Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.

• PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer)

  Tests or procedures that detect specific types of cancer.

• PDQ® Cancer Information Summaries: Prevention

  Risk factors and methods to increase chances of preventing specific types of cancer.

• PDQ® Cancer Information Summaries: Genetics

  Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.

• PDQ® Cancer Information Summaries: Complementary and Alternative Medicine

  Information about complementary and alternative forms of treatment for patients with cancer.

Important:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

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