Description
Extracts of the plant mistletoe (Viscum album) are highly popular in cancer care, particularly in Europe. Mistletoe extracts are usually injected subcutaneously. Providers claim that they improve quality of life and immunomodulation. Numerous studies in humans show immunomodulatory effects
Efficacy
Quality of Life: Based on 18 controlled clinical trials (CCTs), there is reasonably good evidence that mistletoe preparations improve quality of life during chemotherapy.
Survival: Seven out of 14 CCTs also show improvement of survival. Because of heterogeneity and shortcomings of the studies no firm conclusions can be drawn.
Safety
Mistletoe preparations are generally well tolerated and safe.
Citation
Mirjam Wuesthof, CAM Cancer Consortium. Mistletoe (Viscum album) [online document], January 19, 2015.
Document history
Summary fully revised and updated in January 2015 by Mirjam Wuesthof.
Summary first published in March 2011, authored by Edzard Ernst.
Scientific name/brand name/common name
Mistletoe (Viscum album) is a semiparasitic plant that grows on leaf-bearing and coniferous trees throughout Europe, Asia and North Africa. Most commonly it grows on poplar, apple tree, fir and pine but also oak and several other common trees1. Currently available preparations of various forms of mistletoe extract are ABNOBAViscum® (Abnoba), Helixor® (Helixor), Iscador® (Weleda), Iscucin® (Wala), Lektinol® (Madaus).
Ingredients
Mistletoe extracts contain several pharmacologically active substances: mistletoe lectins, viscotoxins, flavonoids, terpenoids, alkaloids and amines2. The composition of an extract may vary according to season, host tree, parts of the plant used and extraction method. Some preparations are, therefore, standardized to the content of mistletoe lectins (Lektinol®).
Application and dosage
Mistletoe is usually injected subcutaneously, but other routes of administration (e.g. intravenous, peritumoural, or intrapleural) also exist. The dosing regimens vary according to extract type and either follow a constant or a variable dose. In most cases, subcutaneous injections are given 2 to 3 times a week, but the overall duration of treatment varies considerably.
History and providers
Mistletoe has been used medicinally for centuries and has been employed to treat a variety of diseases. Recent interest in mistletoe began in the 1920s after it was first proposed for the treatment of cancer by Rudolf Steiner, the founder of anthroposophy and anthroposophical medicine. Since the 1980s, mistletoe therapy has been researched systematically. A number of German phyto-pharmacological providers like ABNOBA, HELIXOR, MADAUS, WELEDA and WALA market a range of different mistletoe preparations. Some products are anthroposophical (ABNOBAViscum®, Helixor®, Iscador®, Iscucin®), whereas Lektinol® is a phytotherapeutical product. Mistletoe extracts are prepared as aqueous solutions and they can be fermented or unfermented. Some extracts, e.g. Iscucin are prepared according to homeopathic principles. Indications within the anthroposophical approach depend on the host tree of the mistletoe plant.
Claims of efficacy / alleged indication
Providers claim that supportive cancer treatment with mistletoe improves quality of life in cancer patients. Further, some proponents claim that mistletoe enhances cancer remission and survival rates. Main indications are solid tumours with the exception of primary brain tumours and cerebral metastases because of the increased risk of perifocal oedemas.
Mechanisms of action
Mistletoe holds interest as a potential anticancer agent because extracts and their constituents, mainly lectins and viscotoxins, have been shown to kill cancer cells in vitro3-8, to stimulate immune system cells both in vitro and in vivo9,14 and to have other mechanisms of action, such as antiangiogenesis15. In view of mistletoe’s ability to stimulate the immune system through induction of several cytokines and activation of lymphocytes, granulocytes and phagocytes, it has been classified as a type of biologic response modifier16-18.
Prevalence of use
Mistletoe is popular in Europe, particularly in Germany and Switzerland. Studies conducted in these countries showed that 16% of patients with a history of early breast cancer and 15% of lung cancer patients used mistletoe preparations, mostly in order to "support the tumour treatment"19,20. The prevalence of usage shows clear national differences.
Legal issues
In Germany, Switzerland and Austria, mistletoe preparations are licensed medicines that are partly reimbursable through the official healthcare system. In other European countries, they are not licensed. In the United States, the FDA presently does not allow the importation or distribution of injectable preparations of mistletoe, including homeopathic formulations, except for the purpose of clinical research. The Medicines and Healthcare Regulatory Agency in the UK states that, if a company places a manufactured herbal remedy on the market and supplies the product to herbalists, then such a product would need to have either a marketing authorisation or traditional use registration. This is in accordance with the European Directives and Regulation of herbs.
Mistletoe is one of the most widely studied complementary and alternative medicine 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 weaknesses that raise doubts about the reliability of the findings.
Systematic reviews and meta-analyses of controlled trials
Several systematic reviews and meta-analyses of more than fifty clinical trials on cancer patients treated with mistletoe extracts have been performed. They are described in table 1. Six systematic reviews published since 2008 addressed multidimemsional measures in terms of improvement of quality of life (QOL), survival, symptom relief and safety in patients with various cancer types21-26,28. Most studies reported an improvement in QOL dimensions such as fatigue, sleep, appetite, anxiety, nausea, pain as well as general physical, emotional and functional wellbeing (Table 1). Weaknesses of controlled trials include small numbers of participants, failure to adequately document drop-outs, use of inadequate randomization procedures and absence of treatment blinding. Oxford quality scoring (Jadad scale) repeatedly led to poor scores, mostly because of absence of treatment blinding. This represents a difficult to solve challenge for clinical trials as the mistletoe treatment usually induces dermal erythema at injection site, therefore the value of blinding may be questionable.
A 2012 meta-analysis of 9 RCTs and 4 non-RCTs revealed some evidence that Iscador® treatment might have moderate beneficial effect on QoL in various cancer types21. Limitations were heterogeneous data and poor methodological quality of included trials.
A 2010 systematic review examined 26 RCTs and 10 non-RCTs22. A total of 22 RCTs and all 10 non-RCTs reported an improvement in QOL. Improvement in fatigue, nausea and vomiting, emotional well-being, and concentration were reported. Some of the studies were well designed, while others showed weaknesses.
Another 2010 systematic review investigated QOL, survival, tumour response and safety23. A total of 19 RCTs, 16 non-RCTs and 11 cohort studies with heterogeneous end points were included. Consistent improvement of QOL dimensions fatigue, sleep, appetite, anxiety, nausea, pain as well as general physical, emotional and functional wellbeing were seen in 21 of 24 trials assessing QOL. Beneficial effects on survival were documented in 12 of 22 trials assessing survival and on tumour response in 3 of 6 trials assessing tumour response. The methodological quality of the studies differed substantially, although some of the more recent studies, especially on quality of life, were reasonable well conducted.
A systematic review from 2009 included 18 trials (RCTs and non-RCTs)24. It confirmed the insufficient evidence in terms of overall survival, but indicated positive effects on quality of life characteristic values, such as increased appetite, better sleep, less fatigue and improvement of general physical and psychological wellbeing. The authors concluded that the quality of the studies was mostly low. Finally, the authors were unable to identify marked differences between various preparations and advocate the use of the umbrella term "mistletoe therapy" for all of them.
Pooled analysis was performed within a 2009 meta-analysis of 22 trials with different designs by Ostermann et al.25. Effects on survival in favour of Iscador® versus no treatment were reported. But there was evidence of publication bias and, when focussing on just randomised studies only, the effect was no longer significant.
In a 2008 Cochrane review of 21 RCTs of various cancers tumour response, QOL, and psychological distress were evaluated26. Survival times were included in 13 of the studies, six of them showed benefits. 14 of 16 studies reported beneficial effects for QOL such as improvement of performance index, symptom scales and psychological measures, although studies where limited by several methodological weaknesses. The two placebo-controlled studies on QOL found significant superiority over placebo. The authors concluded that “the evidence from RCTs to support the view that the application of mistletoe extracts has impact on survival or leads to an improved ability to fight cancer or to withstand anticancer treatments is weak”. Earlier warnings about a potential negative effect of adjuvant treatment with Iscador® in melanoma patients could not be proven but also no benefit could be shown in one trial performed by the EORTC Melanoma Group27. Nevertheless, there is some evidence that mistletoe extracts may offer benefits on measures of QOL during chemotherapy for breast cancer, but these results need replication.
Overall, more high-quality, independent clinical research is needed to truly assess the safety and effectiveness of mistletoe extracts. Patients receiving mistletoe therapy should be encouraged to take part in future trials26.
Controlled trials
Four recent RCTs on cancer patients were published after the most recent systematic reviews (Table 2). In general the methodological quality of the newer trials has improved, but the studies still have some limitations. All trials investigating efficacy found various outcome parameters significantly improved. Comprehensive and conclusive assessments are still difficult to draw.
A randomized phase II trial involving 72 patients with previously untreated advanced non-small cell lung cancer investigated the influence of Iscador® on chemotherapy-related side effects and QOL28. Chemotherapy dose reductions, severe non-hematologic side effects and rates of hospitalization were less frequent in patients treated with Iscador®. There was no statistically significant difference in any of the items of the questionnaires. Therefore, no definite conclusion of a possible effect of Iscador® on quality of life and total adverse events could be drawn by the authors.
A Korean pilot RCT evaluated the effect of AbnobaViscum® Q on chemotherapy related adverse events, QOL and safety in 32 patients with gastric cancer parallel to adjuvant treatment with doxofluridine (a 5FU pro-drug)29. Significantly improved diarrhoea was seen in the mistletoe arm. The overall QOL item “global health status” significantly improved while the specific QoL parameters (physical-, emotional-, cognitive-, social- and role function) did not improve significantly.
A recent phase III randomized trial involving 220 patients with locally advanced or metastatic pancreatic cancer, not eligible for chemotherapy, investigated the effect of mistletoe extract (Iscador® Qu) versus best supportive care on overall survival30. Median overall survival was significantly improved (4.8 months in the mistletoe arm and 2.7 months in control arm). A prognosis-group adjusted hazard ratio of 0.49 (p <0.0001) was estimated.
Adverse effects
The reported adverse events of mistletoe extract have generally been minimal and not life-threatening26. Common adverse events include soreness and inflammation at injection sites, headache, fever and chills.
One systematic review investigated safety of Viscum album L. and isolated mistletoe lectins in both animal and human studies23. Adverse events included local reactions at the injection site and flu-like symptoms such as fever, chills, fatigue, mild gastrointestinal symptoms and headache. Another review reported adverse reactions that included local reactions at the injection site, fever, increased intracerebral pressure, headache, circulatory problems, thrombophlebitis, swelling of lymph nodes, and allergic reactions31.
A few cases of severe allergic reactions, including anaphylactic shock, have been reported32.
Contraindications, precautions, warnings
According to manufacturers, mistletoe preparations should be avoided in case of fever, inflammation, hyperthyroidism, autoimmune disorders or hypersensitiveness to one of the components. Precautions should be taken in case of simultaneous treatment with other immune modulating drugs (e.g. interferone, interleukins)33,34,35. Some precaution notes and contradictions are assigned to particular mistletoe preparations.
While the main indication are solid tumours, primary brain tumours and cerebral metastases are contraindicated due to an increased risk of perifocal oedema33,34. Further contraindications that have been stated for Lektinol® are malignant melanoma, renal cell carcinoma and hematologic malignancies35.
There are no data on mistletoe treatment during pregnancy and lactation.
According to manufacturers’ information, in vitro studies showed no evidence of mutagenity. Data on fertility or carcinogenity are not available33,34,35.
Neither the European Medicines Agency nor the US Food and Drug Administration have posted specific warnings.
Interactions
None reported.
Quality issues
Several different mistletoe extracts exist on the market. They all comply with the accepted quality standards.
- Mills S. The complete guide to modern Herbalism. Great Britain: Thorsons; 1994.
- Schulz V, Hänsel R, Tyler VE. Rational phytotherapy. A physician's guide to herbal medicine. 4th ed. Springer-Verlag; Berlin. 2001.
- Jung ML, Baudino S, Ribéreau-Gayon G et al. Characterization of cytotoxic proteins from mistletoe (Viscum album L.). Cancer Lett 1990; 51: 103-8.
- Kuttan G, Vasudevan DM, Kuttan R. Effect of a prepartion from Viscum album on tumour development in vitro and in mice. J Ethnopharmacol 1990; 29: 35-41.
- Janssen O, Scheffler A, Kabelitz D: In vitro effects of mistletoe extracts and mistletoe lectins. Cytotoxicity towards tumour cells due to the induction of programmed cell death (apoptosis). Arzneimittelforschung 1993; 43: 1221-7.
- Jurin M, Zarkovic N, Hrzenjak M, Hic Z. Antitumourous and immunomodulatory effects of the viscum album L. preparation Isorel. Oncology 1993; 50: 393-8.
- Mengs U, Göthel D, Leng-Peschlow E: Mistletoe extracts standardized to mistletoe lectins in oncology: review on current status of preclinical research. Anticancer Res 2002; 22: 1399-407.
- Kuttan G, Vasudevan DM, Kuttan R. Isolation and identification of a tumour reducing component from mistltoe extract (Iscador). Cancer Lett 1988; 41: 307-314.
- Hajto T. Immunomodulatory effects of Iscador: a Viscum album preparation. Oncology 1986; 43(Suppl): 51-65.
- Beuth J, Stoffel B, Ko HL et al. Immunomodulating ability of galactoside-specific lectin standardized and depleted mistletoe extract. Arzneimittelforschung 1995; 45: 1240-2.
- Beuth J, Ko HL, Tunggal L, Steuer MK, Geisel J, Jeljaszewicz J. Thymocyte proliferation and maturation in response to galactoside-specific mistletoe lectin-1. In Vivo 1993; 7: 407-10.
- Stauder H, Kreuser ED. Mistletoe extracts standardised in terms of mistletoe lectins (ML 1) in oncology: current state of clinical research. Onkologie 2002; 25: 374-80.
- Lenartz D, Stoffel B, Menzel J et al. Immunoprotective activity of the galactoside-specific lectin from mistletoe after tumour destructive therapy in glioma patients. Anticancer Res 1996; 16 (6B): 3799-802.
- 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 1998; 18 (1B): 583-6.
- Elluru SR, VAN Huyen JP, Delignat S et al. Antiangiogenic properties of Viscum album extracts are associated with endothelial cytotoxicity. Anticancer Res 2009; 29: 2945-50.
- Kuttan G, Kuttan R. Reduction of leucopenia in mice by "Viscum album" administration during radiation and chemotherapy. Tumouri 1993; 79: 74-6.
- Beuth J, Ko HL, Tunggal L et al. Immunoprotective activity of the galactoside-specific mistletoe lectin in cortisone-treated BALB/c-mice. In Vivo 1994; 8: 989-92.
- 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 1994; 60: 2-7.
- Templeton A, Thürliman Beat, Baumann M et al. Cross-sectional study of self-reported physical activity, eating habits and use of complementary medicine in breast cancer survivors. BMC Cancer 2013, 13: 153.
- Micke O, Büntzel J, Kisters K et al. Complementary and alternative medicine in lung cancer patients: a neglected phenomenon? Front Radiat Ther Oncol 2010; 42: 198-205.
- Buessing A, Raak C, Ostermann T. Quality of life and related dimensions in cancer patients treated with mistletoe extract (Iscador): a meta-analysis. Evid Based Complement Alternat Med 2012; 2012: 219402.
- Kienle GS, Kiene H. Review article: Influence of Viscum album L (European mistletoe) extracts on quality of life in cancer patients: a systematic review of controlled clinical studies. Integr Cancer Ther 2010; 9: 142-57.
- Kienle GS, Glockmann A, Schink M, et al. Viscum album L. extracts in breast and gynaecological cancers: a systematic review of clinical and preclinical research. J Exp Clin Cancer Res 2009; 28: 79.
- Melzer J, Iten F, Hostanska K, Saller R. Efficacy and safety of mistletoe preparations (Viscum album) for patients with cancer diseases. A systematic review. Forsch Komplementmed 2009; 16: 217-26.
- Ostermann T, Raak C, Büssing A. Survival of cancer patients treated with mistletoe extract (Iscador): a systematic literature review. BMC Cancer 2009; 9: 451.
- Horneber MA, Bueschel G, Huber R et al. Mistletoe therapy in oncology. Cochrane Database Syst Rev 2008; 2: CD003297.
- Kleeberg UR, Suciu S, Bröcker EB et al. Final results of the EORTC 18871/DKG 80-1 randomised phase III trial: rIFN-a2b versus rIFN-g versus ISCADOR M1 versus observation after surgery in melanoma patients with either high risk primary (thickness >3 mm) or regional lymph node metastasis. Eur J Cancer 2004; 40: 390-402.
- Bar-Sela G, Wollner M, Hammer L et al. Mistletoe as complementary treatment in patients with advanced non-small-cell lung cancer treated with carboplatin-based combinations: a randomised phase II study. Eur J Cancer 2013; 49: 1058-64.
- Kim KC, Yook JH, Eisenbraun J et al. Quality of life, immunomodulation and safety of adjuvant mistletoe treatment in patients with gastric carcinoma - a randomized, controlled pilot study. BMC Complement Altern Med 2012; 12: 172.
- Troeger W, Galun D, Reif M et al. Viscum album [L.] extract therapy in patients with locally advanced or metastatatic pancreatic cancer: a randomised clinical trial on overall survival. Eur J Cancer 2013; 49: 3788-97.
- Ernst E, Schmidt K, Steuer-Vogt MK. Mistletoe for cancer? A systematic review of randomised controlled trials. Int J Cancer 2003; 107: 262-7.
- Hutt N, Kopferschmitt-Kubler M, Cabalion J et al. Anaphylactic reactions after therapeutic injection of mistletoe (Viscum album L.). Allergol Immunopathol (Madr) 2001; 29: 201-3.
- Helixor. Mistletoe products from Helixor. Accessed 29 January 2019.
- Weleda. Iscador® manufacturer information “Fachinformation” 2012. Accessed 13 January 2015.
- Meda Pharm GmbH & Co. Lektinol® Madaus, manufacturer information [Fachinformation], accessed 29 January 2019.
- Jadad AR, Moore RA, Carroll D et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clinical Trials 1996; 17: 1-12.
