List of References
Mistletoe in Cancer
Systematic Reviews of Clinical Studies
Numerous reviews are available concerning mistletoe therapy in oncology (for example, [1, 2, 3, 4, 6, 7, 8, 9, 10a, 11-14, 16]), each respectively with more or less systematic methodology. They are presented in the following. Not included are review that are clearly outdated [3, 10a, 12, 16] or do not refer to studies with clinically relevant oncological objectives - like reviews primarily on immunomodulation, tolerance or other indications; these have been excluded.
National Cancer Institute 2009 [13] 
Synopsis: All mistletoe preparations; all study designs; systematic methodology not specified; no criteria described for quality assessment; total of 35 (37) trials identified; many studies missing, in particular recent trials.
Review: The National Cancer Institute of the U.S. National Institutes of Health in Bethesda, Maryland has compiled a comprehensive review of mistletoe research. The review has been published on the Institute’s web-page and is regularly updated. It contains a tabular listing of mistletoe studies with detailed discussion. The essential features of a systematic review are lacking, however, particularly information regarding search strategy, inclusion criteria, quality assessment criteria and evaluation process. The spectrum of selected studies includes all study designs as well as a case report. The review encompasses 29 studies of anthroposophical mistletoe preparations in tabular form (and two more are described in the text), and 7 studies of non-anthroposophical mistletoe preparations. The predominantly positive outcome for mistletoe therapy is described in the review but there is across-the-board criticism with regard to the following points: Frequently small case numbers; high patient loss rates (drop-outs, protocol deviation/violation etc.); absence of blinding; frequently insufficient specification of mistletoe dosage (host tree, treatment duration and therapy pauses); in part, the lack of a comparative group (or only historical); in part, inadequate randomisation processes; frequent reporting of mean instead of median survival time. These weaknesses reduce the reliability of the data.
Comment: A section on preclinical mistletoe research describes many important subject areas. The studies are systematically tabulated, but this is not a systematic review in the classical sense - the review lacks a transparent system for literature searches, selection, quality assessment and specification of authors. The review is incomplete, possibly because many studies have been published in German and these publications are often not listed in international databases. Despite a recent date of actualisation, studies dating from the last years are also missing although they, in part, have clearly improved methodology and are mostly listed in established data bases such as Medline. While the criticism brought forward in the review is partially justified - especially concerning the older studies - there is also criticism of marginalia which is not relevant to the validity of the studies. Some of the criticism requires discussion (for example, the assumption that the median value is generally more reliable than the mean value is not statistically legitimate).
Cochrane Review 2008 [2]
Synopsis All mistletoe preparations, randomised trials, systematic methodology; quality assessment using Jadad score and Delphi list; 21 studies identified; several, especially current studies are missing
Review: A Cochrane-Review was conducted on randomised controlled trials on mistletoe therapy with anthroposophical and phytotherapeutical preprarations. Thirteen electronic databases and reference lists were searched. Published as well as unpublished trials were included. Methodological study quality was assessed using the Jadad Score and the Delphi-Liste. Altogether 21 studies were included, 13 of these investigated survival, 7 tumor response, 16 quality of life and chemotherapy-related adverse effects. Overall, the quality of the studies was regarded as not very high. Some evidence would suggest that mistletoe extracts may offer benefits on quality of life during chemotherapy for breast cancer, but these results would need replication. Evidence regarding survival or tumor behaviour, however, was judged as weak. Therefore, more high quality and independent trials should be conducted.
Comment: This review is incomplete and not update, and 9 RCTs are missing. Furthermore, a re-analysis of an RCT, an HTA-report, a systematic review and a meta-analyses were not taken into account. The formal evaluation procedure is inadequate, and the factual assessments are not consistent and often incorrect. Details can be seen in a comprehensive statement. [9a]
Kienle & Kiene 2007 [7]
Synopsis: Anthroposophical mistletoe preparations; all prospective studies; systematic methodology; detailed criteria-based quality assessment; 37 studies identified; review in tabular form with discussion.
Review: The review is based on the Health Technology Assessment Report (HTA) on anthroposophical medicine (see Kienle et al. 2005, 2006 [8, 9]) and was updated for the presented publication. This review included only prospective clinical studies and only studies of anthroposophically-produced mistletoe preparations. Quality assessment and data extraction were predefined in a protocol.
Nine electronic databases, private databases and all relevant bibliographies were searched, experts in the field and manufacturers of mistletoe preparations were contacted for additional reports. Search strategy, study selection and quality assessment are described. 37 prospective clinical studies were identified: Of these there are 25 comparative trials, 16 of which are randomised, 12 are prospective cohort studies without comparison group. The results of the studies predominantly describe benefits of mistletoe therapy. The methodological quality, however, varies widely: Some studies have major weaknesses and others exhibit good quality concerning design, conduction, and documentation. With regard to quality of studies and consistency of results, the best evidence concerning efficacy of mistletoe therapy exists for the improvement of quality of life and reduction of side effects of cytoreductive therapies (chemotherapy, radiatiotherapy, surgery). Evidence also exists that tumour remission can be induced through the injecting of mistletoe extracts. However, such tumour remissions appear to be dependent upon dosage and method of administration: With respect to the customary low-dose mistletoe therapy, tumour remissions are rare exceptions. A benefit in survival time due to mistletoe treatment is possible. This might depend on the duration of the mistletoe therapy as well as to factors relating to dosage, host tree and choice of preparation.
Comment: This is the most update comprehensive review on prospective clinical studies on anthroposophic mistletoe therapy. Not included, however, are studies of non-anthroposophical preparations.
Kienle et al. 2005, 2006 [8, 9]
Synopsis: Anthroposophical mistletoe preparations; all study designs; systematic methodology; detailed criteria-based quality assessment; 90 (updated, 94) studies identified; review in tabular form with discussion.
Review: The review was carried out as part of a Health Technology Assessment Report (HTA) on anthroposophical medicine, conducted within the context of the Swiss ‘Programm Evaluation Komplementärmedizin’ (PEK). This review included only studies of anthroposophically-produced mistletoe preparations. Two already available systematic reviews (Kienle et al. 2003 [4] and Kienle & Kiene 2003 [6]) have been incorporated into the HTA Report and updated; quality assessment and data extraction of the newly accrued studies strictly followed the protocol. This HTA Report [8] has been updated again for publication in book form [9].
Twelve electronic databases, four private databases and all relevant bibliographies were searched, and about 160 experts in the field consulted. Search strategy, study selection and quality assessment are described. 90 (updated, 94) clinical studies were identified: Of these there are 22 (updated, 23) prospective comparative trials, 14 of which are randomised, 31 (updated, 34) are cohort studies without comparison group, and 37 are retrospective comparative studies. The results of the studies predominantly describe benefits of mistletoe therapy. The methodological quality, however, varies widely: Some studies have major weaknesses and others exhibit good quality concerning design, conduction, and documentation. With regard to quality of studies and consistency of results, the best evidence concerning efficacy of mistletoe therapy exists for the improvement of quality of life and reduction of side effects of cytoreductive therapies (chemotherapy, radiotherapy, surgery). Evidence also exists that tumour remission can be induced through the injecting of mistletoe extracts. However, such tumour remissions appear to be dependent upon dosage and method of administration: With respect to the customary low-dose mistletoe therapy, tumour remissions are rare exceptions. A benefit in survival time due to mistletoe treatment is possible. This might depend on the duration of the mistletoe therapy as well as to factors relating to dosage, host tree and choice of preparation. For details of the results see also Clinical Trials.
Comment: Supplementing the review from Kienle & Kiene 2003 [6], this is to date the most complete review of clinical studies with a detailed discussion of the critical evaluation of the respective studies. Not included, however, are studies of non-anthroposophical preparations published after 2003.
Kienle et al. 2003 [4]
Synopsis: All mistletoe preparations; prospective comparative trials; systematic methodology; detailed criteria-based quality assessment; 23 trials identified; review in tabular form with discussion.
Review: A systematic review of prospective controlled clinical trials has been conducted by an international work group. Eleven electronic databases and all relevant reference lists were searched, and experts in the field and manufacturers of mistletoe preparations were contacted for additional reports. Search strategy, study selection and quality assessment are described. A total of 23 prospective comparative trials were identified, 16 of which were randomised, 2 quasi-randomised and 5 non-randomised. There were 17 trials of anthroposophical preparations (14 trials of Iscador®, 3 trials of Helixor) and 6 trials of phytotherapeutic preparations (Eurixor®). An independent, criteria-based assessment of the methodological quality of the trials was carried out. The quality criteria assess study procedures that protect against important bias factors, general good study methodology, and completeness and transparency of the publication. The methodological quality of the reviewed trials varied considerably and was particularly insufficient in some ot the older trials. Due to the heterogeneity of the trials, non-quantitative (rather than quantitative) data analysis and reporting was carried out. Most of the trials showed favourable results, but there were several limitations with respect to the quality of a number of trials. However, more recent and better conducted trials suggest favourable effects of mistletoe therapy.
Comment: The most complete review of prospective comparative trials up to 2003. In contrast to Kienle et al. 2005 [8] and 2006 [9] it also includes trials with non-anthroposophical mistletoe preparations
Kienle & Kiene 2003 [6]
Synopsis: All mistletoe preparations; all study designs; systematic methodology; detailed quality assessment; 89 trials identified; review in tabular form with discussion of each individual study or trial.
Review: This systematic review encompasses all study designs, not only prospective comparative trials. The above-mentioned review, Kienle et al. 2003 [4], has been integrated into this review. Eleven electronic databases and all relevant reference lists were searched, and experts in the field and manufacturers of mistletoe preparations were contacted for additional reports. Search strategy, study selection and quality assessment are described. A total of 89 studies were identified: Of these, there were 23 prospective comparative trials (16 of which were randomised, 2 quasi-randomised and 5 non-randomised), 37 cohort studies without comparison group (9 of which were prospective, 24 retrospective and 4 unclear), and 29 retrospective comparative studies. An criteria-based assessment of study quality was independently performed by two reviewers. The quality criteria assess study procedures that protect against important bias factors, general good study methodology, and completeness and transparency of the publication. These criteria were differentiated for the various study designs. The methodological quality of the reviewed trials varied considerably and was particularly insufficient in some ot the older trials. Due to the heterogeneity of the trials, non-quantitative (rather than quantitative) data analysis and reporting was carried out. Most of the trials showed favourable results, but there were several limitations with respect to the quality in a number of trials. However, more recent and better conducted trials also suggest favourable effects of mistletoe therapy.
Comment: The most complete review of clinical studies of anthroposophical and non-anthroposophical mistletoe therapy to date. Studies published after 2003 and unpublished studies have not been included.
Ernst et al. 2003 [1]
Synopsis: All mistletoe preparations; only randomised clinical trials; quality assessment using the Jadad score; 10 trials identified; tabulated presentation and discussion of contents; incomplete; simple evaluation method.
Review: A systematic review of randomised clinical trials of all mistletoe preparations. Eight electronic databases were searched, manufacturers of mistletoe preparations and other experts were consulted, and bibliographies of review articles were examined. Inclusion and exclusion criteria for the studies are specified. Quality of the studies was assessed according to the Jadad score (evaluating randomisation, blinding and drop-out). 10 trials were identified; 13 trials were listed in the tabulation. As most of the trials inadequately fulfilled the quality criteria of the Jadad score, it was concluded that the studies do not substantiate efficacy of mistletoe therapy.
Comment: Of the 13 trials presented in tabular form, 3 were duplicated (Kleeberg et al. 1999 [10], Schaefer und Wetzel 2000 [17], Steuer-Vogt 2001 [15]), hence the review ultimately only encompasses 10 trials. Of these, 4 are trials of anthroposophical mistletoe preparations - i.e. only one third of the then-published 12 randomised clinical trials of anthroposophical mistletoe extracts were included. Ernst explicitly excluded two of the relevant RCTs as a result of a lack of understanding for the study design - even though these exclusions did not represent the given inclusion and exclusion criteria. The review is therefore incomplete. The question of whether evaluation with the simple Jadad score is meaningful needs discussion because it only assesses three aspects of the research: Randomisation, double blinding and drop-outs. While these limitations facilitate the evaluation process for the reviewer, they overlook many important details of the study.
Since an audit of other publications by the authors revealed considerable errors [5,6a], this review should also be interpreted with caution.
Stauder & Kreuser 2002 [14]
Synopsis: Only non-anthroposophical mistletoe preparations; prospective clinical and immunological studies; systematic methodology not specified; no criteria-based quality assessment; 6 clinical studies identified; tabulated presentation and discussion.
Review: Stauder and Kreuser published a review of prospective clinical and immunological studies of non-anthroposophical mistletoe preparations in 2002. The methodology applied in the review is not described and a criteria-based quality assessment was not carried out. 7 studies of immunological endpoints and 6 studies of clinical objectives were identified, with the same studies allocated to both categories. Of the 6 clinical studies, 5 are prospective comparative; 1 cohort study had been conducted without a comparison group. The studies are presented in tabular form and discussed individually. Reference is made to methodological problems in most of the studies. The two studies exhibiting the best methodology (Steuer-Vogt et al. 2001 [15], Wetzel & Schäfer 2000 [17]) contain contradictory results, and hence efficacy of the non-anthroposophical mistletoe preparations is referred to as both ‘not proved’ and also ‘not excluded’ in the discussion.
Comment: This review focuses only on non-anthroposophical preparations. The authors stress that they only considered studies of standardised preparations and therefore excluded those testing anthroposophical preparations. The concept of standardisation is frequently confused with the concept of norming: All manufacturers of oncological mistletoe preparations use a standardised production process (process standardisation) to ensure a stable composition of all essential content substances (within defined tolerance limits). In contrast, the non-anthroposophical mistletoe preparations Eurixor® and Lektinol® are normed in the classical sense, i.e. they focus on a defined component which is considered essential for treatment effects (e.g. ML I) and may add more of this substance to the preparation to reach the norm concentration. However, this alone does not guarantee a fixed concentration of the (numerous) remaining components of the plant extract. [1a] A criteria-based quality assessment of the studies was not carried out and the methodological problems of the immunological studies [6b] were not discussed.
Gunver S. Kienle, MD
Last Modified:
March 2009
References 
[1] Ernst, E., K. Schmidt and M. K. Steuer-Vogt, Mistletoe for cancer? A systematic review of randomized clincial trials. Int J Cancer 107, 262-267 (2003).
[1a] Gaedcke, F. and B. Steinhoff, Phytopharmaka. Wissenschaftliche und rechtliche Grundlagen für die Entwicklung, Standardisierung und Zulassung in Deutschland und Europa., pp. 1-184, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart 2000.
[2] Horneber M. A., G. Bueschel, R. Huber, K. Linde, M. Rostock: Mistletoe in oncology (Review). Cochrane Database of Systematic Reviews, Issue 2. Art. No.: CD003297. DOI: 10.1002/14651858.CD003297.pub2. (2008)
[3] Kiene, H., Klinische Studien zur Misteltherapie karzinomatöser Erkrankungen. Eine Übersicht. Therapeutikon 3, 347-353 (1989).
[4] Kienle, G. S., F. Berrino, A. Büssing, E. Portalupi, S. Rosenzweig and H. Kiene, Mistletoe in cancer - a systematic review on controlled clinical trials. Eur J Med Res 8, 109-119 (2003).
[5] Kienle, G. S., H. J. Hamre and H. Kiene, Anthroposophical Medicine: A systematic review of randomised clinical trials. Wiener klinische Wochenschrift 116, 11-12 (2004).
[6] Kienle, G. S. and H. Kiene, Die Mistel in der Onkologie - Fakten und konzeptionelle Grundlagen, Schattauer Verlag, Stuttgart, New York 2003.
[6a] Kienle, G. S. and H. Kiene, Verträglichkeit, Nebenwirkungen, Überempfindlichkeitsreaktionen, Toxizität. In Die Mistel in der Onkologie. Fakten und konzeptionelle Grundlagen. pp. 591-607, Schattauer Verlag, Stuttgart, New York 2003.
[6b] Kienle, G. S. and H. Kiene, Stellenwert, Dosierung und Gefährlichkeit (Tumorenhancement) des ML I - immunologische Schlußfolgerungen und experimentelle Untersuchungen. In Die Mistel in der Onkologie. Fakten und konzeptionelle Grundlagen. pp. 301-332, Schattauer Verlag, Stuttgart, New York 2003.
[7] Kienle GS, Kiene H. Complementary Cancer Therapy: A Systematic Review of Prospective Clinical Trials on Anthroposophic Mistletoe Extracts. Eur J Med Res 12, 103-19 (2007). Download original article as PDF
[8] Kienle, G. S., Kiene, H. and Albonico, H. U. Health Technology Assessment Report: Anthroposophic Medicine. Complimentary Medicine Evaluation Program (PEK) of the Swiss Federal Office for Public Health. 2005. Download: www.ifaemm.de
[9] Kienle, G. S., H. Kiene and H. U. Albonico, Anthroposophic Medicine: Effectiveness, Utility, Costs, Safety, Schattauer Verlag, Stuttgart, New York 2006.
[9a] Kienle, G.S., H. Kiene, Statement on Cochrane review (2008). Statement on Cochrane review for download as pdf
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Lange-Lindberg, A. M., M. Velasco Garrido, R. Busse, Misteltherapie als begleitende Behandlung zur Reduktion der Toxizität der Chemotherapie maligner Erkrankungen. GMS Health Technol Assess 2006; 2:Doc18 (20060919). 2006.
[12] Matthiessen, P. F. and W. Tröger, Die Misteltherapie des Krebses. In Kombinierte Tumortherapie. (Ed. H. Wrba) pp. 271-290, Hippokrates Verlag, Stuttgart 1995.
[13] National Cancer Institute. Mistletoe extracts (PDQ®). 2009. cancernet.nci.nih.gov/cancertopics/pdq/cam/mistletoe/HealthProfessional/page1
[14] Stauder, H. and E.-D. Kreuser, Mistletoe extracts standardised in terms of mistletoe lectins (ML I) in oncology: current state of clinical research. Onkologie 25, 374-380 (2002).
[15] Steuer-Vogt, M. K., V. Bonkowsky, P. Ambrosch, M. Scholz, A. Neiß, J. Strutz, M. Hennig, T. Lenartz and W. Arnold, The effect of an adjuvant mistletoe treatment programme in resected head and neck cancer patients: a randomised controlled clinical trial. Eur J Cancer 37, 23-31 (2001).
[16] University of Texas Center for Alternative Medicine Research in Cancer. Mistletoe. 1999.
[17] Wetzel, D. and Schäfer, M. Results of a randomised placebo-controlled multicentre study with PS76A2 (standardised mistletoe preparation) in patients with breast cancer receiving adjuvant chemotherapy. Phytomedicine Supplement II, 34. 2000.