Abstract

Background

Mistletoe extracts are commonly used in cancer patients. It is claimed that they improve survival and quality of life (QOL) in cancer patients.

Objectives

To determine the effectiveness, tolerability and safety of mistletoe extracts given either as monotherapy or adjunct therapy for patients with cancer.

Search methods

Search sources included the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 3, 2007) Cochrane Complementary Medicine Field Registry of randomized clinical trials (RCTs) and controlled clinical trials, MEDLINE, EMBASE, HEALTHSTAR, INT. HEALTH TECHNOLOGY ASSESSMENT, SOMED, AMED, BIOETHICSLINE, BIOSIS, CancerLit, CATLINE, CISCOM (August 2007).

For the search the Standard Operating Procedures of the Information System in Health Economics at the German Institute for Medical Documentation and Information (DIMDI) were utilized. Reference lists of relevant articles and authors extensive files were searched for additional studies. Manufacturers of mistletoe preparations were contacted.

Selection criteria

We included randomised controlled trials (RCTs) of adults with cancer of any type. The interventions were mistletoe extracts as sole treatments or given concomitantly with chemo‐ or radiotherapy. The outcome measures were survival times, tumor response, QOL, psychological distress, adverse effects from antineoplastic treatment and safety of mistletoe extracts.

Data collection and analysis

Three review authors independently assessed trials for inclusion in the review. All review authors independently took part in the extraction of data and assessment of study quality and clinical relevance. Disagreements were resolved by consensus. Study authors were contacted where information was unclear. Methodological quality was narratively described and additionally assessed with the Delphi list and the Jadad score. High methodological quality was defined if six out of nine Delphi criteria, or four out of five Jadad criteria were fulfilled. Results were presented qualitatively.

Main results

Eighty studies were identified. Fifty‐eight were excluded for various reasons, usually as there was no prospective trial design with randomised treatment allocation. Of the 21 included studies 13 provided data on survival, 7 on tumour response, 16 on measures of QOL or psychological outcomes, or prevalence of chemotherapy‐related adverse effects and 12 on side effects of mistletoe treatment; overall comprising 3484 randomised cancer patients. Interventions evaluated were 5 preparations of mistletoe extracts from 5 manufacturers and one commercially not available preparation. The general reporting of RCTs was poor.

Of the 13 trials investigating survival, 6 showed some evidence of a benefit, but none of them was of high methodological quality. The results of two trials in patients with melanoma and head and neck cancer gave some evidence that the used mistletoe extracts are not effective for improving survival.

Of the 16 trials investigating the efficacy of mistletoe extracts for either improving QOL, psychological measures, performance index, symptom scales or the reduction of adverse effects of chemotherapy, 14 showed some evidence of a benefit, but only 2 of them including breast cancer patients during chemotherapy were of higher methodological quality.

Data on side effects indicated that, depending on the dose, mistletoe extracts were usually well tolerated and had few side effects.

Authors' conclusions

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. 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 trails.

Author(s)

Markus Horneber, Gerd vanAckeren, Klaus Linde, Matthias Rostock

Abstract

Plain language summary

Mistletoe treatment in cancer patients

Preparations from the European mistletoe (Viscum album L.) are among the most prescribed drugs in cancer patients in several European countries. Proponents claim that mistletoe extracts stimulate the immune system, improve survival, enhance quality of life and reduce adverse effects of chemo‐ and radiotherapy in cancer patients. The review found that there was not enough evidence to reach clear conclusions about the effects on any of these outcomes and it is therefore not clear to what extent the application of mistletoe extracts translates into improved symptom control, enhanced tumour response or prolonged survival. Adverse effects of mistletoe extracts were reported, but appeared to be dose‐dependent and primarily confined to reactions at injection site and mild, transient flu‐like symptoms. In the absence of good quality, independent trials, decisions about whether mistletoe extracts are likely to be beneficial for a particular problem should rely on expert judgement and practical considerations.

Author(s)

Markus Horneber, Gerd vanAckeren, Klaus Linde, Matthias Rostock

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

The majority of the included trials reported benefits for patients treated with mistletoe extracts in one or more outcome measures. However, most trials were found to have major methodological drawbacks that raise doubts about the validity and generalizability of the findings and there is no clear evidence for the superiority of one preparation or treatment schedule over another. Therefore, based on the results of RCTs, the evidence is insufficient to provide clear guidelines for the use of mistletoe extracts in oncological practice and it does not support mandatory use of mistletoe extracts.

Safety data indicate that, depending on the dose, mistletoe extracts are usually well tolerated and have only few adverse effects. Although they comprise rare events, caution is advised to allergic reactions and care should be taken to monitor signs of systemic immune stimulation like fever and chills.

Decisions about whether mistletoe extracts are likely to be effective and safe for a particular problem as well as the mode of use must rely on expert judgement and practical considerations. This should be discussed with patients before they give their consent and where possible, patients should be offered entry into well‐designed clinical trials.

Implications for research 

Given the widespread use of mistletoe extracts for cancer patients, the small number of informative trials for some tumour entities, and the limited evidence concerning effects of different mistletoe extracts on clinical relevant outcomes, there is a need for good quality independent clinical evaluation of this treatment modality. It is imperative that trials with positive outcomes should be repeated by other research groups and in different settings.

Concerning the design of future studies with mistletoe extracts the following issues should be taken into account:

• the results of two trials suggesting beneficial effects of mistletoe extracts on QOL of breast cancer patients during chemotherapy need independent replication;
• the results of some trials give reasonable evidence that the used mistletoe extracts are not effective for the purpose for which they have been used;
• the availability of mistletoe extracts and their wide‐spread use in cancer patients, especially in German‐speaking countries, impede the recruitment of controlled clinical trials in this field and expose the trial to the risk of bias through contamination of the control group;
• compliance and/or contamination could be controlled by measuring the formation of mistletoe‐lectin antibodies;
• the lectin content of the investigational mistletoe extracts should be specified in the publications;
• treatment schedules adjusted to the individual's local and systemic reaction, which are recommended by some manufacturers, cannot be properly blinded;
• the context variables between different forms of mistletoe therapy (i.e. anthroposophical, phytomedical) vary in clinical practice and should be considered in future study designs;
• better reporting of study methods, targeted outcomes, characteristics of participants and interventions is needed.

Finally, authors should bear in mind that positive or negative results obtained with a specific mistletoe preparation or application schedule in a defined type of cancer cannot be extrapolated to "mistletoe therapy" in general.

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