Mistletoe Therapy in Oncology
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The primary objective of this review will be:
To assess the effects of mistletoe preparations given alone or in combination with tumour‐specific therapies on:
disease‐free and overall survival.
Secondary objectives will be:
To assess the effects of mistletoe preparations given alone in combination with tumour‐specific therapies on:
quality of life
tumour response
To assess the effects of mistletoe preparations given in combination with tumour‐specific therapies on:
treatment toxicity
Background
The treatment of cancer with extracts from mistletoe was first introduced at the beginning of the 20th century by Rudolf Steiner as part of a holistic and human‐centered therapeutic approach in the frame of anthroposophically‐extended medicine.
Mistletoe is a semi‐parasitic plant which grows on various host trees. The aqueous solutions of mistletoe comprise a variety of bioactive substances. Extracts derived from it showed cytotoxic and immunemodulatory effects both in vitro and in vivo (Hajto 1999). The components which are responsible for the biological effects are lectins, viscotoxins and alkaloids (Büssing 1996; Hajto 1999). The ability of mistletoe preparations to stimulate the immune system has led to its classification as a type of biological response modifier which is being used alone, or in combination with other agents, to treat cancer or to diminish the adverse effects of chemotherapy and radiotherapy.
Mistletoe preparations are amongst the most widely used unconventional remedies in cancer treatment in Europe. In 1998 nearly 0.7 million prescriptions with average sales of 30 million EURO in Germany were registered (Schwabe 1998). Despite this widespread use of mistletoe preparations, there is considerable dispute about the efficacy of this treatment modality and the results of the existing reviews concerning the efficacy and effectiveness of this treatment are inconsistent (Kiene 1991; Hauser 1993; Kleijnen 1994).
For several reasons it seems necessary to systematically review the available evidence of mistletoe treatment of cancer:
* The results of the present reviews are inconsistent.
* Several new clinical trials with mistletoe preparations have been published recently.
* The therapeutic paradigm of this treatment modality and thus the endpoints of the clinical studies have shifted during the last years from tumor response towards quality of life and alleviation of side effects of chemo‐ and radiotherapy.
* A new treatment approach emerged over the last years, which contrasts with the classical treatment modality. Both concepts are subject of substantial debate. The latter works with mistletoe preparations standardized for the manufacturing process and are applied at individual doses whereas the new approach applies preparations standardized for the (‐galactoside‐specific mistletoe lectin I in a constant dosage schedule.
Objectives
The primary objective of this review will be:
To assess the effects of mistletoe preparations given alone or in combination with tumour‐specific therapies on:
disease‐free and overall survival.
Secondary objectives will be:
To assess the effects of mistletoe preparations given alone in combination with tumour‐specific therapies on:
quality of life
tumour response
To assess the effects of mistletoe preparations given in combination with tumour‐specific therapies on:
treatment toxicity
Methods
Criteria for considering studies for this review
Types of studies
Randomized clinical trials will be included. If the number of properly randomized controlled trials is less than 10, trials which use a quasi‐random method (such as alternation, date of birth etc.) for allocation will also be included. If the number of trials is still below 10 prospective controlled clinical trials focussing on a single type of tumor will be included.
Types of participants
Persons diagnosed with cancer, without restriction to the type or stage of the disease.
Types of interventions
Experimental group:
Treatment with any kind of parenterally (i.e. sub‐/intracutaneously, intravenously) applied mistletoe preparation.
Control group:
no treatment, placebo or any type of tumour‐specific treatment.
Types of outcome measures
To be included trials have to report at least one of the following outcomes:
Changes of at least one clinical measure of efficacy related to cancer (e.g. survival rate, tumor remission).
Changes of quality of life measured by a validated questionnaire.
Adverse reactions resulting from antineoplastic treatment.
Trials which report non‐clinical measures only (e.g. immune parameters etc.) will not be included.
Search methods for identification of studies
Studies will be identified using the Standard Operating Procedures of the Information System in Health Economics at the German Institute for Medical Documentation and Information (DIMDI).
Databases which will be included in the search are: AMED, BIOETHICSLINE, BIOSIS, CATLINE, CISCOM, Cochrane Complementary Medicine Field Registry of randomized clinical trials and controlled clinical trials, EMBASE, HEALTHSTAR, INT. HEALTH TECHNOLOGY ASSESSMENT, SOMED.
The databases will be searched using the Cochrane Collaboration search strategy adapted for the retrieval system of DIMDI as specified in its SOP. The following specific terms will be applied: mistletoe; mistletoe‐therapy; viscum album; Iscador; Helixor; Iscucin, ABNOBAviscum; Eurixor; Plenosol; Lektinol; Vysorel; Isorel; Cefalektin; Misteltherapie. Synonyms of the specific terms will be identified by looking up the thesaurus of each database, if available. Depending on the database searched, subject headings will be used if possible, always followed by a search with textwords. The results of the specific terms will be combined by the Boolean operator "or". This result and the results of the Cochrane strategy will be combined by the operator "and". Finally the results will be checked for double citations.
For identifying unpublished material institutions and subjects known to have expertise in cancer treatment with mistletoe preparations and respective manufacturers will be contacted for further information. Beyond this the bibliography of the identified studies will be checked for further trials on the topic which may not be found by the search strategy described above.
Data collection and analysis
Methods of the review
Eligibility:
Eligibility will be assessed by at least two independent reviewers. First the titles of the citations and, if available, abstracts will be screened to sort out clearly irrelevant references. For the remaining citations the full paper will be assessed using an eligibility form. In all steps disagreements will be documented and resolved by discussion.
Extraction:
Information on patients (number randomized, analyzed and complying with the protocol, age, sex, diagnosis, inclusion criteria, stage, treatment situation, setting), methods (design, observation period, analysis), interventions (type of preparation, application and duration of the mistletoe treatment, control procedure, other anti‐tumor therapy), outcomes and results (number and reasons for drop‐outs and follow up, total and disease‐free survival at given time points; other available data on survival such as median survival etc., remission rates, quality of life, number of patients reporting side effects and number of side effects) will be extracted by at least two independent reviewers and documented using an extraction form.
Assessment of methodological quality:
The quality of the trials will be assessed using the Delphi list (Verhagen 1998):
Treatment allocation:
‐ Was a method of randomization performed?
‐ Was the treatment allocation concealed?
Were the groups similar at baseline regarding the most important prognostic indicators?
Were the eligibility criteria specified?
Was the outcome assessor blinded?
Was the care provider blinded?
Was the patient blinded?
Were point estimates and measures of variability presented for the primary outcome measures?
Did the analysis include an intention‐to‐treat analysis?
The questions will be answered with "yes/no/do not know".
Summarizing results:
Trials will be categorized according to
method of allocation
control group
tumour type
Effect size estimates (and their 95% confidence intervals) for single trials will be calculated, as far as available, for all extracted outcomes. For dichotomous data the effect measure will be the relative risk, for continuous data weighted mean differences will be calculated if the same scale is used by all trials, otherwise standardised mean differences. Summary estimates will be calculated only for groups of trials which are identical in respect to the three categories mentioned above. Otherwise effect size estimates from single trials will not be pooled. In case meta‐analyses should be possible the main outcome measure for confirmatory analysis will be total survival (time points: 0‐1 year, 1‐5 years, >5 years) and quality of life (random effects model, category randomized trials for each trype of control group and tumor). Sensitivity analyses will be performed according to type of preparation (lectin‐standardized or not, standardized or indivudal dosage). All analysis will be performed using RevMan Version 4.1 or later.
It is expected that the included trials will be highly heterogenous regarding patients as well as interventions and outcome measures. Furthermore it is anticipated that data in the publications will be often presented with insufficient details (lack of standard deviations, only some of multiple outcomes presented), and that additional information from authors will be hard to obtain (part of the studies are old; authors changing workplace, no sponsors who have to keep detailed records). Therefore we expect that
quantitative meta‐analysis will not be possible and
calculation of effect size estimates will often not be possible.
As far as possible we will summarize available results descriptively in tables.
