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Viscum album L. extracts in breast and gynaecological cancers: a systematic review of clinical and preclinical research |
Kienle GS, Glockmann A, Schink M, Kiene H |
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CRD summary This review reported that there was some evidence to support positive effects of Viscum Album L. (European Mistletoe) extracts (VAE) for breast and gynaecological cancer on quality of life (QoL) and tolerability. However, methodological limitations of the included studies suggested that some findings may not be reliable and should be interpreted with caution. Authors' objectives To determine the effects of extracts of Visum album L. (European Mistletoe) on breast and gynaecological cancers in clinical and pre-clinical studies. Searching EMBASE, MEDLINE, PREMEDLINE, AMED, BIOSIS Previews, The Cochrane Library, NLM Gateway and unspecified private databases were searched from inception to December 2008. Search terms were reported. Reference lists of retrieved studies, relevant reviews and text books were searched. Topic experts and manufacturers of mistletoe preparations were contacted for further studies. No language restrictions were applied. Published and unpublished studies were sought. Study selection Randomised controlled trials (RCTs), non-randomised controlled trials (non-RCTs), uncontrolled cohort studies (such as phase II clinical trials) and pharmacoepidemiological cohort studies that evaluated use of a Viscum album L. extract (VAE) preparation in patients with breast or gynaecological cancer were eligible for inclusion in the review. Eligible studies had to report a clinically relevant outcome such as survival, disease-free interval, remission, relapse, quality of life (QoL) or reduction of side effects (including immune suppression). Retrospective studies (with the exception of pharmacoepidemiological studies) were excluded, as were studies that were ongoing and studies that measured only toxicity, tolerability (phase I trial) or immunological parameters. (Published in vitro studies carried out in human cancer cell lines and animal studies were eligible for inclusion, but these data were not reported in this abstract.)
Included studies assessed commercial VAE preparations, including iscador, helixor, eurixor and lektinol; aviscumine, viscum fraxini and abnobaviscum fraxini preparations were also assessed. Preparations were commonly injected either subcutaneously or intravenously and compared with no treatment or in some cases conventional care (chemotherapy, radiation and hormones). Participants had usually received previous conventional treatments either directly preceding or concurrent with VAE treatment. The most commonly assessed malignancy was breast cancer; other frequently investigated cancers included ovarian cancer, cervical cancer and cancer of the uterus. Various stages of disease from early to advanced and inoperable were included.
The authors stated neither how papers were selected for review nor how many reviewers performed the selection. Assessment of study quality Two reviewers independently assessed validity of controlled clinical studies in accordance with criteria adapted from the Centre of Reviews and Dissemination and earlier reviews of VAE studies. Criteria included: use of adequate randomisation methods; use of pre-stratification or matching to minimise heterogeneity; blinding of patient, care provider and outcome assessor; use of standardised care protocols and documentation of cointerventions; standardisation of outcome assessment; loss to follow-up of less than 10% or use of an intention-to-treat analysis; use of relevant and well-described outcome measures, intervention, population, study design and results; and use of quality assurance methods according to International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH-GCP) guidelines. Criteria were adapted accordingly for cohort studies. Discrepancies were resolved through discussion. Data extraction One reviewer extracted study data and a second reviewer checked data for accuracy. Authors of the primary studies were contacted where necessary for further information. Time to event data were reported as hazard ratios with 95% confidence intervals (CIs) or medians; survival rates, response rates and adverse events were presented as percentages. Differences in quality of life (QoL) data were described. P values were reported where available. Methods of synthesis Studies were grouped by design and the results summarised narratively and accompanied by tables of data and study characteristics. Results of the review Nineteen RCTs (n=2,420), 16 non-RCTs (n=6,399), and 11 uncontrolled cohort studies (n=1,130) were included in the review. Eight RCTs and eight non-RCTs were conducted as part of a larger epidemiological cohort study. Methodological quality differed substantially. Some studies had major limitations, especially RCTs that assessed survival and tumour response with very small sample sizes. Some of the more recent studies (especially those that assessed QoL) were reasonably well-conducted.
Nine RCTs and 13 non-RCTs assessed survival. Twelve reported a statistically significant benefit in favour of VAE; a trend or no difference was reported in the other studies. Three RCTs and six non-RCTs assessed tumour remission or time to relapse: three reported a statistically significant benefit for VAE; a trend, no difference or mixed results were reported in the other studies. QoL and tolerability of chemotherapy, radiotherapy or surgery was assessed in 15 RCTs and nine non-RCTs. Of these, 21 reported a statistically significant positive result in favour of VAE; the others reported either a trend, no difference or mixed results.
Single-arm cohort studies investigated tumour behaviour, QoL, pharmacokinetics and safety of VAE. High dosage VAE and locally applied preparations were most commonly associated with tumour remission. Use of VAE was well tolerated. Authors' conclusions Some evidence was found to support positive effects of VAE in breast and gynaecological cancer on quality of life (QoL) and tolerability. CRD commentary This study assessed a clear review question using a very broad range of both clinical and non-clinical studies. Extensive searches were made for both published and unpublished data. Inclusion of all eligible studies regardless of language suggested that risk of publication and language biases was likely to be low. Two reviewers extracted study data and assessed methodological quality, which suggested that risk of reviewer error and bias was low; it was unclear whether similar precautions were taken during study selection. A very wide range of studies was included in the review, but criteria used to assess validity was adapted to study designs used. Data were grouped by study design in the analysis. Study quality varied between studies, but was generally low in randomised controlled trials that assessed survival and tumour response. Most studies were funded by industry and so may be open to bias. Studies that assessed QoL were generally of better quality. Given the wide range of interventions, study designs and populations, a narrative summary appeared appropriate. However, overall the methodological limitations of the included studies suggested that some findings may not be reliable and should be interpreted with caution. Implications of the review for practice and research Practice: The authors stated that although high-dose and locally applied VAE appeared to be associated with tumour regression, this finding was not thoroughly assessed and the treatment was not generally recommended.
Research: The authors stated that a large independent randomised controlled trial was required to assess the effects VAE on survival in patients with breast and gynaecological cancers. They also noted a number of other interventions that included high-dose VAE and locally applied VAE which had not yet been assessed thoroughly in clinical trials. Funding The review was funded by the Gesellschaft für Biologische Krebsabwehr. Bibliographic details Kienle GS, Glockmann A, Schink M, Kiene H. Viscum album L. extracts in breast and gynaecological cancers: a systematic review of clinical and preclinical research. Journal of Experimental and Clinical Cancer Research 2009; 28:79 Indexing Status Subject indexing assigned by NLM MeSH Animals; Breast Neoplasms /drug therapy; Clinical Trials as Topic; Drug Evaluation, Preclinical; Female; Genital Neoplasms, Female /drug therapy; Humans; Mistletoe; Phytotherapy; Plant Extracts /therapeutic use; Quality of Life; Treatment Outcome AccessionNumber 12009107405 Date bibliographic record published 07/10/2009 Date abstract record published 24/03/2010 Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn. |
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