This review evaluated the effectiveness of fermented mistletoe extract (Iscador) in the survival of cancer patients. Pooled analysis suggested that adjuvant treatment of cancer patients with Iscador was associated with better survival, despite limitations in the literature and the suggestion of publication bias. The authors' conclusions generally reflected the methodological limitations and are likely to be reliable.

To evaluate the effectiveness of mistletoe extract (Iscador) in the survival of cancer patients.

PubMed, EMBASE, the Cochrane Library, DIMDI (Deutsches Institut fur Medizinische Dokumentation und Information) and CAMbase were searched (from February and April 2008) for studies published in English or German language journals. Search terms were reported. Reference lists were searched for further studies. Experts were contacted for grey literature. The manufacturer of the mistletoe extract was contacted.

Controlled clinical studies that assessed survival in cancer patients treated with Iscador (fermented mistletoe extract) were eligible for inclusion. Trial where Iscador was used withHelixor (aqueous mistletoe extract) were excluded.

The included trials involved patients with a variety of tumour types. The comparators were placebo, alternative therapies (no further details reported), or no extra treatment (less than four Iscador packages in five years).

Two reviewers independently selected studies for inclusion; disagreements were resolved by consensus.

Methodological quality was assessed independently by two reviewers in terms of study design, randomisation, comparability of groups, drop-outs, allocation concealment (assessed using Cochrane guidelines), reporting and external validity. Disagreements were resolved by consensus.

Hazard ratios (HRs) and standard errors (SEs) for survival (median, overall or survival at specified time points) were extracted independently by two reviewers, with disagreements resolved by consensus. If hazard ratios were not provided, they were estimated. One trial reported using a placebo control, but was extracted and classified as 'alternative treatment' control in the review.

Hazard ratios were pooled in a random-effects meta-analysis. Data were analysed separately for placebo controlled trials, actively controlled trials, and trials where the control group received standard care only. Control groups with patients that were "insufficiently treated" with Iscador (i.e. less than three packages within several months/years) were considered to have received no extra treatment. Heterogeneity was investigated using the I² and χ² tests.

Meta-regression models were also used to investigate the extent to which the following variables were associated with log hazard ratios: standard error of log hazard ratios, tumour localisation, randomisation, and whether the trial was a matchpair comparison.

Publication bias was assessed using funnel plots; asymmetry was investigated using a weighted linear regression analysis.

Twenty-two trials were included in the analysis (containing 46 strata, i.e. sets of patients, tumour stages or localisation). Twelve trials were prospective, five trials were randomised, and five trials had a matched-pair design. The included trials were of moderate to poor quality, in terms of randomisation, matched-pair building, blinding, multicentre and description of drop-outs.

Iscador versus no extra treatment (n=10,641 patients; range 17 to 1,719): Iscador was associated with better survival rates than no extra treatment (overall HR 0.59, 95% CI 0.53 to 0.66), but this was associated with moderate heterogeneity (I²=38.3%, p<0.0001) and possible publication bias (suggested by asymmetrical funnel plots). The meta-regression showed that when tumour localisation was taken into consideration, the results were not generally significantly different, except for lung cancer trials; these showed slightly better outcomes (ratio of HRs 0.56, 95% CI 0.00 to 1.10). Randomised trials showed lesser effects on survival rates than non-randomised trials (ratio of HR 1.24, 95% CI 0.79 to 1.92). Matched-pair trials showed significantly better results than other study designs (ratio of HRs 0.33, 95% CI 0.17 to 0.65).

Iscador versus placebo (n=224 patients): There was no difference in median survival times between placebo and Iscador (one trial).

Iscador versus alternative therapies (n=912 patients; range 46 to 227): There was no significant difference in survival rates with Iscador compared with alternative therapies; this was associated with moderate heterogeneity (I²-36.6%, p=0.15). There was no indication of publication bias on the funnel plot. Results of meta-regression analyses were similar, except for randomised trials, which showed significantly worse results than non-randomised trials (ratio of HRs 3.20, 95% CI 1.16 to 8.85).

Iscador versus no treatment (n=111 patients): Iscador was associated with better survival rates than "no treatment" (HR 0.39, 95% CI 0.20 to 0.77; one trial).

Pooled analysis suggested that adjuvant treatment of cancer patients with Iscador was associated with better survival, despite limitations in the literature and the suggestion of publication bias.

The research question was supported by clear inclusion criteria. Only studies published in English or German were included, so language and publication bias could not be ruled out. Publication bias was suggested by funnel plots and this was acknowledged as a limitation by the authors. Study selection, validity assessment and data extraction were performed in duplicate, reducing the possibility of reviewer error and bias.

Trial quality was assessed using appropriate criteria and taken into consideration in the analyses. Heterogeneity was investigated and discussed.

Although there were some methodological limitations, the authors' conclusions generally reflected this and are likely to be reliable.

Two authors disclosed financial support (grants) from the Institute Hiscia, Association for Cancer Research, Switzerland (developers of Iscador).

Practice: The authors did not state any implications for practice.

Research: The authors stated that future studies evaluating the effects of Iscador should focus on having a transparent design and description of endpoints.

Verein fur Krebsforschung Arlesheim (Association for Cancer Research), Institute Hiscia, Arlesheim, Switzerland (developers of Iscador).

Bussing A, Raak C, Ostermann T. Quality of life and related dimensions in cancer patients treated with mistletoe extract (Iscador): a meta-analysis. Evidence-Based Complementary and Alternative Medicine 2012; 2012:219402.

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.