There are several meta-analyses and systematic reviews (6, 9, 75, 82, 111, 124, 128, 260, 261, 262, 263, 265, 267, 268, 271, 274, 275, 277, 279, 280, 281, 282) on mistletoe therapy in oncological diseases applying different systematic methods.
Some of these reviews have already been published before 1996 (267, 271, 282) or relate to mistletoe lectin I-standardised, i.e. phytotherapeutic mistletoe preparations (277). These and the reviews on immune stimulation, tolerability, dose finding or other indications than cancer are not analysed here.
In the following, the reviews and meta-analyses are discussed sequentially, following the date of their publication. The most recent publications are always on the top of the list:
Last update: November 24th, 2021/AT1
Due to the expected local reactions, it is difficult or nearly impossible to conduct blinded trials with mistletoe extracts. This generally leads to mistletoe studies being rated low in all official study evaluations, since the evaluation of studies is based on the Jadad Score which awards the following quality points:
For a better assessment of the relevance of studies with mistletoe extracts, the analyses of Davies et al. 2017  and Naci et al. 2019  regarding the approval of cancer drugs by the European Medicines Agency (EMA) should be consulted. The cross-sectional analysis by Naci et al. was summarised in the journal Deutsches Ärzteblatt under the title "Studies on new cancer drugs often prone to errors" . If these quality assessments are compared with those of studies on mistletoe therapy, the quality of these studies can often be classified as equivalent to studies with conventional cancer drugs.
Last update: January 4th, 2021/AT
Loef and Walach 2020 
A systematic search was conducted in several databases such as Medline, Embase, CENTRAL, CINAHL, PsycInfo, Science Citation Index, clinicaltrials.gov, opengrey.org. Search terms were "neoplasia", "quality of life" and "mistletoe". The analysis included studies with a control group in which quality of life or related dimensions were assessed.
The quality of the studies was assessed with the Cochrane Risk of Bias tool version 2 (Rob2) and a quantitative meta-analysis was performed.
Heterogeneity between the studies was assessed with the Cochrane Q test and quantified using the index of heterogeneity (I2). A I2 value of 25 percent indicates low heterogeneity, a I2 value of 50 percent indicates medium heterogeneity and an I2 value of 75 percent indicates high heterogeneity. If heterogeneity was higher than 25 percent, a random effects model was used for pooling the data and fixed effect models were used for exploratory subgroup analyses or sensitivity analyses with low heterogeneity.
After removing the duplicates, 598 studies were identified. Of these, 67 full texts were identified, of which 26 publications with 30 separate data sets fulfilled the inclusion criteria. These included studies on breast carcinoma (9 studies), lung carcinoma (3 studies), stomach carcinoma (2 studies), cervical, colorectal, endometrial, ovarian and pancreatic carcinoma as well as glioma, melanoma, osteosarcoma and head and neck tumours (1 study each). In addition, various unspecified tumour entities were included (3 studies). In almost all studies patients received mistletoe therapy in addition to conventional treatment.
Since heterogeneity of the studies was high (I2 = 84%), a random effects model was used to determine the pooled standardized mean difference for the general quality of life. It showed a significant improvement of quality of life in patients undergoing mistletoe therapy compared to the control group with d = 0.61 (95% CI 0.41-0.81; p<0.0001).
The effect was more significant in case of a longer treatment period. This could be shown especially in randomized studies with a lower risk of bias. Sensitivity analyses confirmed the validity of the results.
Comment: In this meta-analysis of Loef and Walach mistletoe extracts had a significant, medium-size effect on the quality of life of cancer patients (d = 0.61). Since the included studies differed with regard to tumour localisation, control intervention, additional oncological therapies and the type of mistletoe preparation used, sensitivity analyses confirmed the significance and reliability of the findings, but the factors of heterogeneity could not be investigated due to a limited number of 26 studies and 30 data sets.
Although the risk of bias is high in many studies, the following aspects should be considered: The intention-to-treat algorithm of Rob2, representing a more conservative approach, was chosen instead of the per-protocol analysis, which would probably have resulted in a better overall evaluation. In the study evaluation according to Rob2, absence of blinding led to the assumption of a high risk of bias in the measurement of quality of life. Nevertheless, sensitivity analysis showed no evidence between the studies with and without blinding with regard to differences in effect size. The results of the Newcastle-Ottawa Scale also indicate good methodological quality for the non-randomised studies included in the review.
Last update: May 5th, 2020/AB
Ostermann et al. 2020 
Summary: The aim of the study was to evaluate the efficacy of the mistletoe extract Iscador on the overall or event-free survival of cancer patients in current controlled trials. For this purpose, the databases Embase, PubMed, CAMbase, Scopus, AMED and Cochrane were searched for clinical studies with tumour patients receiving therapy with Iscador.
After removal of the duplicates, a total of 188 potentially relevant publications were reviewed, of which 32 studies with 55 strata finally provided adequate data for the meta-analysis. The tumour types were breast carcinoma (14 studies), cervical carcinoma (5 studies), colorectal carcinoma (2 studies), endometrial carcinoma (5 studies), lung carcinoma (7 studies), ovarian carcinoma (7 studies), pancreatic carcinoma (2 studies) and gastric carcinoma (3 studies) as well as osteosarcoma (1 study), melanoma (5 studies) and various unspecified tumour entities (3 studies). In 1 study the influence on liver metastases was investigated.
Study quality and the risk of bias were assessed according to the Cochrane guidelines in the randomised studies and the Newcastle-Ottawa Scale in the non-randomised studies. As the heterogeneity between the individual studies varied, a random effects model was used for the meta-analysis to summarise the estimation between studies, such as the effects of the year of publication, tumour localisation or sample size. In addition, subgroup analyses were performed for type of study, age of studies, and tumour localisation, and an attemption has been made to determine a publication bias in overall survival by using a funnel plot.
Of the 32 studies with 55 strata and 13,745 patients that provided data to determine the hazard ratio (HR) and the confidence interval (CI), 24 studies had a prospective design, two had a retrolective design and 12 had a retrospective design; 14 studies were randomized. The mistletoe preparation was administered subcutaneously in all studies.
The total HR was 0.59 (CI: 0.53 to 0.65, p < 0.0001) in favour of mistletoe therapy. The heterogeneity of the study results was moderate (I2 = 50.9%; p < 0.0001, τ2 = 0.053). The subgroup analysis showed fewer effects in the randomised trials (HR = 0.68; CI: 0.55; 0.83) than in the non-randomised trials (HR = 0.56; CI: 0.50; 0.62), although the difference was not significant (p = 0.13). The subgroup analysis between newly included studies after 2009 (HR = 0.52; CI: 0.43; 0.63) and earlier studies from the first review published in 2009 (HR = 0.65; CI: 0.61; 0.69)  also showed no significant difference (p = 0.33).
However, significant differences were found between the different tumour entities (p < 0.01), with the strongest effects on survival in cervical carcinoma (HR = 0.43) and less strong effects in melanoma (HR = 0.73) and lung carcinoma (HR = 0.84).
Comment: The present meta-analysis by Ostermann et al. confirms a life-prolonging effect of therapy with Iscador in cancer patients. The results are based on a broader data pool with higher quality: current meta-analysis: HR 0.59; CI: 0.54; 0.65, p < 0.0001 compared to the meta-analysis by Ostermann et. al. from 2009: HR = 0.59; CI: 0.53; 0.66, p < 0.0001. The study type (randomised versus non-randomised) and sample size had no influence on the results of the meta-analysis.
But none of the studies included were blinded, so that the risk of a performance bias could be assumed. However, this risk of bias is considered to be low regarding the objective of survival, so the FDA guidelines do not consider blinding to be essential in survival studies either.
The data again show that additive mistletoe therapy with Iscador in cancer patients can be associated with a better survival rate.
Last update: January 4th, 2021/AT
Freuding et al. 2019 
Summary: The aim of the first part of this systematic review was to give a comprehensive overview of the current state of research on mistletoe therapy in oncological patients with regard to survival and safety. For this purpose, the databases Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), PsycINFO, CINAHL and "Science Citation Index Expanded" (Web of Science) were searched in September and October 2017. Only randomized studies were approved.
The search resulted in 3,647 hits, of which 28 studies with 2,639 patients were included in the overview. Mistletoe therapy was used in patients with bladder carcinoma (1 study), breast carcinoma (5 studies), cervical, uterine, ovarian carcinoma (5 studies), colorectal carcinoma (2 studies), stomach and pancreas carcinoma (2 studies), glioma (1 study), head and neck tumours (1 study), lung carcinoma (1 study), melanoma (2 studies), osteosarcoma (1 study) and various unspecified tumour entities (3 studies).
In almost all studies patients received mistletoe therapy in addition to conventional treatment.
For the target parameter overall survival, 14 studies (n = 1,054) were included, for the evaluation of progression-free or disease-free survival or tumour response rate to therapy, ten studies (n = 1,091) were included. Of the 14 studies on overall survival, five studies found significant positive effects of mistletoe therapy on survival time, namely for breast, colorectal, pancreatic carcinoma, non-metastatic corpus carcinoma and advanced glioma. In six studies there was a positive trend in the differences between the treatment and control group. In three studies, no difference was found. Following a detailed review of the literature, it was concluded that there was no evidence to support the prescription of mistletoe preparations in tumour patients in terms of survival.
Comment: In the first part of their review, the authors conclude that most studies failed to show a positive effect of mistletoe therapy on survival rates, and that especially high-quality studies did not demonstrate any benefit. Furthermore, the review’s authors state that it was not possible to conduct a meta-analysis on mistletoe therapy as the patient collectives would have been too heterogeneous. As a part of meta-analyses, however, the heterogeneity of data is generally assessed and – if possible – driving factors are identified and stated, as is done, for example, in the meta-analyses by Ostermann et al. 2009  and 2020  on overall survival under additive mistletoe therapy.
Regarding safety of mistletoe preparations, the authors fail to provide any information on the type and extent of their enquiry. The chapters "Adverse Events in Mistletoe Therapy" and "Potentially Serious Adverse Events" therefore do not fulfil the requirements of a review as the criteria for literature inclusion or exclusion are not transparent.
Additionally, two randomized studies are missing from the review without any substantial explanation. Furthermore, the assessment of the risk of bias is insufficiently explained and partly incorrect, as stated in the "Statement to an Insufficient Systematic Review" by Matthes et. al. 2020  According to the authors of this statement, the review by Freuding et al. does not sufficiently meet the criteria of a systematic review and is classified as qualitatively "low" on the basis of the AMSTAR 2 quality assessment (MeaSurement Tool to Assess Systematic Reviews; Shea et al 2017 ) .
Despite this criticism and a "Letter to the editor" (Matthes et al. 2019 ) the review has not yet been revised by the authors. Matthes et al. 2019, 2020 [269, 270] assess that with regard to the effects of mistletoe therapy on survival time, no meaningful conclusions can be drawn from this overview by Freuding et al.
Last update: May 5th, 2020/AB
Freuding et al. 2019 
Summary: The second part of this systematic review aimed to provide a comprehensive overview of the current state of research on mistletoe therapy in oncological patients with regard to quality of life and side effects of cancer treatments. For this purpose, the databases Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), PsycINFO, CINAHL and "Science Citation Index Expanded" (Web of Science) were systematically searched in September and October 2017.
The search resulted in 3,647 hits, out of which 28 randomized controlled trials with 2,639 patients were included in the overview. Mistletoe therapy was used in treating various tumour entities. In almost all studies patients received mistletoe therapy in addition to conventional treatment.
For the outcome parameter “quality of life”, 17 studies were included (n = 2,167 patients). Out of these, eleven studies used oncological questionnaires such as the EORTC-QLQ-C30 questionnaire, and six studies used the questionnaire on psychosomatic self-regulation by Grossarth-Maticek et al. (1995). Toxicity was determined on the basis of eleven studies (n = 1,409 patients).
According to the authors, there was great heterogeneity with regard to the methods used to assess quality of life, the observation period (three months to three years) and the methodological quality of these studies. Nevertheless, in eight out of nine of the total of eleven studies, a significant benefit of mistletoe therapy with regard to quality of life was found, namely in patients with breast, colorectal, pancreatic, stomach and lung carcinoma.
In two other studies involving glioma and osteosarcoma patients, the improvement in quality of life was greater in the mistletoe group compared to the control group, but the difference was not statistically significant due to the small sample size.
In a study with a phytotherapeutic mistletoe preparation, no significant difference between the mistletoe group and the control group could be found. With regard to self-regulation, significant benefits were observed in most studies (breast cancer, gynaecological tumours, melanoma) for patients treated with mistletoe extracts. However, if only studies with a low risk of bias according to the Jadad score were included, this only applied to one study (with a phytotherapeutic mistletoe preparation) which failed to show any effect of mistletoe therapy on quality of life.
Seven studies examined the influence of mistletoe therapy on the frequency of chemotherapy side effects. In most cases, simultaneous administration of mistletoe extracts was found to reduce the toxicity of chemotherapy. Nevertheless, according to the authors, due to deficiencies in the methodological quality of the studies, there was only little evidence for mistletoe therapy improving any treatment-related side effects.
The authors conclude that a thorough literature review with regard to quality of life and reduction of therapy-related side effects does not justify prescribing mistletoe preparations to cancer patients.
Comment: Although 14 studies showed a significant improvement in quality of life, two studies showed a positive trend and only one study showed no effect, the authors conclude that mistletoe therapy has no effect on quality of life. This is because the authors only included studies classified as high quality according to the Jadad score.
The study by Steuer-Vogt et al. 2006  on the use of a phytotherapeutic mistletoe preparation (Eurixor, now out of sale) in patients with head and neck tumours was considered by the authors to be of the highest quality. It showed no improvement in quality of life, was also not blinded and therefore only reached a maximum of 3 points according to the Jadad score. It remains incomprehensible, why in the conclusion, the authors solely argue their point based on this single study.
Furthermore, the authors point out weaknesses in their own systematic review, as they were unable to prepare a meta-analysis with regard to quality of life due to the heterogeneity of the analysed randomised controlled trials. However, in 2012 Büssing et al.  already published a meta-analysis on the effect of additive mistletoe on quality of life , which was supplemented by Loef and Walach in 2020 with a further meta-analysis on quality of life.
Due to the mentioned points and its methodological limitations, no meaningful conclusions can be drawn from the work of Freuding et al. regarding the influence of mistletoe therapy on quality of life and therapy-related side effects.
Last update: May 5th, 2020/AB
Kröz et al. 2016 
Summary: Cancer-related fatigue (CRF) affects about 70 to 90 percent of all patients receiving chemo- or radiotherapy or who already have metastases. Furthermore, CRF persists in 35 to 40 percent of long-term recurrence-free breast cancer patients even three years after discontinuation of oncological systemic therapy.
To evaluate the effect of mistletoe therapy on CRF, this review examined the available publications in PubMed (68 articles on "mistletoe and quality of life" and 13 on "mistletoe and fatigue"). A total of ten randomised controlled trials (RCTs) were found which investigated mistletoe therapy with regard to fatigue, tiredness and similar criteria or with regard to insomnia and quality of sleep. These ten studies were based on different questionnaires (seven "EORTC QLQ-C30" questionnaires, one "Global Quality of Life" scale, GLQ, one GLQ and "FACT-G" questionnaire, one "Traditional Chinese Medicine" scale, TCM).
Four studies were conducted on mamma carcinoma, one each on non-small cell lung carcinoma (NSCLC), pancreatic carcinoma, osteosarcoma, stomach carcinoma and head and neck tumours. In one publication, patients with mamma carcinoma, NSCLC or ovarian carcinoma were examined. All studies were conducted with single-item or three-item scales, which however did not fulfill he gold standard criteria for measuring cancer-related fatigue or insomnia.
In six of ten studies, mistletoe therapy could significantly reduce fatigue or tiredness, and in six of nine studies, sleep disorders. To date, however, there is no clinical study on the treatment of CRF with mistletoe therapy as the primary study objective.
Comment: In this review, the literature search was conducted in one literature database (PubMed). It resembles a review specifically focused on CRF and the methods of recording it. CRF and insomnia were evaluated descriptively as they were not the primary endpoint.
The review concludes that mistletoe therapy can contribute to improving fatigue symptoms. This may also apply to sleep disorders in cancer patients who received chemotherapy.
Last update: June 16th, 2020/AB
Büssing et al. 2012 
Summary: The aim of this meta-analysis was to investigate the influence of the mistletoe extract Iscador on the quality of life of cancer patients. For this purpose, the databases PubMed/Medline, Embase, CAMbase, Cochrane Library and others were searched for controlled clinical studies. The evaluation of the results was in accordance with MOOSE and QUOROM guidelines.
Quality of life-associated results were calculated as standardized mean differences (SMD) and their standard deviations. Effect sizes < 0.5 indicated a small and > 0.8 a large effect of mistletoe therapy. Heterogeneity between the studies was assessed using the χ2 test and the I2 coefficient. Overall estimates of the treatment effect were determined using a random effects model.
The meta-analysis included 13 prospective-controlled studies (9 randomised, 4 non-randomised) with 741 patients in the control group and 734 in the mistletoe therapy group. The studies were classified according to the Jadad score (blinding, randomisation, dropouts). In all studies there were positive effects in favour of mistletoe therapy.
The variability of the study results was moderate (I2 = 42.1%). A random effects model estimated the overall treatment effect for the standardized mean difference SMD = 0.56 (CI: 0.41 to 0.71, p < 0.0001), indicating a moderate effect.
In the multivariate meta-regression analysis, neither tumour localisation nor study design were significantly associated with a better or worse outcome.
Comment: The methodological quality of the studies on the clinical efficacy of mistletoe extracts included in the analysis has continuously improved. For example, all studies were prospectively designed, randomised and had a parallel group design. Nevertheless, there are further challenges for high-quality study designs.
All of the analysed studies indicate that treatment with the mistletoe preparation Iscador has positive short-term effects on quality-of-life associated parameters and psychosomatic self-regulation.
Last update: January 4th, 2021/AT
Kienle and Kiene 2010 
Summary: This review aimed to analyse controlled clinical studies on the efficacy and effectiveness of Viscum album extracts in relation to quality of life (QoL) of cancer patients. The databases searched were AMED, BIOSIS Previews, CAMbase, Cochrane Library, Embase, Medline/Premedline, NLM Gateway and others. A criteria-based evaluation of the methodological study quality was carried out.
In total, the authors found 26 randomised controlled trials (RCTs) including 4 double-blind studies with 3,058 patients and 10 non-randomised controlled trials with 4,996 patients. Mistletoe therapy was administered to patients with mamma carcinoma (15 studies), ovarian carcinoma (4 studies), cervical carcinoma (2 studies), uterine carcinoma (2 studies), colorectal carcinoma (3 studies), pancreatic carcinoma (1 study) and lung carcinoma (3 studies), gastrointestinal (2 studies) and head and neck tumours (2 studies), melanoma (2 studies), glioma (1 study), osteosarcoma (1 study), malignant pleural effusions (1 study) and unspecified tumour entities (1 study). The stages ranged from early to advanced disease. The 26 studies differed in their methodological quality.
Of the 26 RCTs, 22 studies reported an improvement of quality of life due to mistletoe extracts. None of the studies found a disadvantage in mistletoe therapy. Regarding the non-RCTs all studies showed an improvement in quality of life as a result of mistletoe therapy. Of the four double-blind RCTs, a significant benefit was found in three studies while a small pilot study showed no difference.
Comment: In most of the investigated studies, mistletoe therapy had a positive effect on the quality of life of cancer patients. There was an advantage when mistletoe preparations were used in combination with chemotherapy, radiation and/or surgery – in these cases, the tumour therapies were better tolerated
Best results were obtained in patients with breast cancer, while a study on head and neck tumours showed no benefit for mistletoe therapy.
Some of the more recent studies were well designed, others had methodological weaknesses. In some cases, multiple comparisons were carried out without an a priori definition of the primary outcome and without statistical adjustment for multiple testing. Although this practice is common with oncological studies investigating quality of life, it makes it difficult to differentiate between positive results and random effects.
Last update: January 4th, 2021/AT
Ostermann et al. 2009 
Summary: The aim of this review was to investigate the efficacy of the mistletoe preparation Iscador with regard to survival of cancer patients in controlled clinical trials. For this purpose, several databases such as CAMbase, Cochrane Library, Excerpta Medica Database (Embase), DIMDI and Pubmed/Medline were searched. The methodological quality of the studies was assessed using a checklist which, among other criteria, considered the Jadad score and MOOSE guidelines. 49 publications on the influence of mistletoe therapy with Iscador on the survival of cancer patients were identified which fulfilled the quality criteria mentioned above. Of these, 41 strata from 22 studies provided sufficient data to determine the hazard ratios (HR) and their standard deviations (Iscador versus no additional treatment).
Twelve studies were prospective, five were randomized, and ten had a matched-pair design. Mistletoe therapy was used in patients with bladder carcinoma (1 study), mamma carcinoma (11 studies), cervical, uterine and ovarian carcinoma (13 studies), colorectal carcinoma (4 studies), stomach and pancreas carcinoma (3 studies), lung carcinoma (5 studies), melanoma (7 studies), and various unspecified tumour entities (1 study).
Randomisation and allocation concealment were assessed according to Cochrane guidelines. The relationship between study size and study results was graphically illustrated in funnel plots.
The majority of studies showed positive effects of mistletoe therapy on survival time. The heterogeneity of the study results was moderate (I2 = 38.3%, p < 0.0001), but the funnel plots were clearly distorted, possibly indicating a publication bias. However, the bias in the funnel plot could also occur due to the fact that over time, studies were repeated with those tumour entities that had previously performed successfully.
The random effects model used for the meta-analysis estimated the general hazard ratio to HR = 0.59 (CI 0.53 to 0.66, p < 0.0001). A simple meta-regression resulted in an estimated HR of 0.74 (CI: 0.66 to 0.82, p < 0.0001).
In the multivariate meta-regression analysis, tumour localisation was not significantly associated with a better or worse study outcome, but studies for lung carcinoma showed a slightly better outcome than other tumour entities (ratio of HRs: 0.56, CI: 0.00 to 1.10, p = 0.095). In randomised trials, the effects on survival time were minor compared to non-randomised trials (ratio of HRs: 1.24, CI: 0.79 to 1.92, p = 0.35), and matched-pair studies showed significantly better results than other studies (ratio of HRs: 0.33; CI: 0.17 to 0.65, p = 0.0012).
Comment: The analysis of these clinical trials showed that adjuvant mistletoe therapy correlated with longer survival time. However, the pooled estimates were based on heterogeneous data, although the estimate of I2 = 38.3% was below the critical limit of 0.5 recommended by Higgins & Thompson. However, since long-term survival by definition can only be obtained from studies that date back several years, older studies had to be included.
On the other hand, however, a stratified analysis suggests that the initial year of the study had no influence on the estimated pooled effects. Despite these limitations, the studies found positive effects for mistletoe therapy on the survival time of cancer patients.
Last update: January 4th, 2021/AT
Kienle et al. 2009 
Summary: The aim of this review was the evaluation of preclinical (not discussed here) and clinical studies on patients with breast cancer or other gynaecological tumours regarding the influence of mistletoe therapy. For this purpose, several databases such as AMED, Biosis Previews, Cochrane Library, Embase, Medline/Premedline, NLM Gateway were systematically searched from their introduction until December 2008 and a criteria-based evaluation of the methodological study quality was conducted.
The overview included 46 studies: 19 randomized controlled trials (RCTs) with 2,420 patients, 16 non-randomized controlled trials with 6,399 patients and 11 single-arm prospective cohort studies with 1,130 patients. The investigated tumour entities were mamma carcinoma (n = 20), uterus carcinoma (n = 4), ovarian carcinoma (n = 6), cervical carcinoma (n = 4) and genital carcinoma (n = 1). The stages ranged from early to advanced stages of the disease.
Objective parameters were survival (22 studies), tumour remission, recurrence or time to recurrence or metastases (8 studies), pleurodesis (1 study), quality of life or coping (11 studies) or quality of life or tolerability of the combination with chemo- or radiotherapy or surgery (13 studies).
Four studies were double-blinded. Eight RCTs and eight non-RCTs originated from the same large epidemiological cohort study. The analysed studies differed regarding their methodological quality.
Of the nine RCTs and 13 non-RCTs examining the influence on survival time, 12 (4 RCTs and 8 non-RCTs) showed a statistically significant advantage regarding survival, the other ten showed a trend or no difference. Of the three RCTs and six non-RCTs investigating tumour response (remission or time to recurrence), three studies (2 RCTs, 1 non-RCT) reported a statistically significant benefit.
With regard to the influence of mistletoe therapy on quality of life and tolerability of chemo- and/or radiotherapy or surgery, of the 15 RCTs and 9 non-RCTs a total of 21 studies were identified to yield statistically significant positive results.
Comment: The present review is the first one to investigate the influence of mistletoe therapy on patients with mamma carcinoma or other gynaecological tumours. The review showed a clear heterogeneity in terms of therapy, patient characteristics, clinical diagnosis, final results, study design, methodological quality and possible positive or negative bias.
The studies investigating quality of life and the effects on tolerability of conventional therapies provided the most consistent results.
With regard to survival, the evidence was less conclusive. Most RCTs had a very small sample size and eight out of nine of the RCTs were included in a (large) cohort study.
Last update: May 5th, 2020/AB
Horneber et al. 2008 
Summary: To investigate the efficacy, tolerability and safety of mistletoe therapy, a Cochrane review was conducted in which mistletoe preparations were administered as subcutaneous injections either as monotherapy or concomitantly with chemotherapy or radiotherapy in adult patients with cancer diseases. For this purpose, 13 electronic databases and bibliographies were searched for RCTs until August 2007 and published and unpublished studies were included. The methodological quality of the studies was assessed using the Jadad Score and the Delphi list. Methodological quality was considered as high if four of five Jadad criteria and six of nine Delphi criteria were fulfilled.
A total of 21 studies with 3,484 patients were included. Of these, 13 studies provided data on survival, 7 on tumour response, 16 on quality of life, psychological aspects or prevalence of chemotherapy-related side effects, and 12 on side effects of mistletoe therapy.
Of the 13 studies investigating survival, 6 showed evidence of an advantage for patients in the mistletoe therapy group, but none of these studies had high methodological quality, according to the authors. Of the 16 studies that examined quality of life, psychological parameters, or reduction of side effects of chemotherapy, 14 showed evidence of benefit, but only 2 of those that included patients with breast cancer during chemotherapy were of higher methodological quality, according to the authors.
Studies regarding the side effects of mistletoe preparations indicated generally good tolerability and low rates of side effects.
Evidence from RCTs that the use of mistletoe extracts has positive effects on survival or leads to improved ability to cope with cancer disease or a better tolerance of oncologic therapies is low, according to the authors. However, there is some evidence that mistletoe extracts may improve quality of life during chemotherapy in patients with breast cancer, although more high-quality, independent clinical trials are needed to conclusively assess the safety and efficacy of mistletoe extracts.
Comment: This review is not complete and was already out of date at the time of publication, lacking nine RCTs, a re-analysis of one RCT, an HTA report, a systematic review, and a meta-analysis. Since the Jadad score and the Delphi list were used in the Cochrane review to assess study quality, in which blinding has a strong weighting (of the maximum 5 Jadad points, 2 points are awarded for blinding, and of the maximum 9 Delphi points, 3 points are awarded), the included studies on mistletoe therapy could not achieve a higher rating, even though they showed good study quality in other categories . The problem of blinding in mistletoe therapy studies is discussed in other sections (see under Effects and efficacy and Challenges in clinical mistletoe research).
Last update: November 24th, 2021/AT1
Kienle and Kiene 2007 
Summary: In this review, prospective comparative and prospective non-comparative studies on anthroposophic mistletoe preparations were included. For this purpose, 9 electronic databases were searched and experts and manufacturers of mistletoe preparations were interviewed for further references. Thirty-seven prospective clinical studies were found. Of these, 16 were randomised (RCT), 9 were non-randomised (N-RCT), and 12 were prospective cohort studies without a comparison group (including phase II studies) with a total of 5,365 patients. The studies predominantly showed an advantage for mistletoe therapy. The quality of the studies varied widely, some studies showed considerable weaknesses and others being of high quality. Taking into account the quality or potential weaknesses of each individual study, a reduction of side effects of conventional oncological therapies (chemotherapy, radiotherapy, surgery) as well as an improvement in quality of life appear to be the best documented. A prolongation of survival time under mistletoe therapy could be observed in some cases, whereby the duration of mistletoe therapy seemed to play a role here.
Comment: At the time of publication, this was the most recent systematic review of prospective clinical studies, which, however, only included anthroposophic mistletoe preparations. Thus, studies with phytotherapeutic mistletoe preparations were not included.
Last update: November 24th 2021/At1
Lange-Lindberg et al. 2006 
Summary: A HTA report on mistletoe therapy (anthroposophic and phytotherapeutic mistletoe preparations), in combination with chemotherapy, was commissioned by the German Agency for Health Technology Assessment (DAHTA) of the German Institute of Medical Documentation and Information (DIMDI). Systematic reviews and randomised controlled trials (RCT) were included. The main questions addressed whether additive mistletoe therapy to conventional chemotherapy for malignant diseases can reduce chemotherapy-related toxicity and whether a better quality of life can be achieved compared with conventional chemotherapy alone. For this purpose, 3 major electronic databases were searched. Three published systematic reviews, six published RCTs, and two unpublished RCTs were found and summarised. In addition, the protocol of a Cochrane Collaboration systematic review that had not been published at this time was identified . The methodological quality of the studies was assessed using Jadad Score and other checklists.
The results of the studies were heterogeneous, i.e. both positive and no effects of mistletoe therapy on the frequency or severity of chemotherapy-related side effects were reported. The authors therefore concluded that no clear answer could be given regarding a reduction in chemotherapy-related toxicity with mistletoe preparations, and that the implementation of RCTs in which chemotherapy toxicity is the primary outcome parameter is necessary to clarify this question.
Health-related quality of life was reported as the primary outcome parameter in five of the papers assessed in this HTA report. The results of the studies indicate that the quality of life of women with breast cancer can be positively influenced by additive mistletoe therapy to conventional chemotherapy. Whether this effect can be explained predominantly by the attenuation of chemotherapy-related toxicity, however, cannot be answered with the available evidence.
Comment: The conclusion of the authors is that no clear answer can be given regarding a reduction of chemotherapy-related toxicity by mistletoe preparations. The HTA report is considered outdated at this time and has been cited here for completeness.
Last update: November 24th 2021/AT1