Please also note the case reports for this type of cancer.
Meanwhile, the Society for Integrative Oncology (SIO)’s guideline has been renewed and published as "Clinical practice guidelines on the evidence-based use of integrative therapies during and after breast cancer treatment" [8]. This guideline includes subcutaneous mistletoe therapy with the aim to improve quality of life under a grade C recommendation [8, 72]. In June 2018 this guideline was adopted and recognised by the American Society of Clinical Oncology (ASCO) [72].
Loef et al. 2023 [329]
As standard oncological treatment can severely impair the quality of life of patients with breast cancer, in this systematic review and meta-analysis it was examined if mistletoe extracts, which are already listed in several cancer guidelines, can also improve their quality of life.
For this purpose, randomised clinical trials (RCTs) and non-randomised studies of intervention (NRSIs) were included to compare the quality of life of breast cancer patients treated with mistletoe extracts as an additional therapy with conventionally treated control groups. Both studies on metastatic and non-metastatic tumour stages were considered. Previous systematic reviews and several databases up to January 2023 were searched and a meta-analysis was performed. The risk of bias was assessed using RoB 2 and ROBINS-I according to the Cochrane Handbook and the certainty of evidence was assessed using GRADE.
Nine RCTs with 833 and seven NRSIs with 2831 patients were included. The changes in quality of life before and after treatment resulted in a pooled standardised mean difference for RCTs of SMD = 0.61 (95% CI 0.47-0.75; P < .0001) and for retrospective NRSIs of SMD = 0.46 (95% CI 0.10-0.82; P = .01). The risk of bias was low to high for the RCTs and very high for the NRSIs. The quality of evidence according to GRADE was moderate for the RCTs and low for the NRSIs.
To date, the analysis is the first meta-analysis focusing on the effect of mistletoe extracts in only one type of cancer. A medium effect size on the quality of life of breast cancer patients was found with low heterogeneity between studies, with an effect size comparable to or higher than other interventions such as physical activity.
The results indicate a clinically relevant, moderate effect of mistletoe extracts on the quality of life of breast cancer patients. The limitations of the evidence include the risk of bias, which is mainly due to the difficulty or lack of blinding in mistletoe extracts. The result should be confirmed by further RCTs and real-world data studies.
Tröger et al. 2009, 2014a, Pelzer and Tröger 2018 [44, 47, 49]
These are three publications of a study which has been published under different aspects in several scientific journals.
The aim of this open randomised clinical trial was to investigate if add-on therapy with mistletoe extracts increases quality of life without reducing the therapeutic effect of chemotherapy.
95 patients with breast cancer up to stage T1-3N0-2M0 who received 6 cycles of adjuvant chemotherapy (cyclophosphamide, adriamycin, 5-FU = CAF) were randomized into three groups. The control group of 31 patients received chemotherapy alone, a group of 30 patients received Iscador M additionally, another group of 34 patients received Helixor A additionally. The mistletoe preparations were injected subcutaneously three times a week in increasing doses. With the end of chemotherapy, mistletoe therapy was discontinued as well.
Quality of life was assessed through the European Organization for Research and Treatment of Cancer questionnaire EORTC-QLQ C30. Furthermore, the neutropenia frequency in the mistletoe therapy groups was compared to that in the control group. Neutropenia was defined as neutrophilic granulocytes count < 1,000/µl. Neutrophilic granulocytes were determined at the beginning of the study and directly before the next chemotherapy cycle.
30 patients each in the control and Iscador group and 29 patients in the Helixor group could be analysed. The treatment groups and the control group did not differ significantly in age, tumour stage, body mass index, physical condition, vital signs and previous illnesses. At the basic examination (1st visit) no neutropenia was observed in any of the patients.
In the evaluation of the EORTC-QLQ-C30 at the end of the study, a better quality of life was found in the mistletoe therapy groups compared to the control group. In the Iscador group, 12 of 15 scores differed significantly, of which nine scores were also clinically relevant. In the Helixor group, 10 of 15 scores showed a significant improvement in quality of life, which was clinically relevant in eight scores. In both groups this was mainly associated with a significant reduction in pain, less nausea/vomiting, diarrhoea, insomnia and improved appetite.
During the course of treatment, neutropenia occurred in 3 of 30 patients in the Iscador group, 7 of 29 in the Helixor group and 8 of 30 patients in the control group. Thus there was a reduced occurrence of neutropenia in the Iscador group, although the difference was not statistically significant due to the small number of cases (p = 0.182).
Apart from the desired typical minor local reactions at the injection site, no side effects related to mistletoe extracts were detected; there was also no increase in fever compared to the control group.
In this randomised study, additional mistletoe therapy significantly improved the quality of life of breast cancer patients during chemotherapy with CAF. Furthermore, chemotherapy was better tolerated due to the use of mistletoe extracts because fewer patients discontinued therapy, changed dosages and had fewer delays. There was also a reduced frequency of chemotherapy-related neutropenia in the Iscador group.
Tröger et al. 2012, 2016, Pelzer and Tröger 2018 [46, 48, 49]
These are three publications of a study which has been published under different aspects in several scientific journals.
Patients described in the summary by Tröger et al. [44, 47] were followed up for a period of five years. During this period none of them received mistletoe therapy.
The aim of this prospective non-interventional five-year follow-up study was to investigate the effect of post-operative mistletoe therapy in addition to chemotherapy in patients with early-stage breast cancer (T1-3N0-2M0) on median disease free survival (DFS).
The following inclusion criteria had to be fulfilled for participation in this long-term follow-up study:
The incidence of recurrences and/or metastases was recorded in documentation forms over a period of five years during annual routine visits to the study centre. A deviation of ± 2 months was tolerated for the visits.
In the Iscador group, two patients had an unknown metastasis status (M = x) before starting chemotherapy. In the Helixor group, one patient did not agree to continue participating in the study. In the control group, one patient could not participate in the follow-up due to heart disease, another did not consent. Therefore, 28 patients from both mistletoe therapy groups and 29 patients from the control group were finally included in the study.
The follow-up was carried out over a period of six years. After chemotherapy and mistletoe therapy had been discontinued, the patients received further therapies which could influence disease-free survival. These therapies were also recorded in the documentation forms for both groups. The most common therapies, used equally in all three groups, were radiotherapy (n = 48) and anti-hormonal therapies (tamoxifen; n = 44).
The median disease-free survival time could not be determined because the highest probability of developing recurrence or metastases in the five years was only 28 percent in the Iscador group and only 33 percent in the Helixor group. Thus, six of 28 patients in the Iscador group, nine of 28 patients in the Helixor group and eight of 29 patients in the control group had recurrences or metastases after five years. These differences were not statistically significant.
A subgroup analysis of patients receiving radiation showed that four of 19 patients in the mistletoe group and three of 18 patients in the control group developed recurrences or metastases after five years. In the subgroup of patients treated with anti-hormonal therapy, 4 of 18 patients in the mistletoe group and 4 of 14 patients in the control group developed recurrences or metastases. These differences were also not statistically significant.
The results of this five-year follow-up study indicate that mistletoe therapy administered in addition to chemotherapy had no effect on five-year survival and frequency of relapse or metastasis. There was no evidence of negative interactions during chemotherapy by mistletoe therapy administered concurrently.
Eisenbraun et al. 2011 [77]
In this non-interventional, prospective clinical study, the quality of life of 270 breast cancer patients with tumour stages I to III during adjuvant chemotherapy and mistletoe therapy (abnobaVISCUM Mali) was investigated in a longitudinal analysis. Chemotherapy consisted of 4 to 6 cycles of CMF (cyclophosphamide, methotrexate, 5-FU), EC (epirubicin, cyclophosphamide) or AC (adriamycin, cyclophosphamide).
Quality of life was assessed using the EORTC QLQ-C30 and EORTC QLQ-BR23 questionnaires, with data recorded at the beginning of mistletoe therapy and chemotherapy, four weeks later, at the end of chemotherapy and four weeks after the end of chemotherapy.
Furthermore, tolerability and safety of mistletoe therapy in combination with chemotherapy was determined in everyday practice. Mistletoe therapy was applied three times a week in increasing doses up to 20 mg.
After an initial deterioration, the QLQ-C30 and QLQ-BR23 function scores improved significantly (p < 0.0001) only four weeks after starting therapy. The scores remained stable until the last chemotherapy cycle.
The values of the QLQ-C30 symptom scales also decreased significantly from the first to the last visit (p < 0.001) and remained stable until the last chemotherapy cycle. The tolerability of therapy was assessed by the physicians as good or very good in 91 percent of the patients, and the efficacy even was assessed as good or very good in 94 percent of the patients.
The results of this study indicate that mistletoe therapy can improve quality of life during chemotherapy while simultaneously being well tolerated.
Loewe-Mesch et al. 2008 [27]
In a prospective, open, two-armed, non-randomised study, 33 patients with primary mamma carcinoma simultaneously received mistletoe therapy (Iscador M) and adjuvant chemotherapy with cyclophosphamide, methotrexate and 5-FU (CMF) or epirubicin and cyclophosphamide (EC). In the initial phase, the mistletoe extract was injected subcutaneously in increasing doses daily, in maintenance therapy only twice a week. The control group (n = 33) received no additional mistletoe therapy.
Before and 14 days after chemotherapy, the influence of adjuvant simultaneous mistletoe-/ chemotherapy on blood count, differential blood count, lymphocyte subpopulations, stimulation of lymphocytes and quality of life (EORTC QLQ-C30, -BR23) was assessed, as well its influence on the tolerability of chemotherapy.
Patients in the mistletoe therapy group used fewer oral glucocorticoids (p = 0.006) and showed a better quality of life than those in the control group. They had significantly fewer chemotherapy-related symptoms, particularly nausea and vomiting (p = 0.02) and fewer systemic side effects (p = 0.02). The other therapy-related symptoms also showed a milder course in the mistletoe group.
Since patients in the mistletoe therapy group who could avoid the use of oral glucocorticoids showed a milder decrease in some parameters of their lymphocyte subpopulations, it is assumed that mistletoe therapy is beneficial in this respect. However, the laboratory parameters did not show advantages or disadvantages of the add-on mistletoe therapy under the study conditions.
The simultaneous mistletoe-/chemotherapy was well tolerated and no serious undesirable side effects occurred.
The patients' quality of life was less impaired in the mistletoe therapy group than in the control group. There was no correlation between the tested immune parameters in the patients' blood and the clinical course.
Beuth et al. 2008 [33]
To evaluate the safety and efficacy of complementary mistletoe therapy during the aftercare of breast cancer patients, 53 randomly selected treatment centres (clinics, doctors' practices) were included in this retrospective epidemiological cohort study. These centres recruited 741 patients with primary breast cancer (UICC stages I-III) in order to investigate therapy- and disease-related symptoms in the period of aftercare.
681 of 741 patients were included for the final analysis of the study. The control group (n = 514) received adjuvant chemo- and/or radiotherapy, the therapy group (n = 167) received the mistletoe extract Helixor M, A or P after conclusion of standard therapy. The treatment and observation period was approximately five years.
During the aftercare period, significantly fewer patients in the study group suffered from disease- and treatment-related symptoms compared to the control group (56.3% versus 70.0%, p < 0.001). During the first year of aftercare, the frequency of symptoms in the study group was lower than in the control group. The difference increased until the fifth year of aftercare and was statistically significant from the second year onwards.
Specification of the patients’ symptoms during the aftercare period showed that in particular the incidence of tumour pain and headaches, fatigue syndrome and mucositis decreased.
Side effects of mistletoe therapy occurred in 10.2% of patients. With the exception of a single generalised reaction which led to discontinuation of therapy, they were mild and spontaneously reversible (redness, swelling and itching at the injection site, flu-like symptoms).
With regard to recurrence and metastasis frequency, there were no significant differences between the study and control group (3.6 vs. 2.9% and 3.6 vs. 4.3%, respectively).
Mistletoe therapy has been shown to be effective and safe in the aftercare of breast cancer patients. There was a significant benefit in terms of improvement of quality of life and reduction of persistent disease- and therapy-related symptoms for patients receiving mistletoe therapy. With regard to recurrence and metastasis frequency, there were no significant differences between the study and control group.
Auerbach et al. 2005 [170]
23 patients with histologically confirmed breast cancer in stage T1-2N0-1M0 were recruited for a prospective randomised, double-blinded clinical pilot study to investigate prognostic and immunological parameters as well as quality of life and to assess the feasibility of a double-blind study with mistletoe extract in addition to chemotherapy. 20 patients were analysed after three CMF cycles and 16 patients after completion of the complete cycles and an observation period of twelve months in total.
The patients were randomized into two groups: One group received 0.9% sodium chloride solution as a placebo (n = 12), the other group received the mistletoe extract Helixor A (n = 11) in increasing concentrations of 1, 5, 10, 20, 30, 50 to 100 mg. Both the mistletoe extract and the placebo were administered subcutaneously three times a week.
All patients received six treatment cycles of adjuvant CMF standard chemotherapy on days 1 and 8 of a cycle of 4 weeks over a period of approximately 6 months. 7 patients from the control group and 6 patients from the verum group with breast-conserving surgical therapy received additional radiotherapy with 25x 2 Gy after the 3rd CMF cycle (sandwich scheme).
8 of 9 patients in the mistletoe therapy group (89%) and 5 of 11 patients in the control group (46%) were able to identify the administered medication despite blinding – probably due to the occurring or not occurring of local reactions. In 16 of 20 patients (80%) the attending physician recognised the administered medication. The aim of blinding – to limit the occurrence of a conscious and unconscious bias – could not be achieved with such high rates of unblinding.
In the course of chemotherapy, the sister chromatide exchange rate (SCE rate) in peripheral blood lymphocytes increased as expected in both groups, but to a lesser extent in the mistletoe therapy group, although the differences in favour of mistletoe therapy were not significant.
Furthermore, it was found that in the mistletoe therapy group the proportion of activated NK cells (CD56+/CD69+/CD45) remained almost stable until the 6th cycle, whereas the patients in the placebo group (n = 11) showed a significant decrease in the proportion of activated NK cells (p = 0.001). From cycle 4 of CMF onwards the proportion of activated NK cells was significantly higher in the mistletoe therapy group (n=9) than in the control group (p = 0.005)
Regarding the other laboratory and immunological parameters as well as quality of life, no differences between verum and control group could be found.
The tolerability of mistletoe therapy during chemotherapy was good. In three cases harmless rashes of more than 5 cm diameter at the subcutaneous injection site was detected and in two cases headaches were reported. No other side effects occurred. In contrast to the placebo group, no chemotherapy-induced leukopenia was observed in the mistletoe therapy group.
The findings of the study have shown that the use of mistletoe preparations during chemotherapy significantly influenced immunological parameters, resulting in an increase in the proportion of activated NK cells in the mistletoe therapy group compared to the control group. However, with regard to other laboratory and immunological parameters as well as quality of life no difference between both groups could be observed. Furthermore, this study demonstrated that mistletoe therapy cannot effectively be blinded.
Bock et al. 2004 [41]
In this multicentre, controlled, pharmaco-epidemiological retrospective cohort study with parallel group design, 1,442 patients with primary, non-metastatic breast cancer of UICC stages I to III were enrolled. The study examined the therapeutic efficacy and safety of long-term complementary mistletoe therapy (predominantly Iscador M) in addition to conventional adjuvant oncological therapy. The study was carried out at various centres in Germany and Switzerland and was conducted according to the guidelines of good epidemiological practice (GEP).
After primary surgery, 710 women received mistletoe extract subcutaneously two to three times a week for at least three months in addition to the basic oncological therapy (radio-, chemo- and/or anti-hormonal therapy). The control group with 732 women received only conventional treatment (radio-, chemo- and/or anti-hormonal therapy) after surgery. The patients were followed up for at least three years or until death, respectively.
Initially, the stage of disease in the women of the mistletoe therapy group was more advanced and the prognosis factors were therefore less favourable. After a median follow-up period of more than five years and a median duration of mistletoe therapy of more than four years, significantly fewer patients in the mistletoe therapy group had side effects caused by conventional therapy (16.3%) than patients in the control group (54.1%).
In the mistletoe therapy group most of the disease-related symptoms subsided significantly more often than in the control group. These included nausea, vomiting, loss of appetite, headaches, fatigue and exhaustion. The Karnofsky Index improved more frequently. Body weight increased more significantly and the adjusted relative hazard ratio for mortality was significantly lower (HR = 0.46; p = 0.038), resulting in a 54% reduction in relative mortality risk.
Systemic side effects caused by mistletoe therapy such as weakness, tiredness/exhaustion or gastrointestinal complaints developed in only 6 patients (0.8%); local side effects around the injection site such as erythema, indurations, oedema, itching occurred in 123 patients (17.3%). All side effects were mild to moderate (WHO/CTC grade 1-2) and subsided completely. Severe side effects were not observed.
The results of this cohort study confirm that complementary long-term therapy with a mistletoe extract is well tolerated and can be considered safe in patients with primary, non-metastatic mamma carcinoma. In comparison with the control group, significantly fewer side effects caused by conventional therapy, fewer disease-related symptoms and a reduced relative mortality risk were observed in the mistletoe therapy group.
Piao et al. 2004 [31]
This multicentre, randomised, open, prospective, clinical trial, conducted according to good clinical Practice (GCP) criteria, examined the quality of life and tolerability of polychemotherapy in combination with mistletoe therapy.
The study included 233 patients with breast (n = 68), ovarian (n = 71) and non-small cell lung carcinoma (NSCLC, n = 94). Of the 233 patients originally recruited, 9 could not be included in the final evaluation because they did not meet the inclusion criteria in all respects, so that ultimately 224 patients were available for analysis.
All patients were treated with standard polychemotherapy. The verum group (n = 115) also received Helixor A subcutaneously three times a week in increasing doses from 1 mg to 200 mg. The control group (n = 109) received Lentinan, an immune stimulant commonly used in China and Japan with a proven effect on quality of life. The patients in both therapy arms were comparable with regard to gender, age, type of tumour, tumour stage and conventional therapies.
Quality of life was determined using three different, validated questionnaires or indices (functional living index-cancer = FLIC, Karnofski performance index = KPI, traditional Chinese medicine index = TCMI). The influence of mistletoe therapy on the tolerability of chemotherapy was investigated by group comparison of adverse events attributable to side effects of chemotherapy. The analyses were not performed separately for each tumour entity.
Improvement of quality of life was significantly better under add-on mistletoe therapy compared to control therapy with add-on Lentinan (p < 0.05). There were also significantly fewer chemotherapy-related side effects under add-on mistletoe therapy. The Karnofsky index improved in 50.4 percent of patients in the verum group and in 32.4 percent in the control group, which was statistically significant (p = 0.002).
As a result of mistletoe therapy, especially fatigue, insomnia, loss of appetite, nausea and pain improved. A total of 52 adverse events occurred in the mistletoe therapy group and 90 in the Lentinan group, 28 and 77, respectively, were chemotherapy-related; in 5 and 10 cases respectively, the course was severe.
Most mistletoe therapy-specific adverse events were overreactions at the injection site, which were self-limiting and did not need therapeutic intervention.
In this prospective randomised study conducted according to GCP-criteria, patients with breast, ovarian and non-small cell lung carcinoma showed a significant improvement in quality of life and a reduction in chemotherapy-related side effects when treated with chemotherapy plus mistletoe therapy compared to chemotherapy plus Lentinan.