Mistletoe Therapy Research Articles

Problematik randomisierter Studien in der Komplementärmedizin dargestellt am Beispiel der Misteltherapie bei Patientinnen mit Mammakarzinom

Problems of Randomized Studies in Complementary Medicine Demonstrated in a Study on Mistletoe Treatment of Patients with Breast Cancer Background: Prospective randomized studies on mistletoe therapy repeatedly demonstrated that there is a basic problem in the matter of enrolling the appropriate number of patients within a reasonable amount of time. Most studies have to face this problem. However, recent experience suggests that this problem is more pronounced in the case of mistletoe treatment of cancer patients. Objective: Possibility of recruitment and randomization of breast cancer patients for a mistletoe study. Patients: During a period of 28 months every patient was registered who was admitted to the Gynecological Hospital of the University of Heidelberg because of suspected cancer. Results: Out of 1,922 patients who were operated on for breast tumor, 521 first met the inclusion and exclusion criteria. 154 out of these 521 patients agreed to take part in the study. After availability of the final results on tumor staging and the therapy plan for conventional treatment, 80 out of the 154 women had to be excluded from the study. From the remaining 74 patients (48%), however, only 29 (39%) would have agreed to take part in a randomized mistletoe study. Conclusions: This confirms our suspicion that the difficulties of enrolment and randomization in the case of mistletoe studies exceed those of studies conducted in conventional oncology. The reasons for this dramatic effect and the possibility of alternative study designs are discussed.

Purification and characterization of four isoforms of Himalayan mistletoe ribosome-inactivating protein from Viscum album having unique sugar affinity

Ribosome-inactivating proteins having antitumor and immunomodulatory properties constitute the active principle of widely used mistletoe therapy in Europe. This is the first report of the four isoforms of Himalayan mistletoe ribosome-inactivating proteins (HmRips) from Viscum album parasitized on wild apple inhabiting NW Himalayas. HmRips were purified by affinity chromatography and four isoforms were separated by ion-exchange chromatography. HmRip 1, 2, 3, and 4 have isoelectric points of 6.6, 6.1, 5.2, and 4.7, respectively. Disulfide linked toxin and lectin subunits of HmRip 1 and 2 isoforms have molecular weights of 28 and 34 kDa while those of HmRip 3 and 4 have 28 and 32 kDa. The isoforms lacked blood group specificity and showed positive activity with seven mammalian erythrocyte types but did not show any activity with avian erythrocyte type. Lectin activity of HmRips remained unchanged for a wide range of temperatures (0–65 °C) and pH (3–9). Unlike other type II Rips, the HmRip 1, 2, and 4 showed unique affinity towards l-rhamnose, meso-inositol, and l-arabinose while HmRip 3 has specificity to gal/galNAc. Sugar binding studies with 22 sugars also suggested that the C-4 hydroxyl of galactose might be the critical site involved in sugar binding of HmRips. Type II Rips are known to be galactoside specific and do not have affinity for l-rhamnose and meso-inositol. However, HmRip 1, 2, and 4 having equal affinity for galactose and l-rhamnose do not strictly fit into any of the four structural classes of the lectins and represent a new class of type II Rips and plant lectins.

Anwendung komplementärer/alternativer Therapiemassnahmen bei Patientinnen mit Brustkrebs

Use of Complementary/Alternative Medicine by Patients with Breast Carcinoma Background: Complementary/alternative medicine (CAM) is gaining increasing importance especially in the treatment of patients with breast carcinoma. The purpose of this analysis was to investigate the prevalence of CAM in patients with breast carcinoma, to statistically describe the preparations and therapies used, and to determine the reasons for their use, the source of information and the individual perception. Patients and Methods: The statements of 203 patients with breast carcinoma who underwent radiotherapy were analyzed. The median age was 54 years (range 38–77 years). All patients underwent surgery as first therapy. 36 patients received a second-line radiotherapy because of metastases (27 patients) or local recurrence (9 patients). Results: 159 patients (78%) stated to carry out an additional treatment. 31 out of the 36 patients with metastases or local recurrence used CAM. Vitamin preparations (67%), mistletoe therapy (59%), and mineral preparations (33%) were used most frequently. 70% of the patients used a combination of two or more preparations/therapies. The most cited reason for using CAM was the aim of increasing quality of life (28%) and improving the immune system (27%). 72% stated an improvement of their individual perception. The main source of information was the general practitioner or the gynecologist. Conclusion: The radiotherapist has to take these complementary/alternative therapies into consideration; their importance should be evaluated in further studies.

Retrospektive Untersuchung von Patienten mit malignem Melanom unter einer Misteltherapie

Retrospective Study of Melanoma Patients Treated with Mistletoe Extracts Objective: The aim of the present investigation was to analyze survival time and survival rate of all patients with malignant melanoma who had been counseled at the Tumorambulanz Herdecke of the Community Hospital Herdecke. Patients and Methods: 284 melanoma patients were included in a retrospective questionnaire study. Only those patients were considered for analysis in whom the prognostic factors histology, tumor localization, and Clark level were known. The data of the study population were compared with patient data obtained from the literature. Results: 94 patients were included in the analysis. 66 of whom had received and 7 had not received mistletoe treatment, in the remaining 21 patients there was no information whether or not mistletoe treatment had been given. Thus, we did our study without a clearly defined internal control group. The median survival time among patients treated with mistletoe had been 14.1 years. The 5- and 10-year survival rates were 80 and 68% for the mistletoe-treated patients, respectively. Discussion: The 5-year survival rate of the mistletoe-treated patients is comparable to that of patients without mistletoe therapy while the 10-year survival rate is a little bit lower. This may be due to the fact that, in contrast to the patients from the relevant literature, 33.3% of the patients suffered from lymph node and/or distant metastases already before counseling the Tumorambulanz Herdecke. Moreover, 50% of our patients had melanoma of Clark level IV in contrast to 22.2% or 31% in the relevant literature. Conclusions: In spite of the theoretical reservations against mistletoe treatment in melanoma patients, our retrospective analysis did not show any clues about disadvantages of mistletoe treatment in melanoma patients. A controlled prospective study therefore should prove the efficacy of a mistletoe therapy in patients with malignant melanoma.

Mistletoe therapy in endometriosis

Mistletoe therapy in endometriosis

Metaphorische Aspekte der Misteltherapie im Patientenerleben – eine qualitative Studie

Metaphorical Aspects of Mistletoe Therapy in Patients’ Experiences – a Qualitative Study Objective: Mistletoe therapy is an item of research because of its immunological features. Nevertheless, mistletoe should be also an item of research because of its semiotics. Long before R. Steiner proposed mistletoe as an anticancer drug, this plant seemed to have its meaning not by pharmacodynamics but by pharmacosemiotics and magic. Thus, metaphorical aspects of mistletoe therapy should be described by processing the transcript and paintings from a therapeutic group session of cancer patients. Especially the relation between individually and historically coded metaphors should be looked at. Material and Methods: Sample of this qualitative study is the transcript of a therapeutic session of 12 female malignoma patients getting mistletoe infusions (Isorel(r)) since 1.5 years in a general practitioners’ practice. Sequential coding of the transcript, inventory of themes, and structural hypothesis are the first steps. The structural hypothesis is triangulated by a textual corpus containing anthroposophic and ethnographic material; then a grounded theory is made. Results: The material is divided. On the one hand, there is a huge amount of historically coded, stereotypic metaphors (sun, cancer, ritual). On the other hand, ‘ritual’ seems not only a stereotypic metaphor but also a container of individually coded metaphors concerning body experiences (proprioceptive etc.). Metaphors from anthroposophy are rare – the metaphors seem to stem from a deeper level of ethnographic sources. The whole session has a polyphone narrative structure. Categories of semiotics such as icon, index and symbol are only by the context of interaction a suitable description for mistletoe’s metaphoric function. Conclusions: Problems of bias (denominator problem, valid but not reliable) are discussed, and a proposal is made for further forms of generalization of the results (semantic differentials). Moreover, it has to be asked if different preparations of mistletoe (e.g. lectine standard, draft from planta tota) make different halos of metaphors.

Therapie mit Mistelextrakten bei malignen hämatologischen und lymphatischen Erkrankungen – eine monozentrische retrospektive Analyse über 16 Jahre

Mistle Toe Extracts in the Therapy of Malignant, Hematological and Lymphatic Diseases – a Unicentric, Retrospective Analysis over 16 Years Objective:The aim of the present investigation was to investigate potentials risks of treatment with mistletoe extracts in patients with malignant haematological and lymphatic diseases consulting the Tumour Ambulance of the Community Hospital Herdecke and to evaluate the therapeutic experiences with this treatment. Patients and Methods: All 700 patients with these diseases who had been counselled at the Tumour Ambulance of Community Hospital Herdecke since the foundation of the unit were included in a retrospective questionnaire study to collect information on the course of the disease and the survival time. Therapy with mistletoe extracts had been recommended to all patients. The treatment was carried out by the patient's physician outside the hospital. For inclusion into further analysis, information on survival time and mistletoe treatment had to be available. Survival times of patients who had actually received the recommended mistletoe treatment and of patients who had not received the recommended mistletoe treatment were compared (internal comparison). Furthermore, the results were compared to those of conventionally treated patients obtained from the literature (literature comparison). Results: Of 237 patients for whom sufficient data was available, 14 had not been treated with a mistletoe extract. The median survival time was 9.18 years among patients who had received mistletoe compared to 7.54 years among those without. Before a statistical test was carried out, the equivalent distribution of diagnosis in the 2 groups was tested. Regarding this criterion, only 205 patients treated with mistletoe extract and 9 patients not treated with mistletoe extract could be included into the statistical tests of the median survival time. The median survival time was 11.4 years (mistletoe patients) and 8.6 years (patients whithout mistletoe therapy). The difference was not significant. There were no cases in which mistletoe treatment was associated with deterioration. The comparison with data from the literature yielded very similar survival times among patients not treated with mistletoe extract and those included in our study. Conclusion: No indications to risks of a mistletoe therapy on progress of the disease and the survival time could be found. Therefore, no ethical reservations should be opposed to future prospective investigations of mistletoe therapy in patients with malignant haematological diseases.

Entwicklung lymphozytärer Subpopulationen bei Tumorpatienten nach subkutaner Applikation von Mistelextrakten

Objective: In order to exclude the possibility that mistletoe therapy may result in immunosuppression, as indicated by a significant reduction of defined lymphocyte subsets, Patients and Methods:peripheral blood cells of 23 tumour patients were treated subcutaneously with increasing concentrations of aqueous mistletoe extracts (Helixor^®). Results and Conclusions:Within an observation period of 7 months, the relative amount of lymphocytes and the number of natural killer (NK) cells increased while the number of lymphocyte subsets (i. e. CD19+ B cells, CD4+ T helper cells, CD8+ CD28– suppressor cells, CD8+ CD28+ cytotoxic cells) and the proportion of CD25+ (activated) cells within T cells showed a statistically remarkable trend; due to the multiple test problem of statistical evaluation this trend is not allowed to be termed significant. The leucocytes decreased insignificantly within the observation period. However, we were unable to verify a suggested increase of defined lymphocyte subsets within 2–3 months after the onset of mistletoe treatment. Nevertheless, for the parameters CD19+ B cells, CD4+ T helper cells, CD8+ cells, CD8+ CD28+ cytotoxic cells and CD16+/CD56+ NK cells we observed statistically remarkable peaks within die 2nd and 3rd month of therapy, confirming the hypothesis. The responses to the extracts were obviously interindividually different; the immune responses especially of patients with a lower number of peripheral T cells were less significant as compared to those of patients with adequate T cell numbers. Surprisingly, even an increase of the drug concentration >3 ng mistletoe lectin (as determined within the whole plant extract) per kg body weight enhanced the number of CD4+ T helper cells. A decreased immunological reaction on mistletoe extracts was shown especially for patients with a reduced number of peripheral T cells, whereas patients with normal T-cell number were more reactive.

Recognition of different antigens of mistletoe extracts by anti-mistletoe lectin antibodies

Anti-mistletoe lectin-1 (ML-1) antibodies are produced during treatment of cancer patients with mistletoe extracts. However, little is known about their ability to recognise distinct epitopes present in mistletoe extracts. To estimate this, ML-1, ML-2 and ML-3 were analysed by Western blot analysis using high titred anti-ML antibody positive sera from cancer patients treated with different mistletoe extracts. In these experiments we could clearly demonstrate that anti-ML antibodies bind to ML-1 A- and B-chains and, in addition, that they recognised a spectrum of other antigens. This kind of immunological response varied from one individual to another and was not influenced by the different mistletoe extracts. Elution studies showed that anti-ML-1 A-chain or B-chain specific antibodies cross-reacted with A- or B-chains of the other lectins indicating homologies between these molecules (probably in the glycosylated side chain). However, the unglycosylated ML-3 A-chain was only detectable by antibodies specific for the ML-3 A-chain. From our data it has to be concluded that different epitopes of the mistletoe extracts are involved in the induction of the humoral immune response during mistletoe therapy and also that cross-reactivity between the different ML exist.

Treatment of pancreatic cancer with Viscum album (Iscador): A retrospective study of 292 patients 1986–1996

Pancreatic cancer has a poor prognosis and, with the exception of surgery, no effective therapy is available for this devastating disease. Responsiveness to chemo- or radiotherapy is low. Viscum album preparations with known immunomodulating properties such as Iscador are used in anthroposophically orientated complementary medicine to treat tumor patients. However, the effect of mistletoe therapy on the survival of patients with cancer of the pancreas has not been investigated by controlled clinical studies. As a first step we did a retrospective analysis of survival for all patients with pancreatic cancer treated with Iscador at the Lukas Clinic Arlesheim, Switzerland, between 1986 and 1996. Iscador was given by subcutaneous injection two or three times a week, with doses ranging from 0.1 to 30 mg. Of a total of 320 patients, 292 had died by the end of the observation period and were available for statistical analysis. Patients' characteristics showed a prognostically unfavourable predominance of advanced stages of the disease. Median delay between diagnosis and admission for Iscador treatment was 5 weeks for stage IV cases, and 33 weeks for patients with operable tumors. One year survival rate was 26.3%. Median survival time was calculated for all stages. It was 6.58 months for the complete group, 16.69 months for 29 patients who had undergone resection, and 5.6 months for 161 stage IV cases. Viscum album treated patients had better results or at least survival times in the upper ranges compared with stage related survival reported in the literature. Taking into account the lack of beneficial treatment modalities for pancreatic cancer, research should be done prospectively in order to further evaluate this therapeutic approach.

Effect of a mistletoe extract (Iscador QuFrF) on viability and migratory behavior of human peripheral CD4+ and CD8+ T lymphocytes in three-dimensional collagen lattices.

Migration and tissue distribution of immunocompetent cells may be critical prerequisites for efficient immune surveillance. The effect of various concentrations of the mistletoe extract Iscador QuFrF on the locomotory behavior and viability of immunomagnetically isolated human CD4+ and CD8+ T lymphocytes within three-dimensional collagen gels was investigated. Although variation in baseline activities of spontaneously migrating T cells was donor-dependent, a dose-dependent stimulation of the locomotory activity in both CD4+ and CD8+ T cells for noncytotoxic concentrations of Iscador QuFrF (0.25-1.25 micrograms/ml) was detected. The optimal concentration of mistletoe extract and time of maximal response were specific for each donor. As shown by cell tracking and subsequent data analysis, CD4+ T cells exposed to the mistletoe extract displayed a significant increase in mean velocity and time locomoting; total distance migrated was nearly doubled. In contrast, CD8+ T cells showed less pronounced changes in these critical parameters. Cytotoxic effects of the mistletoe preparation on T lymphocytes, which could at least partially be attributed to the induction of apoptosis, were drastically reduced in the presence of fetal calf serum in the culture system. Our data suggest that the direct stimulation of T-cell migration in the presence of mistletoe components may modulate in a dose-dependent manner the system of immune surveillance and recognition in patients under mistletoe therapy.

Mistletoe therapy and immunological research

Krebsforschung Herdecke, Department of Applied Immunology, Communal Hospital Herdecke, D-58313 Herdecke, Germany

Donor-dependent and dose-dependent variation in the induction of T lymphocyte locomotion in a three-dimensional collagen matrix system by a mistletoe preparation (Iscador).

Controlled activation of non-specific and specific immune defence mechanisms can beneficially manipulate the host's ability to attack malignant cells. In this context, migration and tissue distribution of immunocompetent cells may be prerequisites for an efficient immune surveillance. The effect of various non-cytotoxic concentrations of the Viscum album L. (mistletoe) preparation Iscadore QuFrF on the locomotory activity of immunomagnetically isolated human CD4+ and CD8+ T lymphocytes from healthy donors was investigated. Cellular migration was examined within a three-dimensional collagen matrix. Donor-dependent variations in baseline activities of spontaneously locomoting T cells were accompanied by individual response patterns of T cells from different donors in the presence of various concentrations of mistletoe preparation (0.25-2.5 micrograms/ml). Using the three-dimensional collagen matrix assay an induction of locomotory activity was detected in a highly reproducible fashion although the optimal concentration of mistletoe preparation and the time point of maximal response were individual for each donor. Our data suggest that the direct stimulation of T-cell migration by mistletoe components may modulate the system of immune surveillance and recognition in patients under mistletoe therapy.

Mistletoe therapy for human cancer: the role of the natural killer cells.

Extracts produced from Viscum album L. (mistletoe) as well as certain isolated components are able to stimulate different functions of the immune system. The natural killer cells have been suggested as one of the candidates for direct tumour cell destruction. These cells are defined by their ability to mediate non-major histocompatibility complex (MHC) restricted cytotoxicity without prior sensitization against a specific antigen. However, their effectiveness in tumor defence in vivo is unclear. In general, natural killer cells are unable to lyse fresh autologous tumour cells in vitro unless activated by interleukin-2-preincubation. The results of clinical studies are contradictory, but there is evidence that they may contribute to the prevention of the development of recidives and metastases. In this regard it is interesting that mistletoe extracts are able to stimulate natural killer cell-mediated cytotoxicity in vitro directly as well as indirectly in a cytokine-like manner, with the active components being carbohydrates rather than lectins. Clinical application of mistletoe extracts or isolated lectins is reported to induce augmentation of both number and activity of natural killer cells in peripheral blood in a dose-dependent manner; however, non-responders also have been described. In future work it has to be clarified whether a mistletoe-derived modulation of the natural killer system is of benefit in the tumour defence of cancer patients.

Possibilities and limits of mistletoe therapy in cancer patients

Possibilities and limits of mistletoe therapy in cancer patients

Request for an Impartial Discussion of the So-Called Mistletoe Therapy

Request for an Impartial Discussion of the So-Called Mistletoe Therapy