References for Integrative Cancer

Intravenous Ascorbic Acid:

Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11105-9. Epub 2008 Aug 4.

Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice.

Chen Q, Espey MG, Sun AY, Pooput C, Kirk KL, Krishna MC, Khosh DB, Drisko J, Levine M.

Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, and Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Comment in:

• Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11037-8.

Mistletoe:

This European cancer treatment has been used for many years as a natural chemotherapeutic agent and was developed based on the work of Dr. Rudolph Steiner, the father of Anthroposophical Medicine.  

Phytother Res. 2009 Mar;23(3):407-11.  Immunological response to mistletoe (Viscum album L.) in cancer patients: a four-case series.  Gardin NE. This e-mail address is being protected from spam bots, you need JavaScript enabled to view it

European mistletoe (Viscum album) has been used in complementary cancer treatment, but little is known concerning its effects on immunological parameters, although there is evidence that Viscum may stimulate the immune system. In this study, a trial was conducted with cancer patients to determine whether Viscum album extracts could improve the results of immune tests. These were: white blood cell count (leukocytes, neutrophils, lymphocytes), CD4+ and CD8+ T-lymphocytes, intradermal tests of delayed hypersensitivity (candidin, trichophytin, purified protein derivative-PPD), complement C3 and C4, and immunoglobulin A, G and M. Four patients received seven doses of subcutaneous Viscum album 20 mg, twice weekly. Immunological tests were carried out before and after treatment, and an increase in several parameters of humoral and cellular immunity were shown. Apart from reactions around the injection sites, treatment was well tolerated and all patients benefited from it. These results suggest that Viscum album can enhance humoral and cellular immune responses in cancer patients, but further studies attesting to the possible clinical impact of these immunological effects are necessary.

Cases J. 2009 Jan 22;2(1):77. Mistletoe treatment in cancer-related fatigue: a case report.  Wode K, Schneider T, Lundberg I, Kienle GS.  Vidarkliniken, S-15391 Järna, Sweden. This e-mail address is being protected from spam bots, you need JavaScript enabled to view it

Cancer-related fatigue (CRF) is a major and very common disabling condition in cancer patients. Treatment options do exist but have limited therapeutic effects. Mistletoe extracts are widely-used complementary cancer treatments whose possible impact on CRF has not been investigated in detail. A 36-year-old Swedish woman with a 10-year history of recurrent breast cancer, suffering from severe CRF, started complementary cancer treatment with mistletoe extracts. Over two and a half years a correspondence was observed between the intensity of mistletoe therapy and the fatigue. Mistletoe extracts seemed to have a beneficial, dose-dependent effect on CRF. Although such effect has also been noted in clinical studies, it has never been the subject of detailed investigation. More research should clarify these observations.

World J Gastroenterol. 2008 Sep 14;14(34):5274-81. Active Chinese mistletoe lectin-55 enhances colon cancer surveillance through regulating innate and adaptive immune responses. Ma YH, Cheng WZ, Gong F, Ma AL, Yu QW, Zhang JY, Hu CY, Chen XH, Zhang DQ.  Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.

To investigate the potential role of active Chinese mistletoe lectin-55 (ACML-55) in tumor immune surveillance. METHODS: In this study, an experimental model was established by hypodermic inoculating the colon cancer cell line CT26 (5 x 10(5) cells) into BALB/c mice. The experimental treatment was orally administered with ACML-55 or PBS, followed by the inoculation of colon cancer cell line CT26. Intracellular cytokine staining was used to detect IFN-gamma production by tumor antigen specific CD8+ T cells. FACS analysis was employed to profile composition and activation of CD4+, CD8+, gammadelta T and NK cells. RESULTS: Our results showed, compared to PBS treated mice, ACML-55 treatment significantly delayed colon cancer development in colon cancer-bearing Balb/c mice in vivo. Treatment with ACML-55 enhanced both Ag specific activation and proliferation of CD4+ and CD8+ T cells, and increased the number of tumor Ag specific CD8+ T cells. It was more important to increase the frequency of tumor Ag specific IFN-gamma producing-CD8+ T cells. Interestingly, ACML-55 treatment also showed increased cell number of NK, and gammadeltaT cells, indicating the role of ACML-55 in activation of innate lymphocytes. CONCLUSION: Our results demonstrate that ACML-55 therapy can enhance function in immune surveillance in colon cancer-bearing mice through regulating both innate and adaptive immune responses.

Integr Cancer Ther. 2008 Sep;7(3):162-71.  Mistletoe in conventional oncological practice: exemplary cases.  Legnani W.  Centro Artemedica, Milan, Italy. This e-mail address is being protected from spam bots, you need JavaScript enabled to view it

Mistletoe therapy, a cancer treatment suggested by Rudolf Steiner in 1920, is a typical and specific anthroposophic therapy, but could become more important today in the field of mainstream medicine. This article analyzes some of the most typical effects of mistletoe therapy based on the experience of more than 100 cases. A few patients were chosen who appear exemplary of the opportunities offered by mistletoe therapy. Their clinical history demonstrates an improvement in clinical condition and performance status, better quality of life, improved psychological status, reduction of infective events, better tolerance of concomitant chemoradiotherapy, and even a direct reduction of tumor size. The conclusion is that the patients may be indicative for future prospective clinical studies designed to confirm a real efficacy of mistletoe in cancer therapy.

Phytother Res. 2008 Aug;22(8):1097-103.  Cytotoxic effects of the Viscum album L. extract on Ehrlich tumour cells in vivo.  Cebović T, Spasić S, Popović M.  Biochemistry Department, School of Medicine, Hajduk Veljkova 3, 21000 Novi Sad, Serbia. This e-mail address is being protected from spam bots, you need JavaScript enabled to view it

To date most pharmacological studies on mistletoe (Viscum album L.) have focused on the therapeutic properties of its polar extracts. This study examined the non-polar constituents of Viscum album and their biological activities. Supercritical CO(2) extraction coupled with gas chromatography/mass spectrometry (GC/MS) was used to selectively extract and identify compounds in Viscum album leaves. Several non-polar classes of compounds were identified in the extract. In addition, a volatile fraction was identified that contained several novel terpene molecules. The hypothesis was tested that the Viscum album extract exhibits cytotoxic properties in Ehrlich carcinoma (EAC) cells in vivo due to the induction of oxidative stress. A significant reduction in the incidence of cancer was observed in all groups that received the Viscum album extract compared with the EAC control group. The largest decrease was observed in mice pretreated with the Viscum album extract, although significantly reduced numbers of EAC cells were also observed in animals with developed carcinoma. The activities of antioxidative enzymes in the EAC cells suggested the absence of oxidative stress. However, changes in the antioxidative enzymes activities observed after administration of the Viscum album extract might be due to the induction of oxidative stress in the EAC cells.

Cancer Lett. 2008 Jun 18;264(2):218-28. Epub 2008 Mar 7. Molecular mechanisms of mistletoe plant extract-induced apoptosis in acute lymphoblastic leukemia in vivo and in vitro.  Seifert G, Jesse P, Laengler A, Reindl T, Lüth M, Lobitz S, Henze G, Prokop A, Lode HN.  Department of Pediatric Oncology/Hematology, Otto-Heubner-Center for Pediatric and Adolescent Medicine, Charité, Universitätsmedizin Berlin, Germany. This e-mail address is being protected from spam bots, you need JavaScript enabled to view it

Viscum album (Mistletoe) is one of the most widely used alternative cancer therapies. Aqueous mistletoe extracts (MT) contain the three mistletoe lectins I, II and III as one predominant group of biologically active agents. Although MT is widely used, there is a lack of scientifically sound preclinical and clinical data. In this paper, we describe for the first time the in vivo efficacy and mechanism of action of MT in lymphoblastic leukemia. For this purpose, we first investigated both the cytotoxic effect and the mechanism of action of two standardized aqueous MTs (MT obtained from fir trees (MT-A); MT obtained from pine trees (MT-P)) in a human acute lymphoblastic leukemia (ALL) cell line (NALM-6). MT-A, MT-P and ML-I inhibited cell proliferation as determined by Casy Count analysis at very low concentrations with MT-P being the most cytotoxic extract. DNA-fragmentation assays indicated that dose-dependent induction of apoptosis was the main mechanism of cell death. Finally, we evaluated the efficacy of MT-A and MT-P in an in vivo SCID-model of pre-B ALL (NALM-6). Both MTs significantly improved survival (up to 55.4 days) at all tested concentrations in contrast to controls (34.6 days) without side effects.

BMC Cancer. 2008 Jun 4;8:161.  Induction of maturation and activation of human dendritic cells: a mechanism underlying the beneficial effect of Viscum album as complimentary therapy in cancer.  Elluru SR, van Huyen JP, Delignat S, Kazatchkine MD, Friboulet A, Kaveri SV, Bayry J.  Centre de Recherche des Cordeliers, Université Pierre et Marie Curie - Paris6, UMR S 872, Paris, 75006, France. This e-mail address is being protected from spam bots, you need JavaScript enabled to view it

Viscum album (VA) preparations have been used as a complimentary therapy in cancer. In addition to their cytotoxic properties, they have also been shown to have immunostimulatory properties. In the present study, we examine the hypothesis that the VA preparations induce activation of human DC that facilitates effective tumor regression. METHODS: Four day old monocyte-derived immature DCs were treated with VA Qu Spez at 5, 10 and 15 microg/ml for 48 hrs. The expression of surface molecules was analyzed by flow cytometry. The ability of Qu Spez-educated DC to stimulate T cells was analyzed by allogeneic mixed lymphocyte reaction and activation of Melan-A/MART-1-specific M77-80 CD8+T cells. Cytokines in cell free culture supernatant was analyzed by cytokine bead array assay. RESULTS: VA Qu Spez stimulated DCs presented with increased expression of antigen presenting molecule HLA-DR and of co-stimulatory molecules CD40, CD80 and CD86. The VA Qu Spez also induced the secretion of inflammatory cytokines IL-6 and IL-8. Further, Qu Spez-educated DC stimulated CD4+T cells in a allogeneic mixed lymphocyte reaction and activated melanoma antigen Melan-A/MART-1-specific M77-80 CD8+T cells as evidenced by increased secretion of TNF-alpha and IFNgamma. CONCLUSION: The VA preparations stimulate the maturation and activation of human DCs, which may facilitate anti-tumoral immune responses. These results should assist in understanding the immunostimulatory properties of VA preparations and improving the therapeutic strategies.

Anticancer Res. 2008 May-Jun;28(3B):1893-7.  Local reactions to treatments with Viscum album L. extracts and their association with T-lymphocyte subsets and quality of life. Büssing A, Tröger W, Stumpf C, Schietzel M.  University Witten/Herdecke, Herdecke, Germany. This e-mail address is being protected from spam bots, you need JavaScript enabled to view it

In a previous study a decline of T-lymphocyte function was observed within a 6-month period of Viscum album extract (VA-E) application which did not occur in those patients with dose adaptation in response to strong local reactions (LR) or in those with moderate LR. To further investigate the immunological prerequisites of these differences in the VA-E susceptibilities, an analysis was carried out of the pre-existing differences in the tumor patients' lymphocyte subsets, and of whether the LR pattern (none, moderate, strong) might be associated with distinct aspects of the patients' quality of life. PATIENTS AND METHODS: Seventy-one cancer patients were subcutaneously treated with VA-E (Iscador) at increasing concentrations and their lymphocyte subsets measured by flowcytometry during a 6 month observation period; quality of life was assessed with the HLQ questionnaire. RESULTS: The occurrence of stronger LR was associated with a primarily higher level of T-cells and their CD4+ T-helper/inducer subset, and CD25+ respectively HLA-DR+ (activated) T-cells. Moreover, counts or proportions of T-cells, CD4+ T-helper/inducer cells and CD8+ CD28+ cytotoxic cells were lower, while the relative proportions of CD8+ CD28- suppressor cells, B- and NK-cells were the highest in the group with moderate LR. In particular, this latter group had a significantly higher quality of life. CONCLUSION: Our results indicate that the induction of moderate LR in response to VA-E application was associated with better T cell function and quality of life. Extracts from Viscum album (VA-E) are widely used as a complementary treatment particularly in Germany and Switzerland.

Cochrane Database Syst Rev. 2008 Apr 16;(2):CD003297. Mistletoe therapy in oncology.  Horneber MA, Bueschel G, Huber R, Linde K, Rostock M.  Medizinische Klinik 5, Arbeitsgruppe Biologische Krebstherapie, Prof.-Ernst-Nathan-Str. 1, Nuernberg, Germany, D-90419. This e-mail address is being protected from spam bots, you need JavaScript enabled to view it

Mistletoe extracts are commonly used in cancer patients. It is claimed that they improve survival and quality of life (QOL) in cancer patients. OBJECTIVES: To determine the effectiveness, tolerability and safety of mistletoe extracts given either as monotherapy or adjunct therapy for patients with cancer. SEARCH STRATEGY: Search sources included the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 3, 2007) Cochrane Complementary Medicine Field Registry of randomized clinical trials (RCTs) and controlled clinical trials, MEDLINE, EMBASE, HEALTHSTAR, INT. HEALTH TECHNOLOGY ASSESSMENT, SOMED, AMED, BIOETHICSLINE, BIOSIS, CancerLit, CATLINE, CISCOM (August 2007).For the search the Standard Operating Procedures of the Information System in Health Economics at the German Institute for Medical Documentation and Information (DIMDI) were utilized. Reference lists of relevant articles and authors extensive files were searched for additional studies. Manufacturers of mistletoe preparations were contacted. SELECTION CRITERIA: We included RCTs of adults with cancer of any type. The interventions were mistletoe extracts as sole treatments or given concomitantly with chemo- or radiotherapy. The outcome measures were survival times, tumor response, QOL, psychological distress, adverse effects from antineoplastic treatment and safety of mistletoe extracts. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trials for inclusion in the review. All review authors independently took part in the extraction of data and assessment of study quality and clinical relevance. Disagreements were resolved by consensus. Study authors were contacted where information was unclear. Methodological quality was narratively described and additionally assessed with the Delphi list and the Jadad score. High methodological quality was defined if six out of nine Delphi criteria, or four out of five Jadad criteria were fulfilled. Results were presented qualitatively. MAIN RESULTS: Eighty studies were identified. Fifty-eight were excluded for various reasons, usually as there was no prospective trial design with randomised treatment allocation. Of the 21 included studies 13 provided data on survival, 7 on tumour response, 16 on measures of QOL or psychological outcomes, or prevalence of chemotherapy-related adverse effects and 12 on side effects of mistletoe treatment; overall comprising 3484 randomised cancer patients. Interventions evaluated were 5 preparations of mistletoe extracts from 5 manufacturers and one commercially not available preparation. The general reporting of RCTs was poor.Of the 13 trials investigating survival, 6 showed some evidence of a benefit, but none of them was of high methodological quality. The results of two trials in patients with melanoma and head and neck cancer gave some evidence that the used mistletoe extracts are not effective for improving survival.Of the 16 trials investigating the efficacy of mistletoe extracts for either improving QOL, psychological measures, performance index, symptom scales or the reduction of adverse effects of chemotherapy, 14 showed some evidence of a benefit, but only 2 of them including breast cancer patients during chemotherapy were of higher methodological quality.Data on side effects indicated that, depending on the dose, mistletoe extracts were usually well tolerated and had few side effects. AUTHORS' CONCLUSIONS: The evidence from RCTs to support the view that the application of mistletoe extracts has impact on survival or leads to an improved ability to fight cancer or to withstand anticancer treatments is weak. Nevertheless, there is some evidence that mistletoe extracts may offer benefits on measures of QOL during chemotherapy for breast cancer, but these results need replication. Overall, more high quality, independent clinical research is needed to truly assess the safety and effectiveness of mistletoe extracts. Patients receiving mistletoe therapy should be encouraged to take part in future trails.

Evid Based Complement Alternat Med. 2008 Apr 11. [Epub ahead of print] Individual Patient Data Meta-analysis of Survival and Psychosomatic Self-regulation from Published Prospective Controlled Cohort Studies for Long-term Therapy of Breast Cancer Patients with a Mistletoe Preparation (Iscador).  Ziegler R, Grossarth-Maticek R.  Verein für Krebsforschung, Kirschweg 9, CH-4144 Arlesheim, Switzerland. This e-mail address is being protected from spam bots, you need JavaScript enabled to view it

Mistletoe preparations such as Iscador are in common use as complementary/anthroposophic medications for many cancer indications, particularly for solid cancers. The efficacy is still discussed controversially. This paper presents an individual patient data meta-analysis of all published prospective matched-pair studies with breast cancer patients concerned with long-term application of a complementary/anthroposophic therapy with the mistletoe preparation Iscador. Six sets of data were available for individual patient meta-analysis of breast cancer patients, matched according to prognostic factors into pairs with and without mistletoe (Iscador) therapy. The main outcome measures were overall survival and psychosomatic self-regulation. Overall survival was almost significant in favor of the Iscador group in the combined data set of the randomized studies: estimate of the hazard ratio with 95% confidence interval 0.59 (0.34, 1.02). Overall survival was highly significant in the combined data set of the non-randomized studies: 0.43 (0.34, 0.56). In the combined analysis of the randomized studies, improvement of psychosomatic self-regulation, as a measure of autonomous coping with the disease, was highly significant in favor of the Iscador group: estimate of the median difference 0.45 (0.15, 0.80), P = 0.0051. The analyzed studies show that therapy with Iscador might prolong overall survival and improve psychosomatic self-regulation of breast cancer patients.

Eur J Med Res. 2008 Mar 31;13(3):107-20.  Randomized and non-randomized prospective controlled cohort studies in matched pair design for the long-term therapy of corpus uteri cancer patients with a mistletoe preparation (Iscador).  Grossarth-Maticek R, Ziegler R.  Institute for Preventive Medicine, Heidelberg, Germany.

Mistletoe preparations such as Iscador are in common use as complementary/anthroposophic medications for many cancer indications, particularly for solid cancers. Efficacy of this complementary therapy is still discussed controversially. OBJECTIVE: Does the long-term therapy with Iscador show any effect on survival or psychosomatic self-regulation of patients with corpus uteri cancer? PATIENTS AND METHODS: Prospective recruitment and long-term follow-up in the following 4 controlled cohort studies. (1) Two randomized matched-pairs studies: corpus uteri cancer patients without (30 pairs) and with distant metastases (26 pairs) that never used any kind of mistletoe therapy were matched for prognostic factors. By pairwise random allocation, one of the patients was suggested mistletoe therapy to be applied by the attending physician. (2) Two non-randomized matched-pairs studies: corpus uteri cancer patients without (103 pairs) and with distant metastases (95 pairs) that already received mistletoe (Iscador) therapy were matched by the same criteria to control patients without Iscador therapy. RESULTS: Concerning overall survival in the randomized studies, a significant effect in favour of Iscador therapy was present only in the first study, the second showed no evidence for an effect: estimate of the hazard ratio and 95% confidence interval: 0.36 (0.16, 0.82) and 1.00 (0.46, 2.16) respectively. In the non-randomized studies, the results that adjusted for relevant prognostic variables were: 0.41 (0.26, 0.63), and 0.61 (0.39, 0.93). The effect of therapy with Iscador within 12 months on psychosomatic self-regulation as a measure of autonomous coping with the disease shows a significant rise in the Iscador group against the control group in the randomized as well as in the non-randomized study on patients with corpus uteri cancer without metastases: estimate of the median difference and 95% confidence interval: 0.40 (0.15, 0.70) and 0.70 (0.25, 1.15) respectively. CONCLUSION: The mistletoe preparation Iscador in these studies has the effect of prolonging overall survival of corpus uteri cancer patients. Psychosomatic self-regulation as a measure of autonomous coping with the disease, rises significantly more under Iscador therapy than under conventional therapy alone.

Forsch Komplementmed. 2008 Feb;15(1):22-30. [Adjuvant simultaneous mistletoe chemotherapy in breast cancer--influence on immunological parameters, quality of life and tolerability] [Article in German]  Loewe-Mesch A, Kuehn JJ, Borho K, Abel U, Bauer C, Gerhard I, Schneeweiss A, Sohn C, Strowitzki T, v Hagens C. Ambulanz für Naturheilkunde und Integrative Medizin, Abt. Gynakologische Endokrinologie und Fertilitätsstörungen der Universitätsfrauenklinik Heidelberg, Deutschland.

INTRODUCTION: The objective of this feasibility study was to identify suitable surrogate parameters for a randomized confirmative trial with mistletoe treatment in patients with breast cancer. Tolerability,quality of life, hematological and immunological parameters were evaluated during postoperative chemotherapy. PATIENTS AND METHODS:This prospective open 2-armed non-randomized study compared 33 patients with primary breast cancer during adjuvant chemotherapy (CMF or EC) and simultaneous treatment with Iscador M 5 mg spezial (IM spez) with 33 controls without mistletoe.Before and 14 days after chemotherapy hematology, lymphocyte subpopulations, stimulability of lymphozytes and quality of life(EORTC QLQ-C30, BR23) were assessed. RESULTS: Although there was a slight increase in thrombocytes within normal values (p =0.01), no clinically important laboratory parameter was favorable in the mistletoe group during the trial. There was no difference in immuno suppression due to chemotherapy. We found a lower frequency of nausea/vomiting and systemic therapy side effects (EORTC)during add-on-therapy with mistletoe (p = 0.02 each). Glucocorticoidco treatment in the mistletoe group was less frequent (p = 0.006), as well. In general, the add-on-therapy was well tolerated, taking into account that dose reduction was often necessary at the beginning of the chemotherapy because of large local reactions at the site of the injections. Therefore, blinding seems impossible if treatment with mistletoe and chemotherapy is started more or less simultaneously.  CONCLUSIONS: Reductions in quality of life seem to be smaller during add-on-therapy with mistletoe. Laboratory parameters showed no difference compared to the control group. Quality of life and reduction of glucocorticoid cotreatment should be further evaluated.

Anticancer Res. 2008 Jan-Feb;28(1B):523-7.  Impact of complementary treatment of breast cancer patients with standardized mistletoe extract during aftercare: a controlled multicenter comparative epidemiological cohort study. Beuth J, Schneider B, Schierholz JM.  Institut zur wissenschaftlichen Evaluation naturheilkundlicher Verfahren an der Universität zu Köln, Joseph-Stelzmann-Str. 9, 50931 Köln, Germany. This e-mail address is being protected from spam bots, you need JavaScript enabled to view it

OBJECTIVES: To investigate the safety and efficacy of complementary treatment of breast cancer patients with the standardized mistletoe extract (sME) HELIXOR in routine practice during aftercare through a multicenter comparative epidemiological cohort study with 53 randomly selected hospitals/practices representatively distributed in Germany, including oncologists, gynaecologists and general practitioners. PATIENTS AND METHODS: Data from 741 screened patients fulfilling the inclusion/exclusion criteria were checked. Of these, 681 patients were eligible for the final analysis of the study group (with sME n = 167) and the control group (n = 514). Efficacy (development of disease/therapy-induced signs and symptoms; quality of life) and safety (number and severity of adverse events) of complementary treatment in breast cancer patients treated with sME in the aftercare period were determined. RESULTS: Complementary treatment of breast cancer patients with sME during the aftercare period of approximately 5 years after terminating recommended standard therapies resulted in significantly fewer (p < 0.001) complaints of patients (56.3% study group versus 70.0% control group). The reduced number of disease/therapy-related sign/symptoms (e.g. mucositis, fatigue, pain, headache) correlated to a significantly improved quality of life. Adverse drug reactions to the sME treatment were mostly mild and self limiting. CONCLUSION: Complementary treatment with the sME HELIXOR proved to be beneficial for breast cancer patients since it significantly improved quality of life and significantly reduced persistant signs/symptoms of the disease/treatment during the validated aftercare period of approximately five years.

Forsch Komplementmed. 2007 Jun;14(3):140-7. Epub 2007 Jun 22. Prospective controlled cohort studies on long-term therapy of cervical cancer patients with a mistletoe preparation (Iscador). Grossarth-Maticek R, Ziegler R. Institut für Präventive Medizin, Europäisches Zentrum für Frieden und Entwicklung (European Center for Peace and Development, ECPD), Heidelberg, Germany.

BACKGROUND: Mistletoe preparations such as Iscador are commonly used in complementary medication for many cancer indications, particularly solid cancers. The efficacy of this complementary therapy is still controversial. OBJECTIVE: Does longterm therapy with Iscador show any effect on survival, tumor progression and psychosomatic self-regulation of patients with cervical cancer? PATIENTS AND METHODS: Prospective recruitment and long-term follow-up was carried out in 3 controlled cohort studies: In a randomized matched-pair study (19 pairs), cervical cancer patients with distant metastases and no mistletoe therapy were matched for prognostic factors. By paired random allocation, one of the patients was recommended mistletoe therapy by the attending physician. In 2 non-randomized matched-pair studies, cervical cancer patients without (102) and with (66) metastases, who already received mistletoe therapy, were matched with control patients without Iscador therapy. RESULTS: For survival, the non-randomized studies showed significant effects in favor of Iscador therapy: hazard ratio (HR) estimate and 95% confidence interval (CI): 0.23 (0.14-0.39) and 0.37 (0.17-0.80), respectively. An effect of long-term Iscador therapy on tumor progression was not seen. Psychosomatic self-regulation in the Iscador group improved significantly within 12 months compared with the control group in the randomized as well as in 1 non-randomized study (cervical cancer without metastases): estimate of the median difference and 95% CI: 0.70 (0.15-1.05) and 0.25 (0.15-0.35), respectively. CONCLUSION: Iscador may have the effect of prolonging overall survival of cervical cancer patients. In the short term, psychosomatic self-regulation increases more markedly under complementary Iscador therapy than under conventional therapy alone.

Br J Cancer. 2008 Jan 15;98(1):106-12. Epub 2007 Nov 20.  Low-dose mistletoe lectin-I reduces melanoma growth and spread in a scid mouse xenograft model.  Thies A, Dautel P, Meyer A, Pfüller U, Schumacher U.  Zentrum für Experimentelle Medizin, Institut für Anatomie II: Experimentelle Morphologie, Universitätsklinikum Hamburg Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany. This e-mail address is being protected from spam bots, you need JavaScript enabled to view it

This study investigates the effects of mistletoe lectin-I (ML-I) on melanoma growth and spread in vivo. The human melanoma cell line MV3 was xenografted into severe combined immunodeficient mice and vehicle solution or purified ML-I was administered at 30, 150 and 500 ng per kg body weight (20 mice per group) daily. After 19 days, mice were killed, primary tumours (PTs) and lungs were dissected out, and tumour weights, number of lung metastases (LMs), number of tumour-infiltrating dendritic cells (DCs), and apoptosis rates in the melanoma cells and in the DCs were assessed. A 35% reduction of PT weight (P=0.03) and a 55% decrease in number of LMs (P=0.016) were evident for low-dose ML-I (30 ng kg(-1)) treatment but not for higher doses. Mistletoe lectin-I increased apoptosis rates in the melanoma cells of PTs at all doses, while no induction of apoptosis was noted in the LMs. Low-dose ML-I significantly increased the number of DCs infiltrating the PTs (P<0.0001) and protected DCs against apoptosis, while higher doses induced apoptosis in the DCs (P<0.01). Our results demonstrate that low-dose ML-I reduced melanoma growth and number of metastases in vivo, primarily due to immunomodulatory effects.

Anticancer Res. 2005 Sep-Oct;25(5):3303-7. Binding of recombinant mistletoe lectin (aviscumine) to resected human adenocarcinoma of the lung.  Blonski K, Schumacher U, Burkholder I, Edler L, Nikbakht H, Boeters I, Peters A, Kugler C, Horny HP, Langer M, Wilhelm-Ogunbiyi K, Witthohn K, Laack E. Department of Anatomy II: Experimental Morphology, University Hospital Hamburg-Eppendorf, Hamburg, Germany. This e-mail address is being protected from spam bots, you need JavaScript enabled to view it

BACKGROUND: Lectins, carbohydrate proteins, bind to glycoconjugates of all mammalian cells, including cancer cells. Aberrant glycosylation, detected by lectin histochemistry, can predict outcome in some tumour entities. One such lectin is aviscumine (recombinant mistletoe lectin). Aviscumine has cytotoxic effects and can therefore be used as anti-tumour therapy. MATERIALS AND METHODS: Lectin histochemistry with aviscumine was performed on primary tumour sections from resected adenocarcinoma of the lung. Staining results were then correlated with the clinical course of the patients. RESULTS: Most of the adenocarcinomas (92.5%) bound aviscumine. Kaplan-Meier analysis revealed no correlation between aviscumine binding and progression-free survival or overall survival. CONCLUSION: These results suggest that for the selected group of patients with adenocarcinoma of the lung aviscumine binding activity can not serve as a prognostic factor. More strikingly, however, aviscumine binds to malignant cells in 92.5% of the patients. This is an indicator for the use of aviscumine as a possible target for tumour therapy.

Arzneimittelforschung. 2005;55(1):38-49.  Safety and efficacy of the long-term adjuvant treatment of primary intermediate- to high-risk malignant melanoma (UICC/AJCC stage II and III) with a standardized fermented European mistletoe (Viscum album L.) extract. Results from a multicenter, comparative, epidemiological cohort study in Germany and Switzerland.  Augustin M, Bock PR, Hanisch J, Karasmann M, Schneider B.  Department of Dermatology, University Hospital, University of Freiburg, Freiburg/Brsg (Germany). This e-mail address is being protected from spam bots, you need JavaScript enabled to view it

BACKGROUND: Mistletoe therapy is the most frequently used complementary treatment in cancer patients in Germany and Switzerland. However, its safety and efficacy were controversially discussed, also in case of malignant melanoma (MM). OBJECTIVES: The present study should evaluate the therapeutic safety and efficacy of a long-term therapy with a standardized fermented European mistletoe (Viscum album L.) extract Iscador (FME) during post-surgical aftercare of primary intermediate to high-risk MM (UICC/AJCC stage II-III) patients and compare it with an untreated parallel control group from the same cohort. METHODS: The study was designed as a multicenter, comparative, retrolective, epidemiological cohort study with parallel groups, carried out according to the guidelines of Good Epidemiological Practice (GEP). All patients suffered from surgically treated and histopathologically confirmed primary MM in UICC/AJCC stage II-III without distant metastases. In the study group, FME was administered subcutaneously 2-3 times weekly for at least three months, while the untreated control group was merely observed ("watchful waiting"). In both groups some patients also received radio-, chemo-, and/or immunotherapy. The patients were followed until the last visit or until death. Unselected, chronologically ordered, and standardized anonymous data from medical records that satisfied the predefined eligibility criteria were included for the "per protocol" analysis. Safety was assessed by the number of patients with FME-associated adverse drug reactions (ADRs) and by the search for tumor enhancement. The primary endpoint of efficacy was the adjusted tumor-related survival. Secondary end-points were the overall-, the disease-free- and the brain metastasis-free survival. The survival results were analyzed after adjustment for baseline imbalances, treatment regimens and other potential confounders by the Cox proportional hazard regression method. RESULTS: 686 eligible patients (329 FME vs. 357 controls) from 35 centers were observed for a median aftercare of 81 vs. 52 months. The median FME therapy duration was 30 months. At baseline, both groups were comparable concerning demography, tumor history and risk factors for progression. Additional adjuvant chemotherapy was more frequent in the study group, while immunotherapy was more frequent in the control group. Eleven patients (3.3 %) developed systemic ADRs attributed to the FME-treatment, and 42 patients (12.8 %) developed local ADRs, with mild to intermediate (WHO/CTC grade 1-2) ADR severity and spontaneous resolution in most cases. In six patients the ADRs resulted in therapy termination. Life-threatening ADRs, ADR-related mortality or tumor enhancement were not observed. On the contrary, the incidence rate of lung metastases and the adjusted hazard ratio for brain metastases were significantly lower in the FME group. In the course of the study and during aftercare a total of 212 (30.9 %) patients relapsed or progressed, and 107 (15.6 %) died. A significantly longer tumor-related survival was found in the FME group when compared with the untreated controls (unadjusted tumor-related mortality rate 8.9 % vs. 10.7 %, Kaplan-Meier estimate, Log-rank test, p = 0.017), which was confirmed after adjusting for potential confounders by the tumor-related mortality hazard ratio estimate HR (95 % confidence intervals) = 0.41 (0.23-0.71), p = 0.002. The adjusted HR results of the overall survival, disease-free survival, and the brain metastases-free survival were also significantly superior in the FME group. CONCLUSION: The long-term FME treatment in patients with primary intermediate to high-risk MM appears safe. Tumor enhancement was not observed. When compared with an untreated parallel control group from the same cohort, the results of the FME treatment suggested a significant survival benefit in primary stage II-III MM patients. These results on survival warrant reconfirmation in a prospective randomized clinical trial with optimized study design and treatment conditions.

Anticancer Res. 2004 Jan-Feb;24(1):303-9.  Impact of complementary mistletoe extract treatment on quality of life in breast, ovarian and non-small cell lung cancer patients. A prospective randomized controlled clinical trial.  Piao BK, Wang YX, Xie GR, Mansmann U, Matthes H, Beuth J, Lin HS.  Guang An Men Hospital, Beijing, China.

Standardized aqueous mistletoe extracts have been applied to cancer patients for several decades as complementary medicine. A multicentric, randomized, open, prospective clinical trial was conducted in three oncological centers in the People's Republic of China in Bejing, Shenyang and Tianjin. Following the guidelines of "Good Clinical Practice" (GCP) this study was performed to get information on efficacy safety and side-effects of the standardized mistletoe extract (sME). Two hundred and thirty-three patients with breast (n=68), ovarian (n=71) and non-small cell lung cancer (NSCLC; n=94) were enrolled into this study. Two hundred and twenty-four patients fulfilled the requirements for final analysis (n=115 treated with sME HELIXOR A; n=109 comprising the control group being treated with the approved immunomodulating phytopharmacon Lentinan). All patients were provided with standard tumor-destructive treatment schedules and complementarily treated with sME or Lentinan during chemotherapy according to treatment protocol. Biometrically, the patients of the control and sME treatment group were comparable regarding distribution, clinical classification (WHO) and treatment protocols. Analysis was performed according to the "Intention to treat principle". Quality of life (QoL) was significantly (p<0.05) improved for patients who were complementarily treated with sME, as determined by the questionnaires FLIC (Functional Living Index-Cancer), TCM (Traditional Chinese Medicine Index) and the KPI (Karnofsky Performance Index) in comparison to the control group. Additionally, the occurrence of adverse events (AEs) was less frequent in the sME than in the control group (total number of AEs 52 versus 90 and number of serious AEs 5 versus 10 in study and control group, most of them due to chemotherapy). Only one serious AE was allocated to complementary treatment in each group (1 angioedema in sME group). All other side-effects of the sME (7 harmless local inflammatory reactions at subcutaneous injection site, 4 cases with fever) were self-limiting and did not demand therapeutic intervention. This study showed that complementary treatment with sME can beneficially reduce the side-effects of chemotherapy in cancer patients and thus improve quality of life.

Eur J Med Res. 2003 Mar 27;8(3):109-19.  Mistletoe in cancer - a systematic review on controlled clinical trials. Kienle GS, Berrino F, Büssing A, Portalupi E, Rosenzweig S, Kiene H.  Institute for Applied Epistemology and Medical Methodology, Bad Krozingen/Freiburg, Germany. This e-mail address is being protected from spam bots, you need JavaScript enabled to view it

BACKGROUND: Mistletoe preparations are among the most widely used unconventional cancer therapies in Central Europe. Their clinical effectiveness, however, is controversial. OBJECTIVE: To investigate whether prospective controlled clinical trials provide evidence for efficacy of mistletoe therapy in cancer. DESIGN: Systematic review. MATERIAL AND METHODS: Search of 11 electronic databases, reference lists and expert consultations. Criteria based analysis was performed to assess methodological quality of the studies. RESULTS: Twenty-three studies were identified: 16 randomized, 2 quasi-randomized and 5 non-randomized. Cancer sites included breast, lung, stomach, colon, rectum, head and neck, kidney, bladder, melanoma, glioma, and genital. Among these studies, statistically significant positive outcomes were reported for survival (n = 8), tumor remission (n = 1), overall quality of life (QOL) (n = 3), and QOL in relation to side effects during cytoreductive therapy (n = 3). Further, positive trends were reported for survival (n = 8), disease-free-survival (n = 1), and tumor remission (n = 2). Several studies reported no effect on survival (n = 4), disease-free-survival (n = 1), recurrence (n = 2), remission (n = 3), and QOL (n = 1). One study showed a negative trend for disease-free-survival. However, methodological quality of the studies was sometimes far below the standard that is today regarded as optimal or necessary. In view of substantial heterogeneity of the studies and potential positive and negative biases, we considered effect size estimation by quantitative synthesis to be unreliable and decided on a non-quantitative synthesis and discussion. Mistletoe therapy was well tolerated, and no major side effects were noted. CONCLUSIONS: Among 23 identified studies evaluated for clinically relevant outcome measures, 12 studies showed one or more statistically significant, positive results, another 7 studies showed at least one positive trend, 3 showed no effect and 1 had a negative trend. All studies, however, suffered from methodological shortcomings to some degree, and many of the studies are not conclusive. As several reasonably well conducted studies indicate beneficial effects, further properly designed trials should be encouraged. Future controlled studies should take into account the methodological limitations and potential biases of these past mistletoe trials.

Anticancer Drugs. 2002 Apr;13(4):373-9. Absence of tumor growth stimulation in a panel of 16 human tumor cell lines by mistletoe extracts in vitro. Maier G, Fiebig HH.

Institute of Experimental Oncology, Oncotest GmbH, 79108 Freiburg, Germany.

Extracts of Viscum album (mistletoe) are widely used as complementary cancer therapies in Europe. The mistletoe lectins have been identified as the main active principle of mistletoe extracts. They have been shown to exhibit cytotoxic effects as well as immunomodulatory activities. The latter is exemplified by induction of cytokine secretion and increased activity of natural killer cells. Recent reports, however, indicated possible tumor growth stimulation by mistletoe extracts. Therefore, the three aqueous mistletoe extracts (Iscador M special, Iscador Qu special and Iscador P) were evaluated for antiproliferative and/or stimulatory effects in a panel of 16 human tumor cell lines in vitro using a cellular proliferation assay. The results show no evidence of stimulation of tumor growth by any of the three Iscador preparations, comprising central nervous system, gastric, non-small cell lung, mammary, prostate, renal and uterine cancer cell lines, as well as cell lines from hematological malignancies and melanomas. On the contrary, Iscador preparations containing a high lectin concentration (Iscador M special and Iscador Qu special) showed antitumor activity in the mammary cancer cell line MAXF 401NL at the 15 microg/ml dose level with a more than 70% growth inhibition compared to untreated control cells. In addition, a slight antitumor activity (growth inhibition 30-70%) was found in three tumor cell lines for Iscador M special and in seven tumor cell lines for Iscador Qu special, respectively. Iscador P, which contains no mistletoe lectin I, showed no antiproliferative activity.

Arzneimittelforschung. 1998 May;48(5):497-502.  Effects of a standardized mistletoe preparation on metastatic B16 melanoma colonization in murine lungs. Weber K, Mengs U, Schwarz T, Hajto T, Hostanska K, Allen TR, Weyhenmeyer R, Lentzen H.  RCC Research & Consulting Company Ltd., Itingen, Switzerland.

The immune response-modifying drug Lektinol is a mistletoe preparation which is standardized with respect to bioactive viscum album agglutinin, the most active component of mistletoe. The present study was designed to evaluate the antimetastatic effects of this preparation following intravenous injection of B16 melanoma cells into mice. The standardized mistletoe extract was administered intravenously in doses of 100, 1000 or 5000 microliters/kg (equivalent to 3, 30 or 150 ng/kg of viscum album agglutinin) once daily for three weeks. An inhibition of mean pulmonary metastatic colonization of 58 to 95%, as measured by the number of melanoma cells on lung tissue slides, and a significant decrease of percentage of bronchoalveolar lavage pigmented cells were observed. In addition, a correlation of this antimetastatic activity with cellular immune parameters was investigated. In lavage fluids from the tumor-bearing mice, there was a 5 to 6-fold significant increase in the percentage of MAC-1+ (CD11b/CD18) immunocompetent macrophages in comparison with cells from vehicle-treated animals. The percentages of double-positive immature CD4+8+ thymocytes were significantly increased in animals treated with the standardized mistletoe extract. There were no signs of treatment-related toxicity. The results of this study indicate that the standardized mistletoe extract shows antimetastatic activity against B16 melanoma lung colonization.

Anticancer Drugs. 1997 Apr;8 Suppl 1:S15-6. Anticarcinogenic and antimetastatic activity of Iscador.  Kuttan G, Menon LG, Antony S, Kuttan R.  Amala Cancer Research Centre, Trissur, Kerala State, India.

Methylcholanthrene-induced sarcoma formation in mice was found to be effectively inhibited by the intraperitoneal injection of mistletoe extract (Iscador M). Induction of sarcoma and sarcoma-induced death were inhibited completely at a concentration of 1 mg Iscador/dose. The concentration needed for 50% inhibition was found to be 0.0166 mg Iscador/dose. Mistletoe extract was also found to inhibit lung metastasis induced by B16F10 melanoma cells in mice. Simultaneous administration of the Viscum album extract inhibited lung nodule formation by 92.0% and produced a 71.3% increase in life span.