Can Standardized Plant Extracts Induce Complete Remission in Patients with Metastatic Tumors? Tibor Hajtó1*, András Adámy1, Lilla Baranyai1, Zoltán Langmár2, Angelika Kirsch3, Monika Kuzma1, Lajos Ábrahám4 and Perjési Pál1
1Institute of Pharmaceutical Chemistry, Medical University Pecs, Hungary 22nd Department of Gynecology, Semmelweis University, Budapest, Hungary
Abstract Background: The prognostic significance of malignant tumor-induced imbalance in the innate immune system is well known. The innate system uses a limited number of Pattern Recognition Receptors (PRR) to recognize conserved Pathogenic Associated Molecular Pattern (PAMP) structures expressed by microbes but not by host. PRR engagement often leads to the activation of natural immune cells which are important in the tumor defense. Growing evidence supports the hypothesis that similar to microbes various plant extracts can also contain PAMP-like structures which can activate cellular immune functions. Since the chemical production of PAMP structures is hardly accomplishable, the phytotherapy may be promising for the future tumor therapy. Objectives: The aim of this article is to present and discuss several favorable clinical responses of tumor patients treated with immunologically effective and standardized plant extracts (containing PAMP-like structures) as an addition to the conventional oncologic therapy.
Course of therapy and results: Two standardized plant preparations based on lectin-sugar interactions were the patients given. The dose of the active sugar-binding mistletoe lectin (ML), applied subcutaneously by standardized mistletoe extract (ME) preparations, was between 0.5 and 1.0 ng/kg and the dose of arabinoxylan (given by standardized rice bran preparation, MGN-3/Biobran) was between 12 and 45mg/kg twice a week. In addition, wheat germ extract (WGE) standardized for 2, 6-dimethoxy-p-benzoquinone (50-80 mg/kg Avemar four times a week) was also given which can sensitize tumor cells against natural immune effector cells. Case reports gave an account of complete or nearly complete remissions in patients with sarcoma or with hepatic metastases treated with these standardized plant immunomodulators with and without conventional oncologic therapy.
Conclusion:Standardized plant extracts (such as ME/ML, MGN-3 and WGE) seem to be potent candidates to be regarded as a supportive therapy of metastatic tumors.
Phase II study of viscum fraxini-2 in patients with advanced hepatocellular carcinoma M Mabed1, L El-Helw1 and S Shamaa1
1Hematology and Medical Oncology Unit, Faculty of Medicine, Mansoura University, Mansoura, Egypt
Abstract Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Although a wide range of therapeutic options is available, the efficacy of these methods and the prognosis of patients with HCC remain very poor. This study was conducted to evaluate the efficacy and safety of viscum fraxini-2 in patients with chemotherapy–naïve, advanced hepatocellular carcinoma. 23 patients with unrespectable HCC who had received no prior systemic chemotherapy with objectively measurable tumors were enrolled on this study. The mistletoe preparation for the study is an aqueous injectable solution. It contains one milliliter of viscum fraxini in dilution stage–2 (15 mg extract of 20 mg mistletoe herb from ash tree, diluted in di-natrium-mono-hydrogen phosphate, ascorbic acid and water) which is equivalent to 10 000 ng/ml injection ampoules. 2 ampoules of viscum fraxini–2 were administered subcutaneously once weekly. As assessed by conventional imaging criteria, 3 (13.1%) patients have achieved complete response, 2 (8.1%) patients have achieved a partial response. 9 (39.1%) had progressive disease while 9 (39.1%) patients didn't have evaluation of response due to early death. The median overall survival time for all patients was 5 months (range 2–38 months), for those who achieved a CR was 29 months (range 12–38 months) and, for those who achieved a PR was 6.5 months (range 6–7 months). The median progression free survival for all patients was 2 months (range 1–38 months), for those who achieved a CR, it was 29 months (range 8–38 months) and for those who achieved a partial response, it was 5 months (range 4–6 months). No hematologic toxicity has been encountered. The spectrum of non-hematologic toxicity was mild. The WHO toxicity criteria grade 3–4 were 34.8% drug related fever, 13.1% erthyma at injection site and 17.4% pain at the site of injection. No drug related discontinuation or toxic deaths have occurred. Viscum fraxini-2 seems to be particularly promising in patients with advanced HCC, it shows antitumor activity and low toxicity profile. Further studies in combination with other active agents are clearly warranted.
Survival of cancer patients treated with mistletoe extract (Iscador): a systematic literature review. Ostermann T, Raak C, Büssing A.
Abstract BACKGROUND: In Europe, extracts from Viscum album (VA-E), the European white-berry mistletoe, are widely used to treat patients with cancer.
METHODS: We searched several databases such as Cochrane, EMBASE, NCCAM, NLM, DIMDI, CAMbase, and Medline. Inclusion criteria were controlled clinical studies on parameters associated with survival in cancer patients treated with Iscador. Outcome data were extracted as they were given in the publication, and expressed as hazard ratios (HR), their logarithm, and the respective standard errors using standard formulas.
RESULTS: We found 49 publications on the clinical effects of Iscador usage on survival of cancer patients which met our criteria. Among them, 41 studies and strata provided enough data to extract hazard ratios (HR) and their standard errors (Iscador versus no extra treatment). The majority of studies reported positive effects in favour of the Iscador application. Heterogeneity of study results was moderate (I2 = 38.3%, p < 0.0001). The funnel plots were considerably skewed, indicating a publication bias, a notion which is corroborated by statistical means (AC = -1.3, CI: -1.9 to -0.6, p <= 0.0001). A random effect meta-analysis estimated the overall hazard ratio at HR = 0.59 (CI: 0.53 to 0.66, p < 0.0001). Randomized studies showed less effects than non-randomized studies (ratio of HRs: 1.24, CI: 0.79 to 1.92, p = 0.35), and matched-pair studies gave significantly better results than others (ratio of HRs: 0.33; CI: 0.17 to 0.65, p = 0.0012).
CONCLUSIONS: Pooled analysis of clinical studies suggests that adjuvant treatment of cancer patients with the mistletoe extract Iscador is associated with a better survival. Despite obvious limitations, and strong hints for a publication bias which limits the evidence found in this meta-analysis, one can not ignore the fact that studies with positive effects of VA-E on survival of cancer patients are accumulating. Future studies evaluating the effects of Iscador should focus on a transparent design and description of endpoints in order to provide greater insight into a treatment often being depreciated as ineffective, but highly valued by cancer patients.
Source : Center for Integrative Medicine, Faculty of Medicine, University of Witten/Herdecke, Herdecke, Germany Link to full Article
USE OF ISCADOR, AN EXTRACT OF EUROPEAN MISTLETOE (VISCUM ALBUM), IN CANCER TREATMENT: PROSPECTIVE NONRANDOMIZED AND RANDOMIZED MATCHED-PAIR STUDIES NESTED WITHIN A COHORT STUDY Ronald Grossarth-Maticek, Prof Dr med, Dr phil, Helmut Kiene, Dr med, Stephan M. Baumgartner, Dr sc nat, and Renatus Ziegler, Dr rer nat
Context In anthroposophical medicine, total extracts of Viscum album (mistletoe) have been developed to treat cancer patients. The oldest such product is Iscador. Although Iscador is regarded as a complementary cancer therapy, it is the most commonly used oncological drug in Germany. Objective To determine whether Iscador treatment prolongs survival time of patients with carcinoma of the colon, rectum, or stomach; breast carcinoma with or without axillary or remote metastases; or small cell or nonÐsmall-cell bronchogenic carcinoma; and to explore synergies between Iscador treatment and psychosomatic self-regulation. Design Prospective nonrandomized and randomized matched-pair studies nested within a cohort study. Setting General community in Germany. Participants 10226 cancer patients involved in a prospective longterm epidemiological cohort study, including 1668 patients treated with Iscador and 8475 who had taken neither Iscador nor any other mistletoe product (control patients). Intervention Iscador. Main Outcome Measure Survival time.
Conclusion Mistletoe extracts, which contain a complex of oncologically rellevant active substances and exe rt a variety of anticancer effects, appear to prolong surv i val times in patients with various tumor types. In the studies described here, efficacy was observed in patients with rectum carcinoma, colon carcinoma, stomach carcinoma, breast carcinoma (with or without axillary metastases or remote metastases), and small cell and non-small-cell bronchogenic carcinoma. The study findings support the claim of anthroposophical medicine that mistletoe therapy is generally effective for treating cancer, irrespective of tumor type.2 8 Iscador treatment seems to exert general oncologicaleffects that are not confined to specific tumor cells. An important effect of Iscador, according to our findings, is that it can enhance patients self-regulation.
Quality of Life and Related Dimensions in Cancer Patients Treated with Mistletoe Extract (Iscador): A Meta-Analysis Arndt B¨ussing, Christa Raak, and Thomas Ostermann
Center for IntegrativeMedicine, Faculty of Health, University of Witten/Herdecke, Gerhard-Kienle-Weg 4, 58239 Herdecke, Germany
Abstract The aim of this meta-analysis was to determine the effectiveness of the fermented plant extract Iscador, produced from the white-berry European mistletoe, in the treatment of patients with cancer with respect to quality-of-life- (QoL-) associated measures.
Methods.We searched databases such as PubMed/Medline, Excerpta Medica Database (EMBASE), CAMbase, and other for controlled clinical studies on parameters associated with QoL. Outcome data were extracted and converted into standardized mean differences and their standard errors.
Results. Thirteen prospective and controlled studies which met the inclusion/exclusion criteria reported positive effects in favor of the Iscador application. A random-effect meta-analysis estimated the overall treatment effect at standardized mean difference = 0.56 (CI: 0.41 to 0.71, P < .0001). However, the methodological quality of the studies was poor.
Conclusions. The analyzed studies give some evidence that Iscador treatment might have beneficial short-time effects on QoL-associated dimensions and psychosomatic self-regulation
Source : Evidence-Based Complementary and Alternative Medicine Volume 2012, Article ID 219402 Link to Full Article
Review Article: Influence of Viscum album L (European Mistletoe) Extracts on Quality of Life in Cancer Patients: A Systematic Review of Controlled Clinical Studies
Gunver S. Kienie, MD, Helmut Kiene, MD Institute for Applied Epistemology and Medical Methodology, Freiburg, Germany Objective. To evaluate controlled clinical studies on the efficacy and effectiveness of Viscum album for quality of life (QoL) in cancer.
Materials and methods. The authors conducted a search of 7 electronic databases and reference lists and had extensive consultations with experts. They carried out a criteria-based assessment of methodological study quality.
Results. The authors identified 26 randomized controlled trials (RCTs) and 10 non-RCTs that investigated the influence of V album extracts (VAEs) on QoL in malignant diseases; 26 studies assessed patient-reported QoL. Questionnaires were mostly well established and validated. Half of the studies investigated VAEs concomitant with chemotherapy, radiotherapy, or surgery. Some studies were well designed, whereas others had minor or major methodological weaknesses. Among the 26 RCTs, 22 reported a QoL benefit, 3 indicated no difference, and 1 did not report any result. All the non-RCTs reported a QoL benefit. Of the studies with higher methodological quality, most reported a benefit, whereas 1 found no difference. Improvements were mainly in regard to coping, fatigue, sleep, exhaustion, energy, nausea, vomiting, appetite, depression, anxiety, ability to work, and emotional and functional well-being in general and, less consistently, in regard to pain, diarrhea, general performance, and side effects of conventional treatments. VAEs were well tolerated.
Conclusions. VAEs seem to have an impact on QoL and reduction of side effects of conventional therapies (chemotherapy, radiation) in experimental trials as well as in routine daily application. The influence on fatigue especially should be investigated further.
Viscum album L. extracts in breast and gynaecological cancers: a systematic review of clinical and preclinical research Gunver S Kienle,1 Anja Glockmann,1 Michael Schink,2 and Helmut Kiene11Institute for Applied Epistemology and Medical Methodology, Zechenweg 6, D-79111 Freiburg, Germany2Verein Filderklinik e.V, Research Department, Im Haberschlai 7, D-70794 Filderstadt, Germany
Background Breast and gynaecological cancers (i.e. ovarian, endometrial, cervical, vaginal, vulval, and fallopian cancers) account for a significant amount of morbidity and mortality in women. In Europe an estimated 429,900 cases were diagnosed as breast cancer in 2006 (13.5% of all cancer cases) and 131,900 died from it, despite substantially improved treatment options (surgery, chemotherapy, radiation, hormonal and targeted therapies) . Of female cancer survivors more than half had suffered from breast or gynaecological cancer . 40% to 80% of these patients use complementary therapies additionally to well-established treatments [3-8]. This includes a variety of medicinal plants, but also acupuncture, psychosocial support, yoga, art therapies and others. These are supportive measures to control symptoms, improve quality of life, boost the immune system, and possibly prolong life. Sufficient evaluation is often lacking, however, of the extent to which these therapeutic goals are achieved, as well as of issues relating to safety and mode of action. Medicinal plants in particular have a long history in the treatment of cancer and other conditions connected with tumours, and also play a major role in the development of new drugs today. Over 60% of currently used anti-cancer agents originally derive from natural sources such as plants, marine organisms and microorganisms .
Across Europe, Viscum album L. extracts (VAE or European mistletoe, not to be confused with the Phoradendron species or "American mistletoe") are among the most common herbal extracts applied in cancer treatment [3,7,8,10]. Viscum album is a hemi-parasitic shrub and contains a variety of biologically active compounds. Mistletoe lectins (ML I, II and III) have been most thoroughly investigated. MLs consist of two polypeptide chains: a carbohydrate-binding B-chain that can bind on cell surface receptors, which enables the protein to enter the cell [11-13]; and the catalytic A-chain which can subsequently inhibit protein synthesis, due to its ribosome-inactivating properties, by removing an adenine residue from the 28S RNA of the 60S subunit of the ribosome . Other pharmacologically relevant VAE compounds are viscotoxins and other low molecular proteins, VisalbCBA (Viscum album chitin-binding agglutinin) , oligo- and polysaccharids [15,16], flavonoids , vesicles , triterpene acids , and others [20,21]. Whole VAE as well as several of the compounds are cytotoxic and the MLs in particular have strong apoptosis-inducing effects [22-24]. MLs also display cytotoxic effects on multidrug-resistant cancer cells (e.g. MDR+ colon cancer cells ) and enhance cytotoxicity of anticancer drugs [26,27]. In mononuclear cells VAE also possess DNA-stabilizing properties. VAE and its compounds stimulate the immune system (in vivo and in vitro activation of monocytes/macrophages, granulocytes, natural killer (NK) cells, T-cells, dendritic cells, induction of a variety of cytokines such as IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, GM-CSF, TNF-α, IFN-γ (overview see [20,21]). The cytotoxicity of human natural and lymphokine-activated killer cells, for instance, can be markedly enhanced in vitro by VAE rhamnogalacturonans, which bridge these killer cells with NK-sensitive or insensitive tumour cells [28,29]. Furthermore, VAE seem to interfere with tumoural angiogenesis [30,31]. Injected into tumour-bearing animals, VAE and several of their compounds (MLs, a 5 kDa protein not specified further, protein complexes isolated by Vester and colleagues, oligosaccharids) display growth-inhibiting and tumourreducing effects [20,21]. Despite extensive experimental analyses of their biological properties, many questions regarding the precise mode of action of VAE still remain.
For clinical application VAE are made from mistletoes grown on different host trees [Host trees of VAE: Fir (Abies, A); maple (Acer, Ac); almond tree (Amygdalus, Am); birch (Betula, B); whitethorn (Crataegus, C); ash tree (Fraxinu , F); appletree (Malus, M); pine (Pinus, P); poplar (Populus, Po); oak (Quercus, Qu); willow (Salix, S); lime (Tilia, T), elm (Ulmus, U)], either by aqueous extraction, partly combined with fermentation, or by pressing procedures. Depending on host tree, harvesting time and extraction procedure, VAE vary in regard to their active compounds and biological properties. Different commercial VAE preparations are available, and a recombinant ML (rML) drug is currently being developed and tested in clinical trials [32,33]. Clinical effects of VAE in cancer have been investigated in a variety of studies and assessed in systematic reviews [34-39]. These reviews, however, had inconsistent results, they are outdated, incomplete or concentrate on partial aspects. No review has yet assessed clinical and preclinical effects specifically and comprehensively for breast and gynaecological cancer, although there is widespread usage in these patients [3,7]. Our primary aim was therefore to assess the potential therapeutic effectiveness of VAE, and their potential biological effects on breast and gynaecological cancer in clinical and preclinical studies.
Methods: Systematic review to evaluate clinical studies and preclinical research on the therapeutic effectiveness and biological effects of VAE on gynaecological and breast cancer. Search of databases, reference lists and expert consultations. Criteria-based assessment of methodological study quality. Results: 19 randomized (RCT), 16 non-randomized (non-RCT) controlled studies, and 11 singlearm cohort studies were identified that investigated VAE treatment of breast or gynaecological cancer. They included 2420, 6399 and 1130 patients respectively. 8 RCTs and 8 non-RCTs were embedded in the same large epidemiological cohort study. 9 RCTs and 13 non-RCTs assessed survival; 12 reported a statistically significant benefit, the others either a trend or no difference. 3RCTs and 6 non-RCTs assessed tumour behaviour (remission or time to relapse); 3 reported statistically significant benefit, the others either a trend, no difference or mixed results. Quality of life (QoL) and tolerability of chemotherapy, radiotherapy or surgery was assessed in 15 RCTs and 9 non-RCTs. 21 reported a statistically significant positive result, the others either a trend, no difference, or mixed results. Methodological quality of the studies differed substantially; some had major limitations, especially RCTs on survival and tumour behaviour had very small sample sizes. Some recent studies, however, especially on QoL were reasonably well conducted. Single-arm cohort studies investigated tumour behaviour, QoL, pharmacokinetics and safety of VAE. Tumour remission was observed after high dosage and local application. VAE application was well tolerated. 34 animal experiments investigated VAE and isolated or recombinant compounds in various breast and gynaecological cancer models in mice and rats. VAE showed increase of survival and tumour remission especially in mice, while application in rats as well as application of VAE compounds had mixed results. In vitro VAE and its compounds have strong cytotoxic effects on cancer cells.
Conclusion: VAE shows some positive effects in breast and gynaecological cancer. More research into clinical efficacy is warranted