03 Mistletoe information

Background. In Europe, mistletoe extracts are widely used as a complementary cancer therapy. We assessed the safety of subcutaneous mistletoe as a conjunctive therapy in cancer patients within an anthroposophic medicine setting in Germany. Methods. A multicentre, observational study was performed within the Network Oncology. Suspected mistletoe adverse drug reactions (ADRs) were described by frequency, causality, severity, and seriousness. Potential risk factors, dose relationships and drug-drug interactions were investigated. Results. Of 1923 cancer patients treated with subcutaneous mistletoe extracts, 283 patients (14.7%) reported 427 expected effects (local reactions <5 cm and increased body temperature <38°C). ADRs were documented in 162 (8.4%) patients who reported a total of 264 events. ADRs were mild (50.8%), moderate (45.1%), or severe (4.2%). All were nonserious. Logistic regression analysis revealed that expected effects were more common in females, while immunoreactivity decreased with increasing age and tumour stage. No risk factors were identified for ADRs. ADR frequency increased as mistletoe dose increased, while fewer ADRs occurred during mistletoe therapy received concurrent with conventional therapies. Conclusion. The results of this study indicate that mistletoe therapy is safe. ADRs were mostly mild to moderate in intensity and appear to be dose-related and explained by the immune-stimulating, pharmacological activity of mistletoe.

Citation: Steele, M. L., Axtner, J., Happe, A., Kröz, M., Matthes, H., & Schad, F. (2014). Adverse Drug Reactions and Expected Effects to Therapy with Subcutaneous Mistletoe Extracts (Viscum album L.) in Cancer Patients. Evidence-Based Complementary and Alternative Medicine, 2014, e724258. https://doi.org/10.1155/2014/724258

Viscum album L extracts (VAE, mistletoe) and isolated mistletoe lectins (ML) have immunostimulating properties and a strong dose-dependent cytotoxic activity. They are frequently used in complementary cancer treatment, mainly to improve quality of life, but partly also to influence tumour growth, especially by injecting VAE locally and in high dosage. The question is raised whether these higher dosages can induce any harm or immunosuppressive effects.

Citation: Kienle, G. S., Grugel, R., & Kiene, H. (2011). Safety of higher dosages of Viscum album L. in animals and humans—Systematic review of immune changes and safety parameters. BMC Complementary and Alternative Medicine, 11(1), 72. https://doi.org/10.1186/1472-6882-11-72

Background: Stage IV non-small cell lung cancer (NSCLC) is associated with a five-year survival rate of around 1%. Treatment with Viscum album L. (VA) extracts has been shown to reduce chemotherapy (CTx)-related adverse events, decrease CTx dose reductions and improve quality of life in a number of cancers. Recent data suggest a beneficial effect of add-on treatment with Viscum album L. (VA, European mistletoe) on survival in cancer patients. The objective of this study was to evaluate the effect of VA in addition to chemotherapy on survival in stage IV NSCLC patients.

Methods: The observational study was conducted using data from the Network Oncology clinical registry which is an accredited conjoint clinical registry of German oncological hospitals, practitioners and out-patient centers.Patients were included if they had stage IV NSCLC at diagnosis, lived at least for four weeks post-diagnosis and received chemotherapeutic treatment. Patients with EGFR mutations as well as patients receiving tyrosine kinase inhibitors or immune checkpoint inhibitors were not included. Overall survival and impact on hazard in patients with chemotherapy (CTx) to patients receiving CTx plus VA were compared. To identify factors associated with survival and to address potential sources of bias a multivariate analyses using Cox proportional hazard model was performed.

Results: The median age of the population was 64.1 years with 55.7% male patients. The highest proportion of patients had adenocarcinoma (72.2%) and most of the patients were current or past smokers (70.9%). Of 158 stage IV NSCLC patients, 108 received CTx only and 50 additional VA. Median survival was 17.0 months in the CTx plus VA group (95%CI: 11.0–40.0) and was 8.0 months (95%CI: 7.0–11.0) in the CTx only group (?2 = 7.2, p = .007). Overall survival was significantly prolonged in the VA group (HR 0.44, 95%CI: 0.26–0.74, p = .002). One-year and three-year overall survival rates were greater with CTx plus VA compared to CTX alone (1y: 60.2% vs. 35.5%; 3y: 25.7% vs. 14.2%).

Conclusion: Our findings suggest that concomitant VA is positively associated with survival in stage IV NSCLC patients treated with standard CTx. These findings complement pre-existing knowldedge of add-on VA’s clinical impact, however, results should be interpreted with caution in light of the study’s observational character.

Citation: Schad, F., Thronicke, A., Steele, M. L., Merkle, A., Matthes, B., Grah, C., & Matthes, H. (2018). Overall survival of stage IV non-small cell lung cancer patients treated with Viscum album L. in addition to chemotherapy, a real-world observational multicenter analysis. PLOS ONE, 13(8), e0203058. https://doi.org/10.1371/journal.pone.0203058

Abstract

Background. Intratumoral (IT) injection of European mistletoe (Viscum album L) preparations might induce local tumor response through combined cytotoxic and immunomodulatory actions of the preparations. Although promising in vitro and in vivo data, along with clinical case studies suggest the need for validation of this hypothesis in prospective trials, the safety of IT mistletoe injections has yet to be thoroughly assessed. Methods. The present study summarizes the practice and safety of off-label IT mistletoe therapy within the Network Oncology, a conjoint clinical registry of German hospitals and outpatients specialized in anthroposophic and integrative medicine. Demographic, diagnosis and treatment data of cancer patients who received IT mistletoe applications between 2007 and 2013 were assessed. Suspected adverse drug reactions (ADRs) were analyzed in terms of type, frequency, severity, seriousness and potential risk factors. Results. A total of 123 cancer patients received 862 IT mistletoe injections (preparations from Abnoba, Helixor and Iscucin). The most commonly applied preparations were Abnoba viscum Fraxini (71 patients) and Helixor Mali (54 patients). Of the total patients, 26 patients (21.1%) experienced 74 ADRs. All ADRs were in response to either Abnoba viscum Fraxini (25.4% of exposed patients) or Helixor Mali (18.5% of exposed patients). ADRs were mostly body temperature or immune related and of mild (83.8%) or moderate (14.9%) intensity. Only one possible ADR was described as severe (hypertension) and no serious ADRs occurred. The frequency of ADRs to IT mistletoe injections was 3 times and 5 times higher than has previously been found for subcutaneous and intravenous applications of mistletoe, respectively. Conclusion. IT injection of mistletoe preparations resulted in a relatively high frequency of ADRs. Nearly all ADRs were mild to moderate however, and no serious ADRs occurred. Furthermore, it is possible that immune-related ADRs such as pyrexia and local inflammatory reactions might be critical for tumor response. In light of these results, IT mistletoe therapy seems to be safe and prospective trials are recommended.

Keywords: Viscum album, mistletoe, cancer, safety, adverse drug reactions, adverse events, Anthroposophic Medicine, intratumoral

Citation: Steele, M. L., Axtner, J., Happe, A., Kröz, M., Matthes, H., & Schad, F. (2015). Use and Safety of Intratumoral Application of European Mistletoe (Viscum album L) Preparations in Oncology. Integrative Cancer Therapies, 14(2), 140–148. https://doi.org/10.1177/1534735414563977

Citation: Huber, R., Schlodder, D., Effertz, C., Rieger, S., & Tröger, W. (2017). Safety of intravenously applied mistletoe extract – results from a phase I dose escalation study in patients with advanced cancer. BMC Complementary and Alternative Medicine, 17(1), 465. https://doi.org/10.1186/s12906-017-1971-1

Abstract
Objectives: Evaluate the safety and clinical response of complementary treatment with European mistletoe extracts during chemotherapy.
Design: Monocentric controlled trial with 95 patients randomized into three groups.
Settings/Location: National Cancer Research Center of Serbia.
Subjects: Breast cancer patients (stage T1–3N0–2M 0) undergoing surgery and adjuvant chemotherapy with six cycles of cyclophosphamide, adriamycin, and 5-fluorouracil.
Interventions: Two different European mistletoe extracts (Helixor A, Iscador M Spez) were injected three times per week during 18 weeks of chemotherapy in the mistletoe group. Five-year follow-up of routine visits was documented in case report forms.
Outcome measures: Safety was assessed by measuring adverse events, body temperature during chemotherapy, and probability of relapse or metastasis in a 5-year follow-up. During chemotherapy, the neutrophil count and quality of life according to EORTC QLQ-C30 were assessed.
Results: The two patient groups receiving different complementary mistletoe treatments were integrated into one mistletoe group for this safety analysis. Patients in the mistletoe group did not develop more fever symptoms than patients in the control group (two short-term events in each group). No significant differences in probability of relapse or metastasis were measured between the groups ( p = 0.7637). The mistletoe group
showed a trend toward less neutropenia ( p = 0.178) and improved pain and appetite loss scores ( p < 0.0001 and p = 0.047, respectively) while having positive, but not significant, impact on other EORTC QLQ-C30 scores.
Conclusions: Mistletoe extracts were safe in this clinical study. Neither did subcutaneous injections induce fever, nor did they influence the frequency of relapse and metastasis within 5 years. This result suggests that mistletoe extracts had no adverse interactions with the anticancer agents used in this study. Furthermore, certain side effects of chemotherapy decreased under this complementary treatment in breast cancer patients.
Keywords: mistletoe therapy, chemotherapy, breast cancer, randomized clinical trial, 5-year follow-up, safety

Citation: Pelzer, F., & Tröger, W. (2018). Complementary Treatment with Mistletoe Extracts During Chemotherapy: Safety, Neutropenia, Fever, and Quality of Life Assessed in a Randomized Study. The Journal of Alternative and Complementary Medicine, 24(9–10), 954–961. https://doi.org/10.1089/acm.2018.0159

Background: Bilateral asynchronous renal cell carcinoma (RCC) is infrequent. Immunotherapy is the first-line treatment for advanced RCC not controlled by locoregional therapy. Viscum album extracts (VAE) have been shown to improve quality of life as well as immunological and antineoplastic properties in different types of cancers. Case Report: A 67-year-old man was diagnosed with Fuhrman grade 3/4 RCC, stage pT1bN0M0 in the right kidney. During the subsequent 6 years, he underwent a right nephrectomy and two metastasectomies (lung). Then an RCC lesion of the left kidney was detected. The patient refused a second nephrectomy and was treated solely with high-dose intravenous and subsequent subcutaneous VAE. A central necrotic area and a peritumoral halo were seen on an ultrasound follow-up from month 7. The patient showed no further progression of RCC during the next 2.5 years. Conclusion: As far as we are aware of, this is the first report of a patient with metastatic RCC with an RCC lesion of the second kidney treated solely with high-dose intravenous and subcutaneous VAE, associated with 2.5 years of progression-free survival and a good quality of life. The use of VAE in RCC should be carefully documented and published to determine future research.

Key Words: Renal cell carcinoma, clear-cell, Viscum album, bilateral, asynchronous.

Citation: Reynel, M., Villegas, Y., Kiene, H., Werthmann, P. G., & Kienle, G. S. (2019). Bilateral Asynchronous Renal Cell Carcinoma With Lung Metastases: A Case Report of a Patient Treated Solely With High-dose Intravenous and Subcutaneous Viscum album Extract for a Second Renal Lesion. Anticancer Research, 39(10), 5597–5604. https://doi.org/10.21873/anticanres.13754

Background. Mistletoe therapy (MT) is widely used in patient-centered integrative cancer care. The objective of this study was to explore the concepts, procedures, and observations of expert doctors, with a focus on intravenous MT. Method. A qualitative interview study was conducted with 35 highly experienced doctors specialized in integrative and anthroposophic medicine. Structured qualitative content analysis was applied. For triangulation, the results were compared with external evidence that was systematically collected, reviewed, and presented. Results. Doctors perform individualized patient assessments that lead to multimodal treatment approaches. The underlying goal is to help patients to live with and overcome disease. Mistletoe infusions are a means of accomplishing this goal. They are applied to stabilize disease, achieve responsiveness, induce fever, improve quality of life, and improve the tolerability of conventional cancer treatments. The doctors reported long-term disease stability and improvements in patients’ general condition, vitality, strength, thermal comfort, appetite, sleep, pain from bone metastases, dyspnea in pulmonary lymphangitis carcinomatosa, fatigue, and cachexia; chemotherapy was better tolerated. Also patients’ emotional and mental condition was reported to have improved. Conclusion. Individualized integrative cancer treatment including MT aims to help cancer patients to live well with their disease. Further research should investigate the reported observations.

Citation: Kienle, G. S., Mussler, M., Fuchs, D., & Kiene, H. (2016). Intravenous Mistletoe Treatment in Integrative Cancer Care: A Qualitative Study Exploring the Procedures, Concepts, and Observations of Expert Doctors. Evidence-Based Complementary and Alternative Medicine, 2016, e4628287. https://doi.org/10.1155/2016/4628287

There is a long tradition, going back to the fourth century BC, of using mistletoe as a remedy. This evergreen plant has been used over the ages for menstruation complaints, epilepsy, ulcers, cardiac insufficiency, hypertension and oedema (Ramm 2015).

Based on research by Dr. Rudolf Steiner (1861–1925), the founder of anthroposophy, the white-berried mistletoe (Viscum album L.) was first specifically used in cancer therapy at the beginning of the 20th century. At the end of 1916, he suggested to Dr. Ita Wegman, a physician closely collaborating with him, that mistletoe has specific potential for cancer treatment. Working with an experienced pharmacist, she developed an injection preparation (Iscar), and first treated cancer patients with mistletoe in the summer of 1917 (Selg 2016) . The preparation was further developed in the following years and registered under the name ISCADOR in 1926. Today, after almost a century of clinical and practical experience, ISCADOR is the most frequently prescribed mistletoe preparation in complementary tumour therapy, with the longest and most thorough research history.

ISCADOR, which is manufactured from the leaves, stems and berries of the plant, is a fermented aqueous extract of the white-berried mistletoe (Viscum album L.) originating from the host trees of apple (ISCADOR M = Mali), oak (ISCADOR Qu = Quercus), pine (ISCADOR P = Pini) and elm (ISCADOR U = Ulmi). In Switzerland, fir mistletoe ISCADOR is also available (ISCADOR A = Abietis).

This brochure gives a full account of the constituents of mistletoe, their effects and immunological properties, and current ISCADOR study findings. ISCADOR treatment is also described here in more detail.

Breast cancer is among the most frequent types of cancer in women worldwide. Current conventional treatment options are accompanied by side effects. Mistletoe is amongst the important herbal medicines traditionally used as complementary remedies. An increasing number of studies have reported anticancer activity of mistletoe extracts on breast cancer cells and animal models. Some recent evidence suggests that cytotoxic activity of mistletoe may be mediated through different mechanisms. These findings provide a good base for clinical trials. Various studies on mistletoe therapy for breast cancer patients revealed similar findings concerning possible benefits on survival time, health-related quality of life (HRQoL), remission rate, and alleviating adverse reactions to conventional therapy. This review provides an overview of the recent findings on preclinical experiments and clinical trials of mistletoe for its cytotoxic and antitumor activity and its effect on HRQoL in breast cancer patients. Moreover, studies investigating molecular and cellular mechanisms underlying antitumor activity of mistletoe are discussed in this paper. The analyzed trials provided evidence that there might be a combination of pharmacological and motivational aspects mediated by the mistletoe extract application which may contribute to the clinical benefit and positive outcome such as improved HRQoL and self-regulation in breast cancer patients.

Citation: Marvibaigi, M., Supriyanto, E., Amini, N., Abdul Majid, F. A., & Jaganathan, S. K. (2014). Preclinical and Clinical Effects of Mistletoe against Breast Cancer. BioMed Research International, 2014, e785479. https://doi.org/10.1155/2014/785479

The importance of integrative medicine in oncological care is increasing in accordance with growth of its evidence base. In central Europe, white-berried mistletoe (Viscum album) preparations not only are among the most common types of treatments used in integrative medicine but also have been among of the most commonly prescribed cancer treatments in Germany per se in 2010 [1]. By 2017, mistletoe preparations will have been used in the treatment of cancer patients for 100 years. Mistletoe is a historic, folk remedy, but the first recorded use in oncology was by the Dutch physician Ita Wegman…

Citation: Kröz, M., Kienle, G. S., Feder, G., Kaveri, S., & Rosenzweig, S. (2014). Mistletoe: From Basic Research to Clinical Outcomes in Cancer and Other Indications. Evidence-Based Complementary and Alternative Medicine, 2014, e987527. https://doi.org/10.1155/2014/987527

From the Johns Hopkins Magazine:

In September 2008, Ivelisse Page, a 37-year-old mother of four, was diagnosed with colon cancer. Several weeks later, she had 15 inches of her colon and 28 lymph nodes removed. But in December of that same year, Page's doctor, Luis Diaz, an associate professor of oncology in the Johns Hopkins School of Medicine, had to deliver the devastating news that the cancer had spread to her liver. He told her that she had just an 8 percent chance of surviving for more than two years.

Citation: Sugarman, J. (2014). Are Mistletoe Extract Injections the Next Big Thing in Cancer Therapy? https://hub.jhu.edu/magazine/2014/spring/mistletoe-therapy-cancer/

Mistletoe extracts (Viscum album L., VAE) are among the most widely used integrative cancer care treatments, particularly in Europe [1-5]. They are an old herbal remedy [6,7] and were introduced as cancer treatment in 1920 by Rudolf Steiner and Ita Wegman, founders of Anthroposophic Medicine [8]. Viscum album is a hemiparasitic shrub, growing on different host trees. Different preparations are available for the treatment of cancer (currently Abnobaviscum ® , Helixor ® , Iscador ® , Iscucin ® and Lektinol ® ). They are available from different host trees such as oak, apple, pine and many others. They are applied parenteral, particularly subcutaneous, but also intravenous, intratumoural, intrapleural, intraperitoneal and other sites. Read more…

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.

Citation: Ostermann, T., Raak, C., & Büssing, A. (2009). Survival of cancer patients treated with mistletoe extract (Iscador): A systematic literature review. BMC Cancer, 9(1), 451. https://doi.org/10.1186/1471-2407-9-451