This article is part of the 2018 NMJ Oncology Special Issue. Download the full issue here.
Huber R, Schlodder D, Effertz C, Rieger S, Tröger W. Safety of intravenously applied mistletoe extract - results from a phase I dose escalation study in patients with advanced cancer. BMC Complement Altern Med. 2017;17(1):465.
The primary objective was to determine the maximum tolerated dose (MTD) of intravenous Helixor P. The MTD is determined by the incidence of dose-limiting toxicities (DLTs). A secondary objective was to investigate the safety and tolerability of the different doses and patients’ clinical course.
Prospective, dose-escalating phase I good clinical practice (GCP) study without a control group
Female and male patients > 18 years of age (N=21) with a histologically or cytologically confirmed diagnosis of an advanced malignant disease in an interval without antineoplastic therapies, with an Eastern Cooperative Oncology Group (ECOG) performance status 0-2 and sufficient bone marrow function
Study Medication & Dosage
Helixor P (Helixor Heilmittle GmbH, Rosenfeld: Germany) was used in a classical phase I 3 + 3 dose escalation scheme (200 mg, 400 mg, 700 mg, 1,200 mg, and 2,000 mg). If 3 patients tolerated 3 infusions of the first dose (200 mg) in weekly intervals for 3 weeks, the next 3 patients received 3 infusions of the next dose (400 mg), and so forth. Maximum planned dose was 2,000 mg.
Adverse events (AEs) were assessed based on grade of severity, causality to the study medication, clinical consequences, and outcome classified as serious (SAE) or suspected unexpected serious (SUSAR), if applicable.
Dose-limiting toxicity (DLT) was defined as a specific AE > grade 2. Grading was defined as follows:
- Grade 1: Transient rash, drug fever < 39.8°C for less than 24 hours
- Grade 2: Urticaria, and/or asymptomatic bronchospasm, drug fever > 39.8°C or drug fever > 39.5°C continuing more than 24 hours
- Grade 3: Symptomatic bronchospasm, requiring parenteral medication(s), with or without urticaria; allergy-related edema/angioedema
- Grade 4: Anaphylaxis
Dose-limiting toxicity was also defined as an unexpected increase of aminotransferase levels to > 3 times baseline levels
- MTD was not reached.
- 1 DLT was reported during a 2,000 mg infusion; 3 patients were added to the study, at this same dose, and tolerated it well.
- Weekly infusions of 2,000 mg of pine-mistletoe extract were well-tolerated and can be used in further studies.
- Use of intravenous viscum can cause allergic reactions or fever.
- 155 AEs during the trial. At least 20 of 155 AEs were mostly linked to the 2,000 mg (40,000 ng natural ML III) dose group. These were apart from an allergic reaction in 1 patient; grade 1 fever in 4 patients; weakness the day after infusion (3 patients); eosinophilia (2 patients); and slight temporary elevation of alanine aminotransferase (ALT) in 2 patients.
- Mean levels of ALT, aspartate aminotransferase (AST), and alkaline phosphatase (ALP), neutrophils, and lymphocytes were unchanged.
For several decades, extract preparations from natural mistletoe (Viscum album) have been widely used as an alternative therapy in the management of patients with malignant disease, based on presumed immunostimulatory and antineoplastic effects.
As a natural cancer therapy, mistletoe has one of the most extensive research bases. To date, there are more than 2,600 published scientific papers, over 250 of which reflect inclusion of modern North American scientific thought.1
Six serious AEs occurred during the study, and none of the 6 were attributed to the study medication.
Mistletoe preparations/extracts are most commonly administered as subcutaneous injections starting at a low dose, which is gradually increased over time based on individual responses.2 Increasingly, mistletoe preparations are also administered at high initial doses as subcutaneous injections, intravenous infusions, or intratumorally, depending on the location of the tumor, disease stage, and the experience of the physician.3 There appears to be accumulating evidence that traditional subcutaneous mistletoe therapy is safe, improves quality of life, and reduces adverse drug reactions to conventional therapies. However, the evidence regarding intravenous and intratumoral use is limited or inconclusive.
The major active constituents of natural mistletoe extracts are mistletoe lectins (MLs), which have been reported to induce apoptosis in various cancer cell lines4,5 and elicit immunomodulatory properties.6 Absorption of MLs from the gastrointestinal tract has been shown to be poor because they interact with carbohydrate residues on epithelial cells.7 Therefore, a parenteral route is of interest.
Regarding administration and dosing, the MTD of mistletoe is unknown. The authors of this study investigated the safety and tolerability of intravenous mistletoe extract. Several studies have shown that applications of 1-5 mg were safe and tolerable when given intravenously.6
In general, the investigators of the current study report mistletoe (Helixor P) was well-tolerated, with minimal AEs at a dose of 2,000 mg per week for 9 weeks. A review of literature supports the use of mistletoe having minimal AEs when given subcutaneously or orally.8-11 Some side effects are common, but most are minor, dose-dependent, and subside on their own within a few days after treatment. Common side effects for subcutaneous administration include local reactions at the injection site (eg, swelling, redness, local pain, itchiness, rash, warmth), fatigue, mild flu-like symptoms, anemia, fever, and diarrhea.12-14
Six serious AEs occurred during the study, and none of the 6 were attributed to the study medication. Reasons included progression of disease or other events (eg, hospital admission because of dyspnea due to pulmonary metastasis) that were not drug-related.
Adverse events from intravenous mistletoe administration have been documented through case reports, case series, and other clinical studies, but serious AEs are rare. Reported AEs include urticaria and angioedema,15 hypotension and loss of consciousness,16 anaphylaxis,17 fever,18 hyper-eosinophilia,19 severe delayed type hypersensitivity reaction,20 and liver toxicity.
The authors were unable to define an MTD, due to European Pharmacopeia regulations, but they were able to ascertain that a predefined maximum dose of 2,000 mg has a certain risk of allergic reactions, provokes short-term (< 12 h) elevated body temperature and does not seem to have bone marrow or other organ toxicity.
While this study does address some of the questions around intravenous administration of mistletoe extracts, a concern that is often raised is the potential for interactions with conventional chemotherapy drugs and/or radiation. As part of the exclusion criteria of this study, none of the participants were undergoing chemotherapy or radiation therapy. There is evidence that the risk of chemotherapy-associated AEs might be reduced if patients are treated with subcutaneous mistletoe alongside chemotherapy.21,22 Furthermore, there is a small evidence base that suggests intravenous application of Viscum album has significant beneficial effects with respect to chemotherapy-related side effects (ie, nausea, constipation, pain, stomatitis, appetite),23 and improved quality of life.8
Given the promising safety profile, possible clinical anticancer effects, and extensive research base supporting the use of mistletoe, the parenteral application of mistletoe deserves future investigation.
- Stengler M, Anderson P. Outside the Box Cancer Therapies: Alternative Therapies That Treat and Prevent Cancer. Carlsbad, CA: Hay House; 2018: 179-180.
- Steele ML, Axtner J, Happe A, Kroz M, Matthes H, Schad F. Evid Based Complement Alternat Med. 2014;2014:236310.
- Kroz M, Kienle G, Feder G, Kaveri S, Rosenzweig S. Mistletoe: from basic research to clinical outcomes in cancer and other indications. Evid Based Complement Alternat Med. 2014;2014:987527.
- Huber R, Rostock M, Goedl R, et al. Mistletoe treatment induces GM-CSF and IL-5 production by PBMC and increases blood granulocyte and eosinophil counts: a placebo controlled randomized study in healthy subjects. Eur J Med Res. 2005;10(10);411-418.
- Huber R, Ludtke H, Wieber J, Beckmann C. Safety and effects of two mistletoe preparations on production of Interleukin-6 and other immune parameters- a placebo controlled clinical trial in healthy subjects. BMC Complement Altern Med. 2011;11 (1): 116.
- Elluru S, Duong van Huyen J, Delignat S, et al. Induction of maturation and activation of human dendritic cells: a mechanism underlying the beneficial effect of Viscum album as complimentary therapy in cancer. BMC Cancer. 2008;8:161.
- Bussing A. Biological and pharmacological properties of Viscum album L. In: Mistletoe: The Genus Viscum. London, England: CRC Press; 2000:123-182.
- Horneber M, Bueschel G, Huber R, Linde K, Rostock M. Mistletoe therapy in oncology. Cochrane Databas Syst Rev. 2008;2:CD003297.
- Kienle GS, Kiene H. Complementary cancer therapy: a systematic review of prospective clinical trials on anthroposophic mistletoe extracts. Eur J Med Res. 2007;12(3):103-119.
- Kienle G, Kiene H. Review article: influence of Viscum album L (European mistletoe) extracts on quality of life in cancer patients: a systematic review of controlled clinical studies. Integr Cancer Ther. 2010;9(2):142-157.
- Kienle G, Grugel R, Kiene H. Safety of higher dosages of Viscum album L. in animals and humans--systematic review of immune changes and safety parameters. BMC Complement Altern Med. 2011;11(1):72.
- Schöffski P, Riggert, S, Fumoleau P, et al. Phase I trial of intravenous aviscumine (rViscumin) in patients with solid tumors: a study of the European Organization for Research and Treatment of Cancer New Drug Development Group. Ann Oncol. 2004;15(12):1816-1824.
- Eisenbraun J, Scheer R, Kröz M, Schad F, Huber R. Quality of life in breast cancer patients during chemotherapy and concurrent therapy with a mistletoe extract. Phytomedicine. 2011;18 (2):151-172.
- Hutt N, Kopferschmitt-Kubler M, Cabalion J, Purohit A, Alt M, Pauli G. Anaphylactic reactions after therapeutic injection of mistletoe (Viscum album L.). Allergol Immunopathol (Madr). 2001;29(5);201-203.
- Kienle G, Glockmann A, Schink M, Kiene H. Viscum album L. extracts in breast and gynaecological cancers: a systematic review of clinical and preclinical research. J Exp Clin Cancer Res. 2009;28:79.
- Hutt N, Kopferschmitt-Kubler M, Cabalion J, Purohit A, Alt M, and Pauli G.“Anaphylactic reactions after therapeutic injection of mistletoe (Viscum album L.),” Allergol et Immunopathol, vol. 29, no. 5, pp. 201–203, 2001.
- Bauer C, Oppel T, Rueff F, Przybilla B. Anaphylaxis to viscotoxins of mistletoe (Viscum album) extracts. Ann Allergy Asthma Immunol. 2005;94(1):86-89.
- Schlappi M, Ewald C, Kuehn J, Weinert T, Huber R. Fever therapy with intravenously applied mistletoe extract for cancer patients: a retrospective study. Integr Cancer Ther. 2017;16(4):479-484.
- Huber R, Barth H, Schmitt-Graff A, Klein R. Hypereosinophilia induced by high-dose intratumoral and peritumoral mistletoe application to a patient with pancreatic carcinoma. J Altern Complement Med. 2000;6(4):305-310.
- Shaw H, Hobbs K, Seewaldt V, Kroll D. Delayed-type hypersensitivity reaction with iscador m given in combination with cytotoxic chemotherapy. J Clin Oncol. 2004;22(21): 4432-4433.
- Bock P, Friedel W, Hanisch J, Karasmann M, Schneider B. Efficacy and safety of long-term complementary treatment with standardized European mistletoe extract (Viscum album L.) in addition to the conventional adjuvant oncologic therapy in patients with primary non-metastasized mammary carcinoma [in German]. Arzneimittelforschung. 2004;54(8):456-466.
- Piao B, Wang Y, Xie G, et. al. 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. Anticancer Res. 2004;24(1):303-309.
- Bussing A, Bischof M, Hatzmann W, et al. Prevention of surgery-induced suppression of granulocyte function by intravenous application of a fermented extract from Viscum album L. in breast cancer patients. Anticancer Res. 2005; 25(6C):4753-4758.