February, 2014 |572
Improving Outcomes In Complementary Cancer Care
Mistletoe therapy is an herbal medicine best known for its role in complementary cancer care. Pioneered by Rudolf Steiner, mistletoe, also known as Viscum album L or European mistletoe, has its roots in anthroposophic medicine; today there is a large body of evidence supporting use of mistletoe injection therapy as an adjunctive cancer treatment. Lectins and viscotoxins found in mistletoe appear to be responsible for its antitumor and immune stimulating effects. Mistletoe therapy has been investigated for its effects on survival, quality of life, and tolerability of chemotherapy/ side effects associated with chemotherapy. Meta analyses and systematic reviews have demonstrated a survival benefit associated with use of mistletoe injection therapy alongside chemotherapy or as a supportive therapy. There is also a large body of evidence indicating that mistletoe therapy improves quality of life, with improvements in global quality of life as well as symptoms such as fatigue, nausea and vomiting, pain, sleep disturbances, loss of appetite, and constipation found in a preliminary study. Finally, mistletoe therapy appears to reduce side effects of chemotherapy without decreasing its effectiveness. This article will summarize the history of mistletoe therapy and assess the current evidence surrounding its use in the area of oncology, including breast, lung, and pancreatic cancers to name a few.
Mistletoe therapy is a leading complementary or adjunctive cancer therapy, widely used by naturopathic doctors and medical doctors working in integrative oncology, with known immune stimulatory and antitumor effects. Today an advanced therapy most often administered as a subcutaneous injection, mistletoe has a long history of use and has undergone considerable development over that period of time.
Historically, mistletoe (Viscum album L, European mistletoe) has its roots in German anthroposophic medicine, developed by Rudolf Steiner (1861-1925) (Bar-Sela 2011). This system of medicine sought to “acknowledge a spiritual-existential dimension in humanity” (Hamre 2009) and its interaction with physical health and disease (Hamre 2009, Horneber 2010). Initially, mistletoe therapy was used in the treatment of menstrual disorders, epilepsy, high blood pressure, artherosclerosis, diabetes, asthma, migraines, neuralgias, haemorrhages, endometriosis, eczema, foot ulcers, and labour pains (Bar-Sela 2011, Ostermann 2009). In 1920, Steiner introduced mistletoe extract as a treatment for cancer, recommending an extract produced through a complex preparation method that combined sap from mistletoe harvested in the summer and in the winter (Ostermann 2009). Based on this, mistletoe therapy has been used as a cancer therapy for almost a century. During this time, additional types of extracts have been developed, and are in use today. Presently, mistletoe therapy enjoys a prominent role in complementary cancer therapy, and is the subject of a wealth of research evaluating its impact on cancer treatment outcomes including survival, side effects of chemotherapy, and quality of life. This paper will examine the current use of mistletoe therapy in oncology and discuss the research relating to its effects on cancer related outcomes.
Sources and extracts
European mistletoe (Viscum album, L) is a partially woody, semi-parasitic plant that grows on deciduous and coniferous trees including pine, apple, oak and spruce (Kelter 2007, Melzer 2009). The medicinal parts are the stems, including the sap, and the leaves (Melzer 2009). Mistletoe extracts vary according to the type of plant material used, extraction method, as well as the type of tree that the mistletoe used grows on. The host tree that the product is derived from is denoted by a suffix at the end of the preparation name, for instance, Helixor-M is from mistletoe growing on the apple tree (Malus). Older, anthroposophic extracts are produced through a standardized manufacturing method but are not standardized to their constituents; while newer, “phytotherapeutic” extracts are standardized to their mistletoe lectin (ML-1) content (Melzer 2009). For instance, Eurixor is reported to contain between 50-70ng ML-1 per mL (NCI 2013). Helixor is standardized to its biological activity: degree of cytotoxic effects against a specific leukemia cell line. Iscador may contain between 0.0001–20 mg per mL, however this content refers to the amount of plant material rather than specific constituents such as lectins (Mistel-therapie 2014). The best-known extracts in North America are Helixor and Iscador. Helixor is a cold-water extract, while Iscador is a fermented extract of fresh leafy shoots and fruits harvested in the summer and winter (Ostermann 2009). Other commercially available extracts include Abnoba, Isorel, and Iscucin. Iscucin is produced in accordance with the German Homeopathic Pharmacopoeia. Phytotherapeutic extracts include Eurixor and Lektinol. Table 1 compares the characteristics of selected mistletoe extracts (adapted from Melzer 2009).
European mistletoe contains many constituents, including lectins, viscotoxins, amino acids, flavonoids, phenylpropanoids, triterpenes, phytosterol, alkaloids, polyalcohols, and polysaccharides (Melzer 2009). The active components thought to be responsible for mistletoe’s antitumor effects are mistletoe lectins (ML), and less so, viscotoxins. Lectins are glycoproteins capable of binding to the outside of cells (NCI 2013). Three classes of lectins have been identified: ML-I, ML-II, and ML-III depending on what type of surface molecule they bind (Melzer 2009). Lectins possess direct cytotoxic effects, inhibiting protein synthesis and triggering apoptosis, as well as indirect antitumor effects through stimulation of cytokine release, and increasing NK cell and macrophages activity (Bar-Sela 2011, Kelter 2007). Viscotoxins are small polypeptides related to thionins and have cytotoxic effects (Bar-Sela 2011, Melzer 2009). Viscotoxins possess immunogenic effects, inducing production of anti-viscotoxin antibodies and causing rapid lysis of the cell membrane; and enhance cytotoxic T-cell activity, oxidative granulocyte bursting, and phagocytosis (Bar-Sela 2011, Klein 2002). Viscotoxins also inhibit cell division through inhibition of DNA and RNA synthesis (Bar-Sela 2011).
Tumour Cell Growth
Mistletoe therapy has been shown to inhibit tumour cell growth independently as a monotherapy as well as when used in conjunction with chemotherapy. This is effected both by direct cytotoxic effects mediated by the lectin- and viscotoxin- components as described above, as well as indirectly through immune stimulation (Bar-Sela 2011). Mistletoe therapy inhibits cell cycle progression, and induces tumour cell apoptosis and removal through phagocytosis (Friedel2009). We describe two case reports of mistletoe therapy as monotherapy, followed by stronger evidence for its use as an adjunctive treatment alongside chemotherapy. Two case reports describe decreases in tumour size in response to intratumoral mistletoe injections among patients not undergoing chemotherapy (Orange 2010). A patient diagnosed with Merkel cell cancer was treated with subcutaneous and intravenous mistletoe therapy over a period of 9.8 months, during which the patient received no other anti-cancer treatment (Orange 2010). A second patient diagnosed with bilateral breast cancer, who declined cancer staging and surgical treatment, received subcutaneous and intratumoral mistletoe injections over a period of 31 months. Both patients experienced complete and durable remissions following use of mistletoe as a monotherapy (Orange 2010). A much higher grade of evidence, a 2008 Cochrane review, analyzed twenty-one studies of mistletoe therapy in adult patients with cancer (Horneber 2008). Of these 21 studies, seven provided data on tumour response. Two of seven studies demonstrated additive benefit associated with combined mistletoe plus chemotherapy, compared to chemotherapy alone (Borrelli 2001, Lange 1993). The remaining five studies failed to demonstrate significant benefit on antitumor response compared to standard care alone, however there was no evidence of harm (Horneber 2008).
Data from several systematic reviews and meta-analysis indicate that mistletoe therapy has a survival benefit (Horneber 2008, Kienle 2009, Ostermann 2009, Ostermann 2012). These studies are summarized in Table 2. Ostermann et al performed two systematic reviews and meta analyses including over 50 studies and concluded that mistletoe therapy in addition to standard care resulted in approximately 40% improved survival, compared to standard care alone: HR 0.59 (95%CI 0.53- 0.66 and 0.50-0.70), where HR Preparation Method Host tree Harvest Administration Dosage Standardization Anthroposophic extracts Helixor aqueous (herb) apple (M:Malus) fir (A: Abies) pine (P: Pinus) summer and winter SC 0.01–50 mg/amp (1 ml); or 100 mg (2 ml) process Iscador aqueous lacto-fermented (herb) M,A,P, elm (U: Ulmus) oak (Q: Quercus) summer and winter SC 0.0001–20 mg per amp (1 ml) process Isorel aqueous (whole plant) M, A, P summer and winter SC, IM 1–60 mg process Phytotherapeutic extracts Eurixor aqueous (herb) poplar winter SC, IC, IV 1mg or 70ng per amp (1 ml) ML-I Lektinol aqueous (herb) poplar winter SC, IV 0.02–0.07 mg or 15 ng per amp (0.5 ml) ML-I Table 1. Characteristics of Select Mistletoe Extracts (adapted from Melzer 2009) Legend: amp ampoule; IC intracoelomic (in the abdominal cavity); IM intramuscular; IV intravenous; ML mistletoe lectins; SC subcutaneous Mistletoe RM.indd 75 14-02-18 9:35 AM 76 www.ihpmagazine.com l February / March 2014 <1.0 favours mistletoe (2009, 2012). There was evidence of publication bias, undermining the strength of these findings, however these are nonetheless notable findings. A third, 2009 systematic review assessing the effectiveness of mistletoe in 19 RCTs, 16 non- randomized studies, and 11 cohort studies of patients with breast or other gynaecological cancer found that 12 of 22 studies showed significant benefits on survival, and three of nine studies showed significant benefits for remission or time to relapse (Kienle 2009). Finally, the 2008 Cochrane review included twenty-one studies, of which thirteen evaluated survival as an endpoint (Horneber 2008). Six of these 13 studies showed a survival benefit associated with mistletoe therapy, although it was noted that they lacked methodological rigor. Collectively, the weight of data from these reviews suggests that despite certain limitations in the literature, mistletoe may have clinically important anticancer effects.
A 2013 randomized controlled trial recently assessed mistletoe therapy in 72 patients with advanced non-small-cell lung cancer (NSCLC) (Bar-Sela 2013). All patients received chemotherapy with carboplatin plus gemcitabine or pemetrexed, and were then randomized to receive either mistletoe or no additional treatment. Iscador was dosed three times weekly until progression. This study found a non-significant improvement in time to tumour progression and overall survival associated with mistletoe therapy. Time to tumour progression was 6.0 months in the mistletoe group compared to 4.8 months in the control group. Overall survival (OS) was 15.9 months in the mistletoe group compared to 13.3 months in the control group. Importantly, fewer patients in the mistletoe group required chemotherapy dose reductions (13% versus 44%, p=0.005), experienced grade 3-4 non-haematological toxicities (16% versus 41%, p=0.043), or had hospitalizations (24% versus 54%, p=0.016).
Another recently published randomized controlled trial assessed overall survival among 220 patients with advanced pancreatic cancer not receiving other cancer therapy (Troger 2013). Patients were randomized to treatment with mistletoe or no treatment, although both groups received the best available supportive care. Mistletoe was dosed subcutaneously three times per week, with the primary endpoint being overall survival (OS) at 12 months. At the time of this writing, interim results are available, showing median OS as 4.8 months for the mistletoe group, compared to 2.7 months for control patients (prognosis-adjusted hazard ratio, HR 0.49, p<0.0001). Among the subgroup of patients with a ‘good’ prognosis at baseline, median OS was 6.6 versus 3.2 months (HR 0.43, p<0.0001); while among the ‘poor’ prognosis subgroup, median OS was 3.4 versus 2.0 months, respectively (HR 0.55, p=0.0031). There were no side effects related to mistletoe. These interim results indicate a significant survival benefit associated with use of mistletoe, in this case even as a monotherapy in advanced cancer patients.
Quality of Life
Quality of life (QOL) has proved to be a very important component in terms of cancer treatment. At certain stages of disease, patients are no longer candidates for curative treatment. As a result, practitioners and members of the health care team focus on prolonging life without compromising quality of life, and on relieving symptoms (Bar-Sela 2012).
Clinical data derived from studies of mistletoe therapy indicates an improvement in quality of life and decrease in side effects when used alongside chemotherapy (Bar-Sela 2013, Bussing 2012, Kim 2012). A 2012 RCT found that mistletoe significantly improved QOL (global health) (p <0.01), and increased leukocyte- and eosinophil counts (p ≤0.01) in 32 resected gastric cancer patients starting chemotherapy with doxifluridine, a 5-fluorouracil prodrug, compared to chemotherapy alone (Kim 2012). Diarrhea was also less frequently reported (7% vs. 50%, p=0.014) in the mistletoe group. A cohort study of 25 patients with various cancers reported similar findings, with improvements in QOL as measured by the EORTC QLQ-C30 questionnaire following three months of mistletoe therapy (Brandenberger 2012).
In a 2012 meta analysis, Bussing found a moderate effect size for Iscador in improving quality of life when used alongside chemotherapy, standardized mean difference 0.56 (95%CI 0.41-0.71) (Bussing 2012). Similarly, a 2010 systematic review by Kienle found that of the 26 RCTs included, 22 reported a QOL benefit associated with use of mistletoe extracts, with the remaining four studies showing either no benefit or not reporting results (2010). Improvement was seen for coping, fatigue, sleep, exhaustion, energy, nausea, vomiting, appetite, depression, anxiety, ability to work, and emotional and functional well-being. The 2008 Cochrane review found that of 16 trials evaluating these outcomes, 14 showed significant benefits on QOL, performance score, or side effects of chemotherapy (Horneber 2008).
Side Effects of Chemotherapy
Mistletoe therapy may improve the tolerability of treatment and offset the need for dose reductions among patients undergoing chemotherapy. Most of the clinical research on mistletoe in oncology has beenconducted among patients also undergoing standard care. For instance, the study by Bar-Sela cited above showed that there were significantly fewer dose reductions as well as non-hematological toxicities among NSCLC patients receiving mistletoe (2013). The study by Kim showed a reduction in the incidence of diarrhea among patients on doxifluridine (2012). In addition, several systematic reviews indicate a reduction in side effects of chemotherapy, although in most reviews, this was an endpoint combined with quality of life (Kienle 2010, 2009).
Mistletoe therapy has also been shown to improve symptoms during cancer patients’ aftercare, defined as the five years following the completion of standard care (Beuth 2008). Data from a cohort of 681 breast cancer patients found that use of mistletoe was associated with decreased overall symptoms (56% versus 70%) as well as a reduction in specific symptoms including mucositis, fatigue, pain, and headache during aftercare, compared to patients not using mistletoe (Beuth 2008).
Mistletoe therapy has a good safety profile, with most side effects being mild to moderate soreness and inflammation at injection sites, headache, fever, and chills (NCI 2013). Although rare, allergic reactions and anaphylaxis are possible. Dose escalation strategies are used to prevent such reactions.
Based on a large volume of data evaluating the use of mistletoe alongside standard care including
chemotherapy , and the existence of several meta analyses showing survival benefits (Table 1), mistletoe appears to have a good safety profile alongside chemotherapy. If anything, there appear to be beneficial interactions such that mistletoe reduced side effects of chemo, while
improving cancer treatment outcomes such as survival and time to tumour progression (Bar-Sela 2013,
In particular, human studies have evaluated mistletoe therapy alongside the following chemotherapy regimens, finding that there was no evidence of mistletoe reducing the anticancer effectiveness of chemotherapy:
gemcitabine (Mansky 2013), carboplatin plus gemcitabine or pemetrexed (Bar-Sela 2013), CMF (cyclophosphamide, methotrexate and fluorouracil) (Auerbach 2005,
Horneber 2008), 5-fluorouracil (Heiny 1997, Horneber 2008), and cisplatin and ifosfamide (Lange 1993,
Horneber 2008) (Lange 1993 is an unpublished study cited by Horneber 2008). Newly published in vitro experiments suggest that mistletoe is unlikely to reduce the effectiveness of the following chemotherapy drugs: doxorubicin, gemcitabine, docetaxel and mitoxantrone, and docetaxel and cisplatin (Weissenstein 2014). The study reported that “VAE [Viscum album extract] did not inhibit chemotherapy induced cytostasis and cytotoxicity in any of our experimental settings. At higher
concentrations VAE showed an additive inhibitory effect [with chemotherapy drugs]” (Weissenstein 2014).
Mistletoe therapy has a long history of use as a
complementary cancer therapy, dating from the 1920s. This therapy demonstrates a good safety profile as well as important benefit on several endpoints related to cancer, including up to 40% improvement in survival, as well as benefits tof quality of life and tolerability of
chemotherapy. There are several different mistletoe extracts commercially available, however the best-known and the most researched extracts are Iscador and Helixor. Mistletoe constituents, namely lectins and viscotoxins, exert direct and indirect cytotoxic effects and acts as an immune stimulant. There is a wealth of clinical data on European mistletoe, including several systematic reviews and meta-analyses; however, there is still a need for more rigorous study design and trial reporting in future research on this agent.
Auerbach L, Dostal V, Vaclavik-Fleck I, Kubista E, Rosenberger A, Rieger S, et al.[Signifikant höherer Anteil aktivierter NK–Zellen durch additive misteltherapie bei chemotherapierten Mamma–Ca–Patientinnen in einer prospektiv randomisierten doppelblinden Studie]. Fortschritte in der Misteltherapie – Aktueller Stand der Forschung und klinische Anwendung. Essen: KVC Verlag, 2005:1–11. [Cited by Horneber 2008] Bar-Sela G. White-Berry mistletoe (Viscum album L.) as complementary treatment in cancer: does it help? European Journal of Integrative Medicine. 2011;3(2):55-62. Bar-Sela G, Wollner M, Hammer L, Agbarya A, Dudnik E, Haim N. Mistletoe as complementary treatment in patients with advanced non-small-cell lung cancer treated with carboplatin-based combinations: a randomised phase II study. Eur J Cancer. 2013 Mar;49(5):1058-64.
Borrelli E. Evaluation of the quality of life in breast cancer patients undergoing lectin standardized mistletoe therapy. Minerva Medica 2001;92(Suppl 1 Nr 3):105–7.
Brandenberger M, Simões-Wüst AP, Rostock M, Rist L, Saller R. An exploratory study on the quality of life and individual coping of cancer patients during mistletoe therapy. Integr Cancer Ther. 2012 Jun;11(2):90-100.
Büssing A, Raak C, Ostermann T. Quality of life and related dimensions in cancer patients treated with mistletoe extract (iscador): a meta-analysis. Evid Based Complement Alternat Med. 2012;2012:219402.
Friedel WE, Matthes H, Bock PR, Zänker KS. Systematic evaluation of the clinical effects of supportive mistletoe treatment within chemo- and/or radiotherapy protocols and long-term mistletoe application in nonmetastatic colorectal carcinoma: multicenter, controlled, observational cohort study. J Soc Integr Oncol. 2009 Fall;7(4):137-45.
Hamre HJ, Kiene H, Kienle GS. Clinical research in anthroposophic medicine. Altern Ther Health Med. 2009 Nov-Dec;15(6):52-5.
Heiny BM, Albrecht V. [Komplementäre Therapie mit Mistellektin–1–normiertem Extrakt – Lebensqualitätsstabilisierung beim fortgeschrittenen kolorektalen Karzinom – Fakt oder Fiktion?]. Medizinische Welt 1997;48:419–423. [Cited by Horneber 2008].
Horneber MA, Bueschel G, Huber R, Linde K, Rostock M. Mistletoe therapy in oncology. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD003297.
Kelter G, Schierholz JM, Fischer IU, Fiebig HH. Cytotoxic activity and absence of tumor growth stimulation of standardized mistletoe extracts in human tumor models in vitro. Anticancer Res. 2007 Jan-Feb;27(1A):223-33.
Kienle GS, 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 Jun 11;28:79.
Kienle GS, 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 Jun;9(2):142-57.
Kim KC, Yook JH, Eisenbraun J, Kim BS, Huber R. Quality of life, immunomodulation and safety of adjuvant mistletoe treatment in patients with gastric carcinoma – a randomized, controlled pilot study. BMC Complement Altern Med. 2012 Oct 3;12:172.
Klein R, Classen K, Berg PA, Lüdtke R, Werner M, Huber R. In vivo-induction of antibodies to mistletoe lectin-1 and viscotoxin by exposure to aqueous mistletoe extracts: a randomised double-blinded placebo controlled phase I study in healthy individuals. Eur J Med Res. 2002 Apr 30;7(4):155-63.
Lange O, Scholz G, Gutsch J. Modulation of the subjective and objective toxicity of an aggressive chemoradiotherapy with Helixor [Modulation der subjektiven und objektiven Toxizität einer aggressiven Chemo/Radiotherapie mit Helixor]. 1993: 17268. [Cited by Horneber 2008].
Mansky PJ, Wallerstedt DB, Sannes TS, Stagl J, Johnson LL, Blackman MR, Grem JL, Swain SM, Monahan BP. NCCAM/NCI Phase 1 Study of Mistletoe Extract and Gemcitabine in Patients with Advanced Solid Tumors. Evid Based Complement Alternat Med. 2013;2013:964592.
Melzer J, Iten F, Hostanska K, Saller R. Efficacy and safety of mistletoe preparations (Viscum album) for patients with cancer diseases. A systematic review. Forsch Komplementmed. 2009 Aug;16(4):217-26.
Mistel-therapie. Iscador. No date updated provided. http://www.mistel-therapie.de/index.php5?page=39&lang=1 Accessed 2 February 2014.
NCI, National Cancer Institute. Mistletoe Extracts PDQ. Updated 06/07/2013. URL: http://www.cancer.gov/cancertopics/pdq/cam/mistletoe/HealthProfessional/page1 Accessed 10 Jan 2014.
Orange, M., Fonseca, M., Lace, A., Von Laue, H. B., Geider, S. (2010). Durable tumour responses following primary high dose induction with mistletoe extracts: two case studies. European Journal of Integrative Medicine. 2010;2(2):63-69.
Ostermann T, Büssing A. Retrolective studies on the survival of cancer patients treated with mistletoe extracts: a meta-analysis. Explore (NY). 2012 Sep-Oct;8(5):277-81.
Ostermann T, Raak C, Bussing A. Survival of cancer patients treated with mistletoe extract (iscador): a systemic literature review. Biomed Central. 2009;9:451-460.
Tröger W, Galun D, Reif M, Schumann A, Stankovicec N, Milicevic M. Viscum album [L.] extract therapy in patients with locally advanced or metastatic pancreatic cancer: a randomised clinical trial on overall survival.Eur J Cancer. 2013Dec;49(18):3788-97.
Weissenstein U, Kunz M, Urech K, Baumgartner S. Interaction of standardized mistletoe (Viscum album) extracts with chemotherapeutic drugs regarding cytostatic and cytotoxic effects in vitro. BMC Complement Altern Med. 2014 Jan 8;14(1):6.