Mistletoe - from folklore to the forefront of modern medicine, is it ready for primetime?
Reviewing the Current Status of Mistletoe Extracts in Cancer
Mistletoe is a semiparasitic evergreen shrub that grows on the branches of deciduous and coniferous trees.(1) To date, botanists have identified over 1,500 species of mistletoe, many of which have been used since antiquity to treat numerous medical maladies.(2) Its diverse applications, ranging from pain control to diabetes, reflects the variety of biologically active compounds found in its leaves, stems, and berries.(1) The lectins and viscotoxins associated with mistletoe primarily account for the plant’s immunomodulatory effects;(3,4) results from several studies suggest that its phenolic acids, triterpene acids, and non-polar compounds confer additional anticancer properties.(5,6,7) Because complete mistletoe extract appears to inhibit tumor cells more effectively than isolated compounds, it is very likely that there are synergistic modes of action among the plant’s different compounds.(8)
Mistletoe lectins are glycoproteins consisting of a cytotoxic A-chain of 254 amino acids and a B-chain of 264 amino acids. Both chains exert anticancer effects through distinct mechanisms. The A-chain inhibits protein synthesis in ribosomes and promotes apoptosis, whereas the B-chain enhances cytokine secretion and natural killer cell activity.(2) Additionally, mistletoe lectins down-regulate cyclins and cyclin-dependent protein kinases, which results in the arrest of the cell cycle.(1) While mediating these changes, mistletoe extract also critically appears to spare normal cells from degradation.(9) This selectivity compares favorably with immune checkpoint inhibitor therapies, whose use can lead to a panoply of treatment-related adverse events like inflammatory arthritis, myositis, vasculitis, and alveolitis.(10) Such effects may, in part, explain increasing interest among clinicians and researchers in complementary, natural medicines in oncology management.(9) In this setting, mistletoe boasts an 80-year history of use and remains popular as an adjuvant therapy in many European countries.(10)
Despite this longstanding history, mistletoe therapy is highly controversial because of mixed results obtained from studies assessing its ability to treat cancer. In a systematic review of existing randomized controlled studies, one group of researchers noted that mistletoe therapy had no effect on survival. Furthermore, other evidence suggests that mistletoe may increase the likelihood of anaphylactic reactions in patients with allergies or immune reactions on cancer drugs.(11) Although such reactions are reported rarely in the literature, it is possible that they are underreported because oncologists do not view the use of complementary medicine as risky.(12) This possible drawback, coupled with no clear survival benefit, weigh against widespread integration of mistletoe extract into cancer therapy. Some experts particularly also advise against its use in patients with leukemia, lymphoma, and brain metastases because of problematic immunostimulation.(11)
Obtaining consensus on the value of mistletoe therapy remains difficult, as extensive data on its use in various cancers are generally lacking. Additionally, study heterogeneity among existing investigations complicates efforts to draw useful comparisons. The manufacturing processes and formulations of mistletoe extracts can vary considerably across trials, along with the route of delivery and dose.(13) In case reports, clinicians have administered mistletoe therapy subcutaneously, intravenously, or subcutaneously and intravenously. Duration of treatment with Viscum album extract, one kind of formulation, also ranges between several weeks to upwards of five years and more. Considering these methodological issues, caution may be warranted when interpreting a meta-analysis of existing trials, whose results suggested a positive treatment effect with mistletoe therapy.(14)
More recent data support the use of a specific mistletoe extract derived from ash trees (Fraxini) in the context of hepatocellular carcinoma (HCC). In a Hep3B xenograft model, Fraxini-treated (8 mg/kg) mice had significantly smaller tumors than control mice. Additionally, Fraxini-treated Hep3B cell xenografts had reduced c-Myc protein expression than mice in the control group. These findings are significant, as c-Myc is overexpressed
in upwards of 70% of tumor tissues from human patients with viral or alcohol-related HCC. By destabilizing c-Myc, Fraxini inhibited the proliferation of HCC cells and tumor tissue in a novel manner.9 Results from this study also appear to corroborate previous findings from a phase 2 clinical trial conducted in 2004, in which 13% of patients exhibited a complete response and 8% achieved a partial response on Fraxini.(15) Although these lines of evidence require more validation, they justify closer and continued exploration of mistletoe extracts in the context of certain cancers, particularly HCC.
In the clinic, many patients enter on mistletoe therapy in their recent past, and most are progressing or have failed the program, raising doubts regarding its efficacy. The prospect of many patients switching care after deterioration may contribute to clinician bias against mistletoe’s “observational” track record. Because many were already receiving the standard of care for their cancer, in addition to a wide variety of medications, it is impossible to quantify the benefit-to-risk ratio of mistletoe therapy regimens without well-designed, clinical trials. Notably, the trusted Cochrane Review healthcare decision-making database still withholds formal support for mistletoe therapy in cancer because of insufficient evidence.(16) Although mistletoe therapy lacks formal endorsement, existing data collected from case reports suggest that the strategy is well-tolerated, and further studies are forthcoming to investigate possible applications.
Treatment-emergent adverse events are dose dependent and typically confined to injection-site reactions, increased body temperature, and mild, transient flu-like symptoms.(17) Benefits, like improved appetite, sleep, energy, and a lower sensitivity to pain, sometimes offset these side-effects. Relative to other cancer treatments, mistletoe therapy is also affordable. An initial kit costs $685, and monthly treatments thereafter range between $200 and $400. That said, patients interested in pursuing adjunctive mistletoe therapy must still pay out-of-pocket, as health insurers currently classify the procedure as alternative medicine.(18)
Going forward, studies with larger sample sizes and sound methodology are needed to clarify the clinical utility of mistletoe therapy. The incidence of cancers is rising worldwide, and the need for well-tolerated adjuvant therapies is growing. In specific cancers, like HCC, conventional chemotherapies have limited benefit in advanced stages, and a minority of patients qualify for surgical transplant at diagnosis.(9) As the mechanism of action underlying mistletoe is better elucidated, oncologists will hopefully have a better idea of the circumstances in which mistletoe therapy can substantially improve patient outcomes. To this end, a phase 1 study by Johns Hopkins is currently underway to evaluate the safety and toxicity of Helixor M (mistletoe extract) thrice weekly in patients with advanced solid tumors (Table 1). Estimated completion is in March 2022, and findings from the trial may finally bring some long-awaited answers to the many unresolved questions surrounding mistletoe therapy in cancer patients.(19)
Table 1: Recruiting and active clinical trials assessing the efficacy and safety of mistletoe therapy in patients diagnosed with cancer:
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Charles J. Meakin MD, MHA, MS
Chief Medical Executive Care Oncology
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2 Marvibaigi M, Supriyanto E, Amini N, et al. Preclinical and clinical effects of mistletoe against breast cancer. Biomed Res Int. 2014;2014:785479.
3 Thies A, Nugel D, Pfuller U, et al. Influence of mistletoe lectins and cytokines induced by them on cell proliferation of human melanoma cells in vitro. Toxicology. 2005;207:105-116.
4 Schaller G, Urech K, Giannattasio M. Cytotoxicity of different viscotoxins and extracts from the European subspecies of Viscum album L. Phyther Res. 1996;10:473-477.
5 Melo MNO, Oliveira AP, Wiecikowski AF, et al. Phenolic compounds from Viscum album tinctures enhanced antitumor activity in melanoma murine cancer cells. Saudi Pharm J. 2018;26:311-322.
6 Delebinski CI, Twardziok M, Kleinsimon S, et al. A natural combination extract of Viscum album L. containing both triterpene acids and lectins is highly effective against AML in vivo. PLoS ONE. 2015;10:e0133892.
7 Cebovic T, Spasic S, Popovic M. Cytotoxic effects of the Viscum album L. extract on Ehrlich tumour cells in vivo. Phyther Res. 2008;22:1097-1103.
8 Felenda JE, Turek C, Stintzing FC. Antiproliferative potential from aqueous Viscum album L. preparations and their main constituents in comparison with ricin and purothionin on human cancer cells. J Ethnopharmacol. 2019;236:100-107.
9 Yang P, Jiang Y, Pan Y, et al. Mistletoe extract Fraxini inhibits the proliferation of liver cancer by down-regulating c-Myc expression. Sci Rep. 2019;9:6428.
10 Oei SL, Thronicke A, Schad F. Mistletoe and immunomodulation: insights and implications for anticancer therapies. Evid Based Complement Alternat Med. 2019;2019:5893017.
11 Freuding M, Keinki C, Micke O, et al. Mistletoe in oncological treatment: a systematic review. J Can Res Clin Oncol. 2019;145(3):695-707.
12 Conrad AC, Muenstedt K, Micke O, et al. Attitudes of members of the German Society for Palliative Medicine toward complementary and alternative medicine for cancer patients. J Cancer Res Clin Oncol. 2014;140:1229-1237.
13 Horneber MA, Bueschel G, Huber R, et al. Mistletoe therapy in oncology. Cochrane Database Syst Rev. 2008(2):CD003297.
14 Loef M, Walach H. Quality of life in cancer patients treated with mistletoe: a systematic review and meta-analysis. BMC Complement Med Ther. 2020;20:227.
15 Mabed M, El-Helw L, S Shamaa. Phase II study of viscum fraxini-2 in patients with advanced hepatocellular carcinoma. Br J Cancer. 2004;90(1):65-69.
16 Horneber M, van Ackeren G, Linde K, et al. Mistletoe treatment in cancer patients. Cochrane Review. https://www.cochrane.org/CD003297/GYNAECA_mistletoe-treatment-cancer-patients/. Published November 17, 2020. Accessed June 28, 2021.
17 Steele ML, Axtner J, Happe A, et al. Adverse drug reactions and expected effects to therapy with subcutaneous mistletoe extracts (Viscum album L.) in cancer patients. Evid Based Complement Alternat Med. 2014;2014:724258.
18 Riordan Clinic. Mistletoe therapy for cancer treatment. https://riordanclinic.org/2021/01/mistletoe-therapy-for-cancer-treatment/. Published January 2021. Accessed June 28, 2021.
19 Trial of Mistletoe Extract in Patients with Advanced Solid Tumors. https://clinicaltrials.gov/ct2/show/NCT03051477. Updated February 24, 2021. Accessed June 28, 2021.