Use of Mistletoe Extract in Cancer 

By Melinda Ring, MD, and Marjorie Alschuler, PhD

When actress Suzanne Somers announced her decision to use mistletoe in place of conventional chemotherapy to treat her breast cancer, many thought her decision was unique. But in fact, mistletoe is among the most widely used non-traditional cancer treatments in Europe.1 It’s estimated that more than $30 million per year is spent on mistletoe extracts in Germany alone. A survey of 200 German physicians showed that almost 45% prescribed this herb to their cancer patients.2

Proponents claim it stimulates the immune system, promotes cancer cell reversion to more differentiated forms, improves overall well-being, and may extend survival in certain cancers.3 Additionally, it is used for cancer prevention in high-risk patients, such as those with ulcerative colitis, cervical dysplasia, papillomatosis of the bladder, and intestinal polyposis. Mistletoe also is being investigated for utility in AIDS patients, and deserves a closer look for cancer.

Introduction

Complementary and alternative medicine (CAM) treatments are used extensively by cancer patients. In 1998, a systematic review of 26 surveys from 13 countries found an average prevalence of use of 31% in this patient population; other studies have suggested rates approaching 60-70%.4 Herbal remedies, homeopathy, and relaxation therapies are employed most frequently. In one investigation into CAM’s popularity, cancer patients cited a desire to "leave no stone unturned" in searching for a cure, a belief in the mind-body connection, a preference for a holistic approach, and media publicity.5

History

Mistletoe’s history as a medicinal spans centuries. It reportedly was cut from trees with a golden sickle by Celtic druids for use as a panacea. Hippocrates recommended mistletoe for disorders of the spleen. In the 16th century, mistletoe was used to treat epilepsy and other nervous system diseases. Subsequent applications included hypertension, tachycardia, headache, menopausal symptoms, infertility, and arthritis.

Interest in mistletoe as a cancer therapy developed in the 1920s under the rubric of anthroposophy, a scientific framework founded by the Austrian philosopher Rudolf Steiner, PhD. Anthroposophy blends spiritual and scientific principles and applies them to healing practices, with a strong focus on cancer therapies. According to anthroposophical theory, there are four distinct classes of natural forces: materia, forma, anima, and geist—roughly translated as physical body, life, soul, and spirit. Imbalances of these forces lead to human disease; treatment aims to restore the equilibrium by activating the patient’s self-healing capacities.

Steiner proposed that the parasitic nature and other growth characteristics of mistletoe made it uniquely valuable in the fight against the parasitic growth of cancer. He applied the homeopathic principles of "like cures like" and dilutional potentization (the more diluted the substance, the greater its potency) and developed mistletoe preparations for cancer patients.

At the present time mistletoe extracts are used most extensively by physicians in anthroposophic clinics in Switzerland and Germany. Since the establishment of the clinics in the 1920s, more than 80,000 patients have been treated with regimens that include homeopathic extracts, dietary manipulation, and movement therapies.

Laboratory Evidence/Active Constituents

Since Steiner popularized mistletoe extract, research to identify active components and determine anticancer properties has proliferated. Mistletoe, like some other plants, does activate the immune system in vitro. Activation of NK-cells, monocytes/macrophages, and T-cells (especially T-helper cells) and stimulation of cytokine release, including interleukin-1, interleukin-6, and tumor necrosis factor, have been demonstrated.6 Studies using cell systems have identified effects such as increased DNA stability and inhibition of cell growth.3

The lectin viscumin (also known as mistletoe lectin I [ML-I] or VAL) and protein viscotoxin are the two major active components in mistletoe preparations.3 Lectins are glycoproteins that can bind sugar portions on cell surfaces. Actions of viscumin include: interference with intracellular protein synthesis, stimulation of cytokine production, and activation of leukocytes. Additionally, viscumin may influence the processes of metastasis and apoptosis. Viscotoxin works primarily by damaging the cell membrane and inducing cell necrosis, rather than immune system modulation. Other biologically active constituents under investigation include polysaccharides and alkaloids.

Clinical Evidence

Despite the long history of mistletoe use, data from human studies are limited and often of poor quality. Problems include the use of different mistletoe preparations or doses, and the use of immune system effects rather than tumor response or survival as an endpoint.

A review article in 1994 evaluated 11 controlled clinical trials, all of which were originally published in German.7 Most of the trials enrolled patients with a single type of cancer, including colorectal, gastric, lung, breast, and female genital cancer. Survival duration was the primary endpoint in all cases. Although 10 trials reported prolonged survival, significant flaws limited the validity of the results. The one trial found to have a satisfactory design failed to show any difference in lung cancer survival with mistletoe extract compared to placebo.

Subsequent randomized studies reported improvement in quality of life (as measured by standard questionnaires) in breast cancer (n = 25) and glioma (n = 38) patients when mistletoe extract was added to their treatment regimens.8,9 No change in disease-free or overall survival was noted. Similarly, 16 patients with stage III-IV pancreatic cancer enrolled in a phase I/II trial showed no partial or complete remissions, but quality-of-life scores stabilized in the treatment group.10 A phase II trial involving 14 patients with stage IV kidney cancer found no survival advantage with mistletoe extract.11

Within the past year, several large prospective randomized controlled clinical trials were published in English-language journals. Steur-Vogt et al studied the clinical effectiveness of adjuvant mistletoe extract in 477 patients with head and neck squamous cell cancer.12 The patients first were divided into two groups after TNM (tumor, node, metastasis) staging, either undergoing surgery alone (n = 202) or surgery combined with postoperative radiotherapy (n = 275). Both sets then were randomized to standard treatment alone (control group), or standard treatment plus Eurixor, an extract standardized to ML-I. Statistical analysis after an average of four years of follow-up showed no significant improvement in disease-free survival or tumor-related mortality. Additionally, no changes were noted in cellular immunity as measured by lymphocyte subsets or quality-of-life scores, as assessed with the European Organization for Research and Treatment of Cancer Quality of Life Score 30 instrument. The investigators concluded that Eurixor cannot be recommended as adjuvant treatment in head and neck cancer patients.

Eggermont et al studied 830 patients with high-risk melanoma, defined as a primary tumor greater than 3 mm diameter with negative regional lymph nodes or any size primary tumor with 1-2 positive regional nodes and no distant metastases.13 After potentially curable surgery, patients were randomized to receive adjuvant treatment for one year with subcutaneous injections of interferon-alpha, interferon-gamma, or IscadorM (a mistletoe preparation), or no further treatment. Analysis after six years of follow-up showed no prolongation in time to tumor recurrence or improvement in overall survival with any of the tested adjuvant treatments.

In contrast to these results, an extensive cohort study conducted in Germany found a positive effect from mistletoe treatment.14 Non-randomized and randomized matched pairs were studied in the context of a prospective, long-term epidemiological study of cancer survival involving 10,226 patients. A total of 1,668 of these patients had used a mistletoe extract. In the non-randomized study of 396 matched pairs, mean survival time was 40% longer in the mistletoe group (4.23 years) compared to control (3.05 years; P < 0.001). The two randomized, matched-pair studies supported this finding. Survival time was prolonged in all cancer types studied: carcinoma of the colon, rectum, or stomach; breast carcinoma with and without axillary or remote metastases; and small cell or non-small cell bronchogenic cancer. The research also found that Iscador use tended to improve patient psychosomatic self-regulation, or ability to achieve a sense of well-being and control in a stressful situation.

Preparation/Administration

Mistletoe is a semi-parasitic evergreen bush, which grows on deciduous trees such as oak, pine, elm, and apple.15 Although mistletoe species are found in the United States (Phoradendron leucarpum) and Korea (Viscum album coloratum), only the European Viscum album Loranthacea is employed in cancer preparations.

Iscador is the trade name of the most commonly available extract of European Viscum album, manufactured by Weleda AG in Switzerland and West Germany. It is distributed in the United States by Weleda Inc., as a homeopathic remedy with the brand name Iscar.

Iscador and Iscar are produced by taking an aqueous extract of the whole mistletoe plant. The extract then is fermented with the bacterium Lactobacillus plantarum, mixed, filtered for bacteria removal, standardized, and packaged into ampules. Iscador is identified further by the type of host tree: IscadorM, apple tree; IscadorP, pine tree; IscadorQ, oak tree; and IscadorU, elm tree.

Other mistletoe formulations, available under the trade names Helixor, Eurixor, Isorel, Plenosol, Vysorel, and ABNOB Aviscum, may be fermented or unfermented, standardized to one of the purported active constituents rather than including the whole plant, or modified by the addition of homeopathic doses of metals, such as mercury, silver, or copper.

Iscador typically is injected subcutaneously into the abdominal wall, preferably near the tumor site. Some anthroposophic practitioners inject the substance directly into the tumor. The drug regimen is individualized for patients following a protocol established by Steiner, in which escalating doses are given 3-7 times weekly over several weeks to months. Maintenance-phase injections may be prescribed on an individual basis.

Safety/Adverse Effects

Side effects related to mistletoe preparations administered subcutaneously have been minimal and non-life threatening in clinical studies. Injections commonly lead to localized soreness and inflammation, with headache, fever, and chills.16 These reactions are viewed favorably by anthroposophic practitioners as signs of immune system stimulation. Transient episodes of gingivitis, eosinophilia, and elevations in serum urea nitrogen and creatinine also may occur.17 Toxic ingestion of mistletoe plants and berries can lead to seizures, bradycardia, blood pressure fluctuations, emesis, and death.

Regulation

Since 1999 Iscar has been listed with the U.S. Food and Drug Administration in accordance with requirements for homeopathic medicines. It is available by prescription only. In Germany, mistletoe remedies have the status of a biological standard therapy.

Conclusion

Extensive laboratory evidence supports mistletoe’s biological activity and potential benefit to oncology patients. However, human studies to determine whether this activity translates into clinically relevant effects remain inconclusive. In the past few years, several well-designed studies were conducted, with conflicting results.

Recommendation

Given the favorable toxicity profile and potential utility of aqueous Viscum album abstracts, further research is warranted. Oncology patients should be cautioned that mistletoe extracts are being investigated as an adjuvant treatment, and are not intended to supplant standard medical therapy.

Dr. Alschuler is Medical Education Specialist, and Dr. Ring is Clinical Training Attending Physician and Coordinator, CAM Curriculum, Internal Medicine Residency Training Program, St. Joseph Hospital, Chicago, IL.

References

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2. Munstedt K, et al. Oncologic mistletoe therapy: Physician’s use and estimation of efficacy [in German]. Dtsch Med Wochenschr 2000;125:1222-1226.

3. Kaegi E. Unconventional therapies for cancer: 3. Iscador. Task Force on Alternative Therapies of the Canadian Breast Cancer Research Initiative. CMAJ 1998;158:1157-1159.

4. Ernst E, Cassileth BR. The prevalence of complementary/alternative medicine in cancer. A systematic review. Cancer 1998,83:777-782.

5. Ernst E. Mistletoe for cancer? Eur J Cancer 2001;37: 9-11.

6. Becker H. Botany of European mistletoe (Viscum album L.). Oncology 1986;43(suppl 1):2-7.

7. van Wely M, et al. Toxicity of a standardized mistletoe extract in immunocompromised and healthy individuals. Am J Ther 1999;6:37-43.

8. Gorter RW, et al. Tolerability of an extract of European mistletoe among immunocompromised and healthy individuals. Altern Ther Health Med 1999;5: 37-44, 47-48.

9. Stein GM, et al. Mistletoe in immunology and the clinic (short review). Anticancer Res 1998;18: 3247-3249.

10. Kleijnen J, Knipschild P. Mistletoe treatment for cancer: Review of controlled trials in humans. Phytomedicine 1994;1:255-260.

11. Heiny BM, Beuth J. Mistletoe extract standardized for the galactoside-specific lectin (ML-1) induces beta-endorphin release and immunopotentiation in breast cancer patients. Anticancer Res 1994;14:1339-1342.

12. Lenartz D, et al. Survival of glioma patients after complementary treatment with galactoside-specific lectin from mistletoe. Anticancer Res 2000;20(3B):2073-2076.

13. Friess H, et al. Treatment of advanced pancreatic cancer with mistletoe: Results of a pilot trial. Anticancer Res 1996;16:915-920.

14. Kjaer M. Mistletoe (Iscador) therapy in stage IV renal adenocarcinoma. A phase II study in patients with measurable lung metastases. Acta Oncol 1989;28: 489-494.

15. Steuer-Vogt MK, et al. The effect of an adjuvant mistletoe treatment programme in resected head and neck cancer patients: A randomised controlled clinical trial. Eur J Cancer 2001;37:23-31.

16. Eggermont AM, et al. European Organization for Research and Treatment of Cancer Melanoma Group trial experience with more than 2,000 patients, evaluating adjuvant treatment with low or intermediate doses of interferon alpha-2b. In: Educational Book from the 37th Annual Meeting of the American Society of Clinical Oncology. Available at http://www.asco.org.

17. Grossarth-Maticek R, et al. 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. Altern Ther Health Med 2001;7:57-66, 68-72, 74-76.