By Melinda Ring, MD, Associate Program Director, Medicine Residency Program, and Coordinator, CAM Program, St. Joseph Hospital, Chicago, IL.
While many complementary practices, such as mind-body therapies, have little downside for cancer patients receiving treatment, the issue of safety with concomitant use of dietary supplements remains paramount. Not only can some supplements fail to help, but in certain cases they may lessen the efficacy of proven chemotherapy and radiotherapy regimens. Some patients forego conventional medical approaches to cancer treatment in favor of only using supplements, even when conventional approaches have been shown beneficial. Extreme caution should be taken, therefore, when approving the use of supplements in this setting, and then only when sufficient efficacy and safety data exist.
Mistletoe, Viscum album L., garnered significant attention in the U.S. cancer community after it was employed by actress Suzanne Somers in her fight against breast cancer in the 1990s.2 Mistletoe is one of the most widely used nontraditional cancer treatments in Europe; 74% of cancer patients acknowledged using mistletoe therapies in a recent survey in Switzerland.3 This herb is the most commonly prescribed cancer therapy in Germany, with associated costs topping $30 million per year. The appeal of mistletoe therapy is far from waning in Europe; expenditures have increased 20% annually in recent years.4
Proponents of mistletoe 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.5 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.
History
Mistletoe’s history as a medicinal can be traced back to the time of the Celtic druids. However, it was not until the 1920s that the Austrian philosopher-scientist Rudolf Steiner, PhD, drew attention to the use of mistletoe as a cancer therapy.6 Steiner was struck by a perceived parallel between the mistletoe plant’s parasitic nature and cancer’s parasitic invasion of the human body. He hypothesized that mistletoe extracts could stimulate the body’s innate healing processes to battle cancer from precancerous to invasive stages.
Steiner is credited with the formation of a healing science known as anthroposophic medicine, a field still thriving in Germany and Switzerland, and with a growing presence in other European countries and the United States. Currently, physicians in specialized anthroposophic clinics use mistletoe extracts most extensively. Since the establishment of the clinics in the 1920s, more than 80,000 patients have been treated, primarily for cancer.
Anthroposophy blends spiritual and scientific principles and applies them to healing practices. A central concept is that humans are composed of the interactions of physical body (materia), inner life body (forma), soul (anima), and spiritual ego (geist). Illness is the result of disharmony and imbalance among these systems. Anthroposophic treatment might include conventional medication accompanied by any of the following complementary therapies: dietary manipulation, natural remedies (herbs, essential oils, potentized metals), medicinal baths, external compresses or ointments, artistic therapies, therapeutic eurythmy (movement therapy), rhythmical massage (a light-touch massage), and psychological counseling.
Anthroposophic natural remedies, including mistletoe, are prepared according to classic homeopathic principles of "like cures like" and dilutional potentization (the more diluted the substance, the greater its potency). The strong belief in an integral human connection to nature is evidenced by the use of natural elements, with special attention to timing and biological rhythms when making and administering these medicines.
Laboratory Evidence/Active Constituents
Since Steiner popularized mistletoe extract, research to identify its active components and anticancer properties has proliferated. Mistletoe augments immune system activation in vitro, including stimulation of the quantity and activity 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.7 Studies using human and animal cancer cell systems have identified effects such as increased DNA stability, induction of cell apoptosis, and inhibition of cell growth. The cytotoxic effect appears most pronounced during the G0 (resting) phase of the cell cycle.8
Lectins and viscotoxins are the two major active components in mistletoe preparations. Lectins are glycoproteins that can bind sugar portions on cell surfaces; of the four identified in mistletoe, ML-1 (also known as viscumin) is thought most critical to the biologic activity of the plant. When ML-I was selectively removed from mistletoe extracts, a marked reduction in measured activity was noted.9 Actions of ML-1 include: interference with intracellular protein synthesis, stimulation of cytokine production, and activation of leukocytes. Additionally, ML-1 may therapeutically influence the processes of metastasis and apoptosis.
In contrast, viscotoxins work primarily by damaging the cell membrane and inducing cell necrosis, rather than through immune system modulation. It was suggested in one study that mistletoe itself could promote cancer development; however, subsequent studies have disputed this concerning claim.10
Clinical Evidence
Mistletoe has been evaluated as a treatment for cancer in more than 30 clinical studies, about half of which were randomized controlled trials. The majority were performed in Germany and Austria, and published exclusively in foreign language journals. The mistletoe products tested include Iscador, Eurixor, Helixor, Lektinol, and recombinant lectin ML-I. Although most studies concluded positive efficacy in at least one major endpoint (survival, time to tumor recurrence, quality of life), they have been criticized for weaknesses that cast significant doubt on the reliability of the findings.
In 2003, Ernst et al conducted a systematic review of all randomized clinical trials found in eight databases.11 Ten trials met the inclusion/exclusion criteria; however, prominent weaknesses and heterogeneity precluded a pooled analysis. A narrative summary concluded that some weaker studies implied benefits of mistletoe extracts, particularly in terms of quality of life. However, none of the methodologically stronger trials exhibited efficacy in terms of quality of life, survival, or other outcome measures.
Published in the same year, Kienle et al performed a search of 11 electronic databases, reference lists, and expert consultations.12 Twenty-three studies were identified: 16 randomized, two quasi-randomized, and five nonrandomized. Cancer sites included breast, lung, stomach, colon, rectum, head and neck, kidney, bladder, skin, brain, and genitals. Like Ernst, the reviewers identified substantial study design differences and biases, and did not perform a quantitative synthesis. Of the 23 studies examined, 12 showed one or more statistically significant positive result (survival or quality of life), another seven studies showed at least one positive trend (survival, disease-free survival, tumor remission), three showed no effect, and one had a negative trend.
Stauder et al performed a review limited to mistletoe extracts standardized to mistletoe lectin.13 The authors concluded that the clinical database does not support direct anticancer action or improvement in time to tumor progression or overall survival.
Some of the more rigorous studies explored in these reviews are summarized below.
Steur-Vogt et al studied the clinical effectiveness of adjuvant mistletoe extract in 477 patients with head and neck squamous cell cancer in a phase III trial.14 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. Eurixor was given in four treatment cycles; each cycle lasted 12 weeks and was followed by a four-week break period. During each cycle, Eurixor was administered by subcutaneous injection twice a week. 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. The investigators concluded that Eurixor cannot be recommended as adjuvant treatment in head and neck cancer patients.
In another phase III trial, the German Cancer Society studied 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.15 After potentially curable surgery, 407 patients were randomized to receive adjuvant treatment for one year with subcutaneous injections of interferon-alpha, interferon-gamma, or Iscador M, or no further treatment. Analysis after eight 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 2002, a prospective, randomized phase II trial explored whether adjuvant Eurixor therapy could reduce recurrence of noninvasive bladder cancer.16 After surgery, 45 patients were randomly assigned to receive either three cycles of treatment with Eurixor or no further therapy. Three cycles of Eurixor treatment were given; each consisted of three months of twice-weekly subcutaneous injections, followed by a three-month break. After 18 months of follow-up, no difference in recurrence rate or disease-free interval was noted. Some critics have identified a lack of weight-based dosing of the extract as a potential reason for the failure to see benefits.
In contrast to these results, a large cohort study conducted in Germany found a positive therapeutic effect from mistletoe treatment.17 Nonrandomized 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 nonrandomized 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). Results of 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. This study has been criticized primarily for the lack of consistency in determining compliance, as well as dose and types of Iscador used. The retrospective nature of the data is another major weakness.
Several studies have been published over the past year further examining the role of mistletoe extract in varied cancers with endpoints including tumor response, quality of life, and survival.
A phase II trial was designed to determine whether mistletoe extract can induce objective tumor response in patients with metastatic colorectal cancer resistant to 5-fluorouracil and leucovorin (5FU/LCV).18 Twenty-five patients were given three weekly subcutaneous injections of Abnoba-viscum Quercus with gradual dose increases. Treatment was continued in 14 patients until they became bedridden, and 11 patients elected to stop treatment after their illnesses progressed. Median duration of therapy was 14 weeks (range 4-66). Objective tumor response was not seen in any of the 25 patients; symptomatic relief was reported by 10 (40%) patients.
Bock et al examined the efficacy of Iscador in reducing adverse side effects attributable to conventional chemotherapy.19 A total of 1,442 patients with nonmetastatic breast cancer were enrolled, 710 of whom received adjuvant subcutaneous mistletoe extract for three to 52 months. After three years of follow-up, the authors reported a significant reduction in adverse reactions from chemotherapy with mistletoe therapy (16.3% vs. 54.1%). They conclude that Iscador reduced disease and treatment-associated symptoms, and may prolong overall survival. However, the lack of consistency in dose duration, lack of placebo, and poor accountability is concerning.
Another trial also examined quality-of-life issues in breast cancer patients receiving CMF chemotherapy.20 Two hundred seventy-two patients were randomized to placebo vs. low, medium, or high doses of a stand-ardized mistletoe extract, PS76A2. After 15 weeks of therapy, the researchers reported a significant improvement with mistletoe based on a self-assessed quality-of-life scores and Spitzer’s quality-of-life scale for the medium dose only.
Preparation/Administration
Mistletoe is a semi-parasitic evergreen bush that grows on deciduous trees such as oak, pine, elm, and apple. 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. Weleda Inc. distributes it in the United States as a homeopathic remedy with the brand name Iscar. Iscador/Iscar is produced by taking an aqueous extract of the whole mistletoe plant. The extract is fermented with the bacterium Lactobacillus plantarum, mixed, filtered for bacteria removal, standardized, and packaged into ampules. Iscador is identified further by the host tree: pine (Pini-Iscador P), Oak (Quercus-Iscador Qu), and Apple (Mali-Iscador M). Anthroposophic practitioners believe different cancers respond better to mistletoe from specific host trees; for example, mistletoe from pine trees may be beneficial in the treatment of skin cancer.
Other mistletoe formulations (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. While most extracts are prepared according to homeopathic principles, some are not.
Iscador typically is injected subcutaneously into the abdominal wall, preferably near the tumor site. Some anthroposophic practitioners inject the substance directly into the tumor. Other routes include oral and intrapleural. 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.21 The optimal dose is based upon a temperature rise after administration, felt to be an indicator that the immune system is responding. Maintenance-phase injections may be prescribed on an individual basis.
Oral preparations, far less commonly used in Europe, are the only commercially available form of Viscum album in the United States. The remedies are available in capsule form, liquid extract, and tea made from either the whole plant or only the leaf.22
Safety/Adverse Effects
Side effects related to subcutaneous mistletoe preparations have been minimal and non-life threatening in clinical studies. A few anaphylactic reactions have been reported in a case series.23 More commonly, the injections lead to localized soreness and inflammation, with headache, fever, and chills. Anthroposophic practitioners view these reactions favorably as signs of immune system stimulation. Transient episodes of gingivitis, eosinophilia, and elevations in serum urea nitrogen and creatinine were noted in one clinical study in both control and test subjects.24
Contraindications for oral mistletoe extracts are pregnancy, intolerance to the extract, and hyperthyroidism.22 Ingestion of toxic levels of mistletoe plants and berries can lead to seizures, bradycardia, blood pressure fluctuations, emesis, and death.25
Regulation
Viscum album is listed in the U.S. Homeopathic Pharmacopoeia, the standard accepted compendium.26 However, it is only available commercially in oral preparations in the United States. Since the 2002 Bioterrorism Act, the FDA disallowed general importation or distribution of injectable mistletoe extracts, including homeopathic formulations. U.S. patients interested in receiving injections of mistletoe extract have three options. They may participate in FDA-approved Investigational New Drug studies on mistletoe as a treatment for cancer; currently at least two such projects are ongoing.27,28 Individual patients may travel outside the United States to receive treatment. In regions such as Germany, where mistletoe remedies have the status of a biological standard therapy, injectable aqueous extracts are readily available by prescription. Finally, patients and physicians in the United States may apply for a three-month supply of the formulations under the FDA Compassionate Use Act, and order Iscador directly from Weleda.
Conclusion
The use of European mistletoe in cancer as an adjuvant therapy has been in vogue in Europe for the past several decades. Bench research points to two main actions of Viscum album L.: immunomodulation and cytotoxicity. However, clinical studies have failed to produce convincing data that mistletoe extract can positively affect relevant endpoints such as tumor recurrence, survival, or quality of life. Injectable mistletoe extract is not approved by the FDA as a cancer therapy. Two other organizations, the National Cancer Institute and the American Cancer Society, also caution against its use except in the setting of clinical trials.
Recommendation
The popularity of mistletoe extracts in Europe appears to rely on a weak evidence base. Although several higher-quality clinical trials have been published in the past few years, the results are by no means uniform. However, Viscum album and its associated lectins do have potential utility based on pre-clinical research. Given the large number of extracts available, and their variable effects in different tumors, it is unlikely that we will have an answer to the mistletoe conundrum in the near future. For now, it seems prudent to remind patients that mistletoe extracts should not replace conventional therapy, and should only be considered for adjuvant therapy in controlled settings.
References
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