Mistletoe Extracts (PDQ®): Complementary and alternative medicine - Health Professional Information [NCI]
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Mistletoe Extracts
Overview
This complementary and alternative medicine (CAM) information summary provides an overview of the use of mistletoe as a treatment for people with cancer. The summary includes a brief history of mistletoe research, the results of clinical trials, and possible side effects of mistletoe use.
This summary contains the following key information:
- Mistletoe is a semiparasitic plant that has been used for centuries to treat numerous human ailments.
- Mistletoe is used commonly in Europe, where a variety of different extracts are manufactured and marketed as injectable prescription drugs. These injectable drugs are not available commercially in the United States and are not approved as a treatment for people with cancer.
- Mistletoe is one of the most widely studied CAM therapies for cancer. In certain European countries, the preparations made from European mistletoe (Viscum album, Loranthaceae) are among the most prescribed drugs offered to cancer patients.[1]
- Although mistletoe plants and berries are considered poisonous to humans, few serious side effects have been associated with mistletoe extract use.
- The use of mistletoe as a treatment for people with cancer has been investigated in clinical studies. Reports of improved survival and/or quality of life have been common, but nearly all of the studies had major weaknesses that raise doubts about the reliability of the findings.
- At present, the use of mistletoe cannot be recommended outside the context of well-designed clinical trials. Such trials will be valuable to determine more clearly whether mistletoe can be useful in the treatment of specific subsets of cancer patients.
Many of the medical and scientific terms used in this summary are hypertext linked (at first use in each section) to the NCI Dictionary of Cancer Terms, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window.
Reference citations in some PDQ CAM information summaries may include links to external Web sites that are operated by individuals or organizations for the purpose of marketing or advocating the use of specific treatments or products. These reference citations are included for informational purposes only. Their inclusion should not be viewed as an endorsement of the content of the Web sites, or of any treatment or product, by the PDQ Cancer CAM Editorial Board or the National Cancer Institute.
References:
| 1. | Horneber MA, Bueschel G, Huber R, et al.: Mistletoe therapy in oncology. Cochrane Database Syst Rev (2): CD003297, 2008. |
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General Information
Mistletoe, a semiparasitic plant, holds interest as a potential anticancer agent because extracts derived from it have been shown to kill cancer cells in vitro[1,2,3,4,5,6,7,8] Reviewed in[9,10] and to stimulate immune system cells both in vitro and in vivo.[11,12,13,14,15,16,17,18,19] Reviewed in [10,20,21,22,23,24] Two components of mistletoe, namely viscotoxins and lectins, may be responsible for these effects.[25,26,27,28,29,30,31,11,12,13,17,18,19] Reviewed in [10,21,22,23,32] Viscotoxins are small proteins that exhibit cell-killing activity and possible immune-system-stimulating activity.[1,6,18,19] Reviewed in [33,34] Lectins are complex molecules made of both protein and carbohydrates that are capable of binding to the outside of cells (e.g., immune system cells) and inducing biochemical changes in them. Reviewed in [10,35,36,37,38] In view of mistletoe's ability to stimulate the immune system, it has been classified as a type of biological response modifier. Reviewed in [35] Biological response modifiers constitute a diverse group of biological molecules that have been used individually, or in combination with other agents, to treat cancer or to lessen the side effects of anticancer drugs. Mistletoe extracts have been demonstrated in preclinical settings to have other mechanisms of action, such as antiangiogenesis.[39]
Preparations from mistletoe extracts are most frequently used in the treatment of cancer patients in German-speaking countries.[40] Commercially available extracts are marketed under a variety of brand names, including Iscador, Eurixor, Helixor, Isorel, Iscucin, Plenosol, and Abnoba-viscum. Some extracts are marketed under more than one name. Iscador, Isorel, and Plenosol are also sold as Iscar, Vysorel, and Lektinol, respectively. All of these products are prepared from Viscum album (Loranthaceae) (Viscum album L. or European mistletoe). They are not sold as a drug in the United States.
In addition to European mistletoe, extracts from a type of Korean mistletoe (Viscum album var. coloratum [Kom.] Ohwi) have demonstrated in vitro and in vivo cytoxocity in laboratory studies.[41,42,43,44,45]
Mistletoe grows on several types of trees, and the chemical composition of extracts derived from it depends on the species of the host tree (e.g., apple, elm, oak, pine, poplar, and spruce), the time of year harvested, how the extracts are prepared, and the commercial producer.[46,47] Reviewed in [8,48,36,49]
Mistletoe extracts are prepared as aqueous solutions or solutions of water and alcohol, and they can be fermented or unfermented.[6,46] Reviewed in [4,20,47,50,51,52,53] Some extracts are prepared according to homeopathic principles, and others are not. Reviewed in [10,54] In addition, the commercial products can be subdivided according to the species of host tree. Iscador, a fermented aqueous extract of Viscum album L. that is prepared as a homeopathic drug, is marketed as IscadorM (from apple trees), IscadorP (from pine trees), IscadorQ (from oak trees), and IscadorU (from elm trees). Helixor, an unfermented aqueous extract of Viscum album L. that is standardized by its biological effect on human leukemia cells in vitro, is marketed as HelixorA (from spruce trees), HelixorM (from apple trees), and HelixorP (from pine trees). Reviewed in [51] Eurixor, an unfermented aqueous extract of Viscum album L. harvested from poplar trees, is reportedly standardized to contain a specific amount of one of mistletoe's lectins (i.e., the lectin ML-1; refer to the History section of this summary for more information). Reviewed in [51] Some proponents contend the choice of extract should depend on the type of tumor and the gender of the patient.[55] Reviewed in [49,51,56]
A recombinant ML-1 from Escherichia coli bacteria known as rViscumin or aviscumine has been studied in the laboratory and in phase I clinical trials. Since this is not an extract of mistletoe, it is out of the purview of this summary.[57]
Mistletoe extracts are usually given by subcutaneous injection, although administration by other routes (i.e., oral, intrapleural, intratumoral, and intravenous) has been described.[17,21,22,23,32,58,59,60,61,62,63] Reviewed in [20,24,36,49,51,54] In most reported studies, subcutaneous injections were given 2 to 3 times a week, but the overall duration of treatment varied considerably.
Viscum album is listed in the Homeopathic Pharmacopoeia of the United States, which is the officially recognized compendium for homeopathic drugs in this country.[64] Although the U.S. Food and Drug Administration (FDA) has regulatory authority over homeopathic drugs, this authority is usually not exercised unless the drugs are formulated for injection or there is evidence of severe toxicity. At present, the FDA does not allow the importation or distribution of injectable preparations of mistletoe, including homeopathic formulations, except for the purpose of clinical research. The extracts are not available commercially in the United States and are not approved as a treatment for people with cancer.
Before researchers can conduct clinical drug research in the United States, they must file an Investigational New Drug (IND) application with the FDA. IND approval is also required for clinical investigation of homeopathic drugs. The FDA does not disclose information about IND applications or approvals; this information can be released only by the applicants. At least two U.S. investigators were given IND approval to study mistletoe as a treatment for people with cancer (NCCAM-02-AT-260 and TJUH-01F.45). The final clinical trial results have not been reported.
In this summary, the mistletoe extract or product used in each study will be specified wherever possible.
References:
History
Mistletoe has been used for centuries for its medicinal properties. Reviewed in [1,2,3,4,5,6] It was reportedly used by the Druids and the ancient Greeks, and it appears in legend and folklore as a panacea. It has been used in various forms to treat cancer, epilepsy, infertility, menopausal symptoms, nervous tension, asthma, hypertension, headache, and dermatitis. Modern interest in mistletoe as an anticancer treatment began in the 1920s. Reports of more than 30 clinical studies of mistletoe as a treatment for people with cancer have been published since the early 1960s.[7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36] Reviewed in [37,3,38] Most of the results of these studies were published exclusively in German. (Refer to the Human/Clinical Studies section of this summary for more information.)
As indicated previously (refer to the General Information section of this summary for more information), proposed mechanisms of action for mistletoe that are relevant to cancer include stimulation of the immune system [39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,7,63,64,65,66,67,68] Reviewed in [69,70,1,8,37,2,71,72,3,9,10,11,38] and a direct toxic effect on tumor cells.[73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89] Reviewed in [1,69,71,90]. Another reported activity that may be relevant to optimum functioning of the immune system in individuals with cancer is stabilization of the DNA in white blood cells, including white blood cells that have been exposed to DNA-damaging chemotherapy drugs.[91,92,93,94] Reviewed in [95]
Mistletoe has been shown to stimulate increases in the number and the activity of various types of white blood cells.[40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,7,63,64,65,66,67,68] Reviewed in [69,70,8,2,71,72,3,9,11,29,93,95,96,97,98,38] Immune-system-enhancing cytokines, such as interleukin-1, interleukin-6, and tumor necrosis factor -alpha, are released by white blood cells after exposure to mistletoe extracts.[42,47,57,61,64] Reviewed in [69,70,1,8,37,71,3,72,11,29,91,93,94,95,96,98,38] Other evidence suggests that mistletoe exerts its cytotoxic effects by interfering with protein synthesis in target cells [73,81,90,4,99] Reviewed in [79,86,69,61,8,70,71,72,3,89,100,92,95,98,101] and by inducing apoptosis.[83,95,102] Reviewed in [87,69,63,72,3,98] Mistletoe may also serve a bridging function, bringing together immune system effector cells and tumor cells.[46,103]
More information about the immune system and how it works.
References:
Laboratory / Animal / Preclinical Studies
The immune-system -stimulating and cytotoxic properties of mistletoe have been investigated in laboratory and animal studies.
Viscotoxins and lectins have been investigated as active components in mistletoe; however, most research has focused on the lectins.[1,2,3,4,5,6,7] Reviewed in [8,9] Purified mistletoe lectins have demonstrated cytotoxic and immune-system-stimulating activities. To date, four different lectins: ML-1, ML-2, ML-3, and Viscum albumchitin -binding agglutinin have been identified in mistletoe extracts. ML-1 (or viscumin) may be responsible for many of mistletoe's biological effects. When a laboratory method was used to selectively deplete ML-1 from Viscum album extracts, their cytotoxic and immune-system-stimulating properties were markedly reduced.[10,11] It should be noted that fermentation eliminates most of the ML-1 in mistletoe extracts.[12] Reviewed in [13,14] Polysaccharide and oligosaccharide components of mistletoe extracts with substantial immune-stimulating properties have been reviewed.[15,16]
The molecular structure of ML-1 consists of an alpha chain and a beta chain, which can be separated from one another.[1,17,18] Reviewed in [1,8,9,13,6,7] Each chain type appears to mediate a subset of the activities described for the intact lectin. Cytotoxicity is associated mainly with the alpha chain. In laboratory studies, the ML-1 alpha chain has been coupled to monoclonal antibodies to produce immunotoxins that target and kill specific cell types.[19,20] Reviewed in [21]
Recombinant ML-1, rML (also known as rViscunim or aviscumin) appears to have the same efficacy as plant-based ML-1 in laboratory studies.[22] Since this is not an extract of mistletoe, it is out of the purview of this summary.
The beta chain of ML-1 is responsible for binding to the surface of a target cell.[23] Studies of mistletoe lectin binding to cancer cells have examined whether the extent of cell binding can predict disease outcome or survival. Studies show that the prognostic value of ML-1 binding depends on the type of cancer.[24] For human breast cancer cells, the amount of lectin-bound cells correlates positively with disease outcome. However, for human adenocarcinoma of the lung, there is no correlation between the amount of lectin-bound cells and disease survival.[25] Though much research has looked at this particular aspect, there have not been studies that directly link the concentration of that component to any clinical activity of mistletoe.
Laboratory studies have shown that mistletoe extracts can stimulate the activity of white blood cells in vitro and cause them to release molecules thought to be important for anticancer immune responses. [17,26,27,28,29,30,31,32] Reviewed in [4,6,8,9,33] In addition, mistletoe extracts have demonstrated cytotoxic activity against a variety of mouse, rat, and human cancer cells in vitro. [34,1,35,23,36,37] Reviewed in [8]
There are conflicting reports concerning the stimulation of cancer cell growth in vitro. In one study, the in vitro growth of several types of human cancer cells was stimulated by treatment with low doses of the purified lectin ML-1.[1] However, various other studies found that ML-1 and mistletoe extracts did not induce cell proliferation.[38,39]
A 2004 in vitro study of IscadorQ, a fermented aqueous extract from European mistletoe grown on oaks, against various cell lines demonstrated that sensitivity to this extract varies greatly among cell lines. In sensitive cell lines, a strong effect was seen in epidermal (HaCaT), lung adenocarcinoma (NCI-H125), and breast adenocarcinoma (MCF-7) cell lines whereas, little or no effect was seen in lung squamous cell carcinoma (MR65) and colon carcinoma (Cac0-2, HT-29). Some cells lines were responsive to high or low concentrations of IscadorQ. IscadorQ showed early cell cycle inhibition followed by apoptosis in a dose-dependent manner.[40]
Studies of the ability of mistletoe to inhibit cancer cell growth in animals have yielded mixed and inconsistent results.[41,42,43,44,45,46,47,5,6,7,36,48] Reviewed in [8,9,49] In most of these studies, mistletoe extracts were administered either by subcutaneous injection or by intraperitoneal injection.
In one animal study, treatment with IscadorM increased the survival time of mice that had been implanted with Ehrlich ascites mouse cancer cells, but not L1210 leukemia or B16 melanoma cancer cells.[50] The effect of IscadorM on the growth of tumors formed in mice by three additional types of mouse cancer cells (i.e., Lewis lung carcinoma, colon adenocarcinoma 38, and C3H mammary adenocarcinoma) was also assessed in this study. Treatment with IscadorM substantially reduced the growth rate of all three types of tumors.
In another animal study, mice were administered IscadorM before, during, or after injection with either of two types of mouse cancer cells (i.e., Dalton lymphoma or Ehrlich ascites).[51] In this study, all groups of mice treated with mistletoe showed substantially slower tumor growth than the control groups.
No antitumor effect or improvement in survival was observed when IscadorM was used to treat rats bearing chemically induced mammary carcinomas or tumors formed from rat Walker 256 carcinosarcoma cells.[52] In this study, IscadorM was also not effective in treating mice that had been injected with Ehrlich ascites cells. In addition, IscadorP was found ineffective in treating rats with tumors formed from rat L5222 leukemia cells.
In another study, intratumoral injections of mistletoe extract (Abnoba-viscum Fraxini-2) demonstrated more antitumor activity than intravenous gemcitabine when injected into mouse xenografts of human pancreatic cancer.[53]
Treatment with the mistletoe extract Lektinol (also sold as Plenosol; refer to the General Information section of this summary for more information) has likewise yielded mixed results in animal experiments.[7] Treatment with Lektinol slowed the growth of tumors formed in mice from implants of three types of mouse cancer (i.e., colon adenocarcinoma 38, Renca renal cell carcinoma, and F9 testicular carcinoma) but not in two other mouse cancers (i.e., B16 melanoma and Lewis lung carcinoma).
The anticancer effects of Isorel (also sold as Vysorel; refer to the General Information section of this summary for more information) have been examined in at least two animal studies.[54,36] In one study, IsorelM was used alone or in combination with local x-ray therapy in mice bearing mouse CMC-2 fibrosarcoma tumors.[54] When IsorelM was used alone, no effect on either tumor growth or animal survival was observed. When IsorelM injections were combined with local x-ray therapy of tumors, substantial improvements in survival were found in comparison with the survival of mice treated with local x-ray therapy alone. With local x-ray therapy alone, 22% of mice were cured of their tumors. When local x-ray therapy was combined with IsorelM injections, administered before or after the x-ray treatment, the cure rate increased to 43%. When IsorelM was administered both before and after local x-ray therapy, the proportion of cured mice increased to 67%.
In another study, IsorelM showed antitumor and antimetastatic effects in mice that had been injected with mouse mammary carcinoma cells.[36] The antitumor effects appeared most pronounced when IsorelM was injected in the vicinity of tumors.
The ability of purified or recombinant lectin ML-1 to inhibit the formation of chemically induced bladder tumors in rats has been evaluated in three studies.[55,5,48] Reviewed in [8] In two of the studies, purified ML-1 was administered by subcutaneous injection.[55,5] Reviewed in [8] Treatment with ML-1 did not reduce the frequency of bladder tumor formation or increase immune system activity in the bladder wall in either study. In the third study, recombinant ML-1 was introduced directly into the bladder through a process known as intravesical instillation.[48] Reviewed in [8] In this study, the frequency of bladder tumor formation was reduced by approximately 50% in ML-1-treated animals. As in the other two studies, immune system activity in the bladder wall was not increased substantially. It was concluded that the antitumor effect observed in this study was the result of direct cytotoxic action by the recombinant lectin against malignant cells.[48]
A few animal studies have suggested that mistletoe is beneficial in decreasing the side effects of conventional anticancer therapy (e.g., chemotherapy and radiation therapy) and that it counteracts the effects of drugs used to suppress the immune system.[56,57,58] Reviewed in [59] In one study, IscadorM was shown to increase the number of white blood cells in mice treated with cyclophosphamide chemotherapy or radiation therapy and to decrease the amount of weight loss due to radiation, but not during cyclophosphamide treatment.[58] In another study, IscadorM was shown to accelerate the recovery of hematopoietic tissue in the bone marrow and spleens of irradiated rats and mice.[56] In another study, the mistletoe product Eurixor was shown to counteract the immunosuppressive effects of treatment with the drug cortisone.[57]
References:
Human / Clinical Studies
Mistletoe has been evaluated as a treatment for people with cancer in numerous clinical studies.[1,2,3,4,5,6,7,8,9,10,11,12,13,14] Reviewed in [15,16,17,18,19,20] One phase II study in Israel involved carboplatin /gemcitabine in combination with mistletoe as a complementary treatment in patients with non-small cell lung cancer (NCT00516022). Most studies have been conducted in Europe, primarily in Germany and Austria. However, in 2002, the National Center for Complementary and Alternative Medicine in cooperation with the National Cancer Institute (NCI) began accruing patients to a phase I trial (NCCAM-02-AT-260) of mistletoe (Helixor A) and gemcitabine in patients with advanced solid tumors. The Helixor A and gemcitabine combination showed limited toxicity with clinical benefit in 48% of patients.[21] The trial is now closed and the data is being analyzed. Another U.S. trial (NCT00283478) of the mistletoe extract Iscar with gemcitabine versus gemcitabine alone as a second-line therapy for non-small cell lung cancer patients who have failed one prior line of chemotherapy has been completed.
The mistletoe extracts and products studied in clinical trials were Iscador, Eurixor, Helixor, Lektinol, Isorel, Abnoba-viscum,[22] and recombinant lectin ML-1 (refer to the tables at the end of this section for more information).
Approximately half of the reported studies were controlled studies, and a majority of these were randomized clinical trials. Survival was the principal endpoint measured in most reported studies; however, other endpoints included tumor response, tumor recurrence, and quality of life. A systematic review of all controlled clinical studies of mistletoe found consistent improvement in chemotherapy-associated fatigue as well as other quality-of-life measures.[23]
Although mistletoe was found to be therapeutically effective in most of the reported studies, many of the studies had one or more major weaknesses that raised doubts about the reliability of the findings. These weaknesses include registration of small numbers of patients; presence of large numbers of patients who either were not evaluable or were otherwise excluded from the analyses; failure to adequately document mistletoe use, mistletoe dose, and/or interruptions of mistletoe use; absence of control subjects or use of historical control subjects; use of inadequate randomization procedures; absence of treatment blinding; extensive use of subset analysis; and the measurement of mean as opposed to median survival. (Note: In studies with small numbers of patients, the mean survival time [i.e., the average survival time] can be greatly exaggerated if one or more patients exhibit unusually long survival; median survival, therefore, is a less biased measure.) In addition, evaluation of the studies is often hindered by incomplete descriptions of the study design and by incomplete reporting of clinical data, including data about previous and concurrent therapies received by the patients. A selection of studies is discussed below, organized by the type of mistletoe extract used.
Iscador
A three-arm, randomized phase III trial that involved 408 patients with previously untreated, inoperable non-small cell lung cancer was conducted between 1978 and 1987.[24] Patients were randomly assigned to one of the following treatments: (1) subcutaneous injection 3 times a week with IscadorU or IscadorQ (refer to the General Information section of this summary for more information); the concentration of mistletoe was increased during a seven-injection sequence or cycle, followed by a 3-day pause, and then the process was repeated; IscadorU was administered for two cycles, followed by two cycles of IscadorQ; both mistletoe preparations contained mercury); (2) intramuscular injection once a week with Polyerga Neu, which is a sheep spleen glycopeptide that is reported to be an immunostimulant and an inhibitor of tumor cell glycolysis; and (3) intramuscular injection once a week with a vitamin B mixture, which served as a placebo. Complete follow-up information was available for 337 patients, and 312 patients (105 Iscador treated, 100 Polyerga Neu treated, and 107 placebo treated) were included in the survival analysis. No statistically significant differences in survival were found between the three groups. Median survival for the Iscador group was 9.1 months; for the Polyerga Neu group, it was 9.0 months; and for the placebo group, it was 7.6 months. The researchers reported that 11.5% of the patients in the Iscador group survived 2 years from the time they entered the trial; the corresponding survival values for the Polyerga Neu and the placebo groups were 13.9% and 10.1%, respectively. In addition, no differences were found between the three groups with respect to tumor response, median body weight, blood chemistry values, Karnofsky Performance Status, and quality of life. However, more patients in the Iscador group than in the Polyerga Neu or the placebo groups reported subjective improvement in feelings of well-being (59.4% vs. 43.2% and 44.8%, respectively).
Another randomized phase III trial of mistletoe as a treatment for people with cancer involved 830 patients with high-risk melanoma (i.e., a primary tumor >3 mm in diameter and no regional lymph nodes positive for cancer or a primary tumor of any size, one or two regional lymph nodes positive for cancer, and no distant metastases) who were randomly assigned to one of the following four groups after potentially curative surgery: (1) treatment with low-dose interferon -alpha, (2) treatment with low-dose interferon-gamma, (3) treatment with IscadorM, or (4) no further treatment. Both types of interferon and IscadorM were administered by subcutaneous injection for a period of 1 year.[5] The interferon injections were administered every other day, whereas IscadorM was administered 3 times a week. After 8 years of follow-up, no increase in survival time or increase in time until melanoma recurrence was demonstrated for mistletoe treatment or treatment with either type of interferon. A nonrandomized, case-control study of long-term mistletoe extract for patients with melanoma, however, showed a survival advantage among patients with high-risk disease.[25]
Three other studies of mistletoe were described in a single published report.[4] One of the three studies was a large cohort study on the effectiveness of Iscador as a treatment for people with rectal cancer, colon cancer, breast cancer, stomach cancer, or lung cancer.[4] The second and third studies were small, prospective, randomized, matched-pair studies (one randomized, one nonrandomized) that involved patients who were selected from a group of 8,475 individuals who had not been treated with mistletoe.[4]
These studies are summarized in Table 1. The overall conclusion of the authors in the report of these three studies was that Iscador treatment can produce a clinically significant increase in survival in cancer patients. However, there were several weaknesses in the design and execution of these studies. In a large cohort study, the investigators were unable to find matching cohorts for 61% of eligible patients, and even among the patients for whom matches were found, fewer than two-thirds were judged to adhere strictly to the matching criteria; thus, the final analysis contained fewer than 25% of eligible patients. In the two small prospective studies, no records on the amount or duration of Iscador use were kept.
The use of Iscador as an adjuvant treatment has been examined in several studies. In the following studies, Iscador proved safe and effective and also showed a significant survival advantage over untreated controls.
In a phase l/ll trial of Iscador as an adjuvant postoperative treatment for superficial bladder cancer, mistletoe extract was found to be a safer and more effective alternative to Bacillus Calmette-Guérin (BCG). Thirty patients were administered Iscador instillations 4 weeks after surgery. Patients treated with Iscador did equally well with fewer side effects than a group of historical controls treated with BCG.[26,27]
A retrospective multicenter cohort study of parallel groups examined Iscador as a postoperative adjuvant using safety and efficacy as the main endpoints. A total of 1,442 patient records (710 treated patients and 732 untreated controls) were randomly selected from medical institutions that provided both standard and alternative treatments. Safety and efficacy were measured by the number and severity of adverse drug reactions. The treatment group showed significantly less adverse reactions (confidence interval = 95%; P = < .001) compared with the controls.[28,29]
A multicenter, controlled, retrospective observational cohort study that involved nonmetastatic colorectal cancer patients treated between 1993 and 2002 was conducted to evaluate safety and efficacy measures with Iscador. Eight hundred and four consecutive colorectal patients (429 treated with Iscador and 375 controls) from 26 hospitals and practices were included. Iscador was well tolerated, with a significant reduction in adverse events, a higher rate of symptom relief, and improved disease-free survival compared with the control group. The study concluded the use of Iscador has a beneficial effect as an adjuvant therapy and long-term treatment for patients with stage I to III colorectal cancer.[30]
In another retrospective multicenter cohort study to determine safety and efficacy of Iscador as an adjuvant long-term treatment following surgery for malignant melanoma, 686 patient records were examined (e.g., 357 untreated controls and 329 treated with Iscador). Safety, efficacy, and a cluster of survival endpoints (tumor-related, disease-free, brain-metastases free, and overall survival) were measured. Only mild to intermediate adverse drug reactions were seen in the treated group. Survival analyses showed no evidence of tumor enhancement and no increased incidence of brain or other metastases in the Iscador group. Results suggest significant survival benefit for all survival-related endpoints in the treatment group.[25]
Eurixor
Five randomized controlled trials of Eurixor have been published as peer-reviewed articles. The largest of these studies involved 477 patients with squamous cell carcinoma of the head and neck.[2] Reviewed in [15] These patients were randomly assigned to treatment with surgery or surgery and radiation therapy, and they were randomly assigned again to either no additional treatment or treatment with Eurixor. This double randomization produced the following four groups: (1) 105 patients treated with surgery alone; (2) 97 patients treated with surgery and Eurixor; (3) 137 patients treated with surgery and radiation therapy; and (4) 138 patients treated with surgery, radiation therapy, and Eurixor. Eurixor was administered in four treatment cycles over a 60-week period. Each treatment cycle lasted 12 weeks and was followed by a 4-week break period. During each cycle, Eurixor was administered by subcutaneous injection twice a week. Each injection contained enough standardized mistletoe extract to yield a dose of 1 nanogram of ML-1 lectin per kilogram of body weight. The results of this randomized trial showed that treatment with Eurixor did not improve either 5-year disease-free survival or 5-year disease-specific survival. In addition, no stimulation of the immune system or improvement in quality of life was found with Eurixor treatment.
It has been suggested that a less-than-optimum dose of mistletoe was administered to patients in this trial.[4] The same dose of Eurixor, however, has been used in other clinical studies, including studies in which benefit was reported.[1,31] In addition, both the dose and the duration of Eurixor treatment in this trial are consistent with those recommended by the manufacturer.[2]
A prospective, randomized phase II trial involved 45 patients who had noninvasive bladder cancer.[3] After surgery, the patients were randomly assigned to receive either three cycles of treatment with Eurixor or no further therapy. The goal of the study was to determine whether Eurixor treatment could reduce bladder cancer recurrence. Twenty-three patients were randomly assigned to the treatment group, and 22 were randomly assigned to the control group. Each cycle of Eurixor treatment consisted of 3 months of subcutaneous injections, administered twice a week, followed by a 3-month break period. One milliliter of Eurixor was administered at each injection. After 18 months of follow-up, 11 recurrences were observed in the treatment group, and 8 were observed in the control group. The average time of recurrence for the treatment group was 6.3 months; for the control group, it was 6.4 months. The median disease-free interval for the treatment group was 9 months; for the control group, it was 10.5 months. None of these differences was considered significant.
A major concern about this study, however, is that the dose of lectin ML-1 administered to patients was not adjusted for body weight. If different batches of Eurixor were used for individual patients, the patients may not have received uniform doses throughout the trial. Each milliliter of Eurixor has been reported to contain 50 to 70 nanograms of ML-1. Reviewed in [31,1,32] Therefore, the dose of lectin administered to a person weighing 120 pounds (approximately 55 kg) could have ranged from 0.91 nanograms per kilogram body weight to 1.27 nanograms per kilogram body weight. For a person weighing 160 pounds (approximately 73 kg), the dose of lectin could have ranged from 0.68 nanograms per kilogram body weight to 0.96 nanograms per kilogram body weight. As indicated above, the manufacturer of Eurixor recommends a dose of 1 nanogram per kilogram body weight. Since 33 of the 45 patients in this trial were men, and men tend to weigh more than women, it is conceivable that a substantial fraction of the patients were treated with lower-than-recommended doses of ML-1.
Isorel
Only two trials of Isorel have been reported in the publicly available, online indexed peer-reviewed medical literature. In one study, 64 patients with advanced colorectal cancer (Dukes C and D) were randomly assigned to three groups: (1) surgery and chemotherapy; (2) surgery and chemotherapy plus Isorel; and (3) surgery alone. Patients receiving treatment with Isorel had a significantly better median survival advantage and a better cumulative survival advantage than patients in the other two groups. In addition there were no side effects to treatment in the Isorel group.[33]
Another study showed that perioperative use of Isorel in patients with cancer of the digestive tract resulted in an increase in lymphocytes through 14 days of drug administration. In a group of 70 surgically treated patients, 40 patients were assigned to the Isorel-treated group, and 30 patients were assigned to the control group. The treatment group showed an increase in CD4/CD8 ratio (P = < .05) from the start to the end of treatment and an increase in natural killer (NK) cell determinants. NK cell activity and lymphocyte levels declined in the controls. Quality-of-life measures also increased in the treatment group.[34]
Helixor
In a three-arm randomized trial, breast cancer patients were randomly assigned to one of the following groups after surgery: Helixor, chemotherapy, or control. Some patients in each group were also treated with local radiation therapy. The number of evaluable patients in the chemotherapy group was 177, with survival in the chemotherapy group superior to that in the control group and equivalent to that in the Helixor group.[35] In another three-arm randomized trial, metastatic colorectal cancer patients were randomly assigned to receive chemotherapy only (n = 20), chemotherapy plus Helixor (n = 20), or chemotherapy plus Ney-Tumorin (n = 20); Ney-Tumorin is a mixture of peptides and proteins from 15 different organs of fetal and young pigs or cows that is reported to have both antitumor and immunostimulatory properties. The mean survival time (in months) of patients treated with either Helixor or Ney-Tumorin was approximately twice that of patients treated with chemotherapy only.[36] The use of Helixor has also been examined in other studies.[37,38,39,40]
Abnoba-viscum
No tumor response was seen in any of the 25 patients in a phase ll trial that examined the effect of a mistletoe extract in metastatic colorectal cancer resistant to standard treatment (5-fluorouracil and leucovorin chemotherapy), which used an extract known as Abnoba-viscum. The endpoint of the study was objective tumor response. Patients were administered a gradually increasing daily dose of 0.15 mg to 15 mg. Treatment duration ranged from 4 weeks to 66 weeks. Toxicity levels were mild. Some patients reported relief of disease symptoms.[41]
Table 1. Use of Iscador in Cancer Treatment: Clinical Reports Describing Therapeutic Endpointsa
| Reference Citation(s) | Type of Study | Type(s) of Cancer | No. of Patients: Enrolled; Treated; Controlb | Strongest Benefit Reportedc | Concurrent Therapyd | Level of Evidence Scoree |
| LN+ = lymph node-positive disease; No. = number. | ||||||
| a See text and theNCI Dictionary of Cancer Termsfor additional information and definition of terms. | ||||||
| b Number of patients treated plus number of patients controlled may not equal number of patients enrolled; number of patients enrolled = number of patients initially recruited/considered by the researchers who conducted a study; number of patients treated = number of enrolled patients who were administered the treatment being studiedAND for whom results were reported; historical control subjects are not included in number of patients enrolled. | ||||||
| c Strongest evidence reported that the treatment under study has anticancer activity or otherwise improves the well-being of cancer patients. | ||||||
| d Chemotherapy, radiation therapy, hormonal therapy, or cytokine therapy administered/allowed at the same time as mistletoe therapy. | ||||||
| e For information about levels of evidence analysis and an explanation of the level of evidence scores, seeLevels of Evidence for Human Studies of Cancer Complementary and Alternative Medicine. | ||||||
| f Control patients were treated with a vitamin B mixture as a placebo; 100 additional evaluable patients were treated with Polyerga Neu, a sheep spleen glycopeptide reported to be an immunostimulant and an inhibitor of tumor cell glycolysis; treatment with Polyerga Neu was not found to be beneficial. | ||||||
| g Radiation therapy for metastases distant from the site of the primary tumor was permitted; radiation therapy to the primary tumor site or use of other anticancer treatment was not permitted. | ||||||
| h Among 10,226 cancer patients enrolled in a retrospective matched-pair, case-control study, 1,751 had been treated with Iscador or another mistletoe product and 8,475 had not been treated with mistletoe; from the 8,475 untreated patients, two sets of matched pairs were formed for prospective studies; in the prospective studies, one member of each pair was randomly assigned to be treated with Iscador and the other member served as a control subject. | ||||||
| i Patients were strictly matched according to gender, year of birth ±3 years, year of diagnosis ±3 years, type of tumor, stage of disease, and conventional therapy received. | ||||||
| [24] | Randomized trial | Lung, non-small cell, inoperable | 408; 105; 107f | Subjective improvement in quality of life | Yesg | 1iiA |
| [42] | Randomized trial | Lung, non-small cell, stages I–IV | 218; 87; 96 | Improved median survival, LN+ patients only | No | 1iiA |
| [5] | Randomized trial | Melanoma, stages II–III | 830; 102; 102 | None | No | None |
| [28] | Comparative, retrolective, cohort study | Breast, stages I–IV | 1,442; 710; 732 | Improved survival | Yes | 2B |
| [25] | Comparative, retrolective, cohort study | Melanoma, stages II–III | 686; 329; 357 | Improved survival | Unknown | 2A |
| [4] | Cohort study | Breast, stage III | 8,475h; 17i; 17i | Improved mean survival | Yes | 1iiA |
| [4] | Cohort study | Various types, stages I–IV | 8,475h; 39i; 39i | Improved mean survival | Yes | 1iiA |
| [4] | Cohort study | Various types, stages I–IV | 10,226h; 396i; 396i | Improved mean survival | Yes | 3iiiA |
| [30] | Retrospective, observational cohort study | Nonmetastatic colorectal | 804; 429; 375 | Lower incidence of diarrhea, nausea, loss of appetite, dermatitis, fatigue, and mucositis | Yes | 2C |
| [43] | Nonconsecutive case series | Pancreas | 292; 292; various historical controls | Improved median survival | Yes | 3iiiA |
| [44] | Case report | Lung, small cell, stage IV | 1; 1; None | Partial response | Yes | None |
Table 2. Use of Eurixor in Cancer Treatment: Clinical Reports Describing Therapeutic Endpointsa
| Reference Citation(s) | Type of Study | Type(s) of Cancer | No. of Patients: Enrolled; Treated; Controlb | Strongest Benefit Reportedc | Concurrent Therapyd | Level of Evidence Scoree |
| No. = number. | ||||||
| a See text and theNCI Dictionary of Cancer Termsfor additional information and definition of terms. | ||||||
| b Number of patients treated plus number of patients controlled may not equal number of patients enrolled; number of patients enrolled = number of patients initially recruited/considered by the researchers who conducted a study; number of patients treated = number of enrolled patients who were administered the treatment being studiedAND for whom results were reported; historical control subjects are not included in number of patients enrolled. | ||||||
| c Strongest evidence reported that the treatment under study has anticancer activity or otherwise improves the well-being of cancer patients. | ||||||
| d Chemotherapy, radiation therapy, hormonal therapy, or cytokine therapy administered/allowed at the same time as mistletoe therapy. | ||||||
| e For information about levels of evidence analysis and an explanation of the level of evidence scores, seeLevels of Evidence for Human Studies of Cancer Complementary and Alternative Medicine. | ||||||
| f This trial was a four-arm trial; patients were randomly assigned to surgery only or to surgery plus radiation therapy, followed by a second randomization to no mistletoe treatment or to treatment with Eurixor; the resulting treatment groups contained the following numbers of evaluable patients: surgery only = 105, surgery plus Eurixor = 97, surgery plus radiation therapy = 137, and surgery plus radiation therapy plus Eurixor = 138; radiation therapy and Eurixor treatment overlapped; no treatment approach was superior in terms of disease-free survival, disease-specific survival, improvement in quality of life, or stimulation of the immune system; in the table, mistletoe-treated and nontreated (control) patients were grouped (i.e., number treated = 97 + 138 = 235, and number control = 105 + 137 = 242). | ||||||
| [3] | Randomized trial | Bladder, noninvasive | 45; 23; 22 | None | No | 1iiDi |
| [1,31] | Randomized trial | Brain, glioma; 74% of patients, stages III–IV; 26% of patients, no stage information | 47; 20; 18 | Improved survival, stages III–IV patients only | Yes | 1iiA |
| [45,46] | Randomized trial | Colorectal, metastatic | 107; 38; 41 | Improved quality of life | Yes | 1iiA |
| [2] | Randomized trial | Head and neck, squamous cell, stages I–IV | 495; 235f; 242f | None | Yesf | 1iiA |
Table 3. Use of Helixor in Cancer Treatment: Clinical Reports Describing Therapeutic Endpointsa
| Reference Citation(s) | Type of Study | Type(s) of Cancer | No. of Patients: Enrolled; Treated; Controlb | Strongest Benefit Reportedc | Concurrent Therapyd | Level of Evidence Scoree |
| No. = number. | ||||||
| a See text and theNCI Dictionary of Cancer Termsfor additional information and definition of terms. | ||||||
| b Number of patients treated plus number of patients controlled may not equal number of patients enrolled; number of patients enrolled = number of patients initially recruited/considered by the researchers who conducted a study; number of patients treated = number of enrolled patients who were administered the treatment being studiedAND for whom results were reported; historical control subjects are not included in number of patients enrolled. | ||||||
| c Strongest evidence reported that the treatment under study has anticancer activity or otherwise improves the well-being of cancer patients. | ||||||
| d Chemotherapy, radiation therapy, hormonal therapy, or cytokine therapy administered/allowed at the same time as mistletoe therapy. | ||||||
| e For information about levels of evidence analysis and an explanation of the level of evidence scores, seeLevels of Evidence for Human Studies of Cancer Complementary and Alternative Medicine. | ||||||
| [35] | Randomized trial | Breast, stages I–III | 692; 192; 274 | Improved survival | Yes | 1iiA |
| [36] | Randomized trial | Colorectal, metastatic | 60; 20; 20 | Improved mean survival | Yes | 1iiA |
Table 4. Use of Other Mistletoe Products in Cancer Treatment: Clinical Reports Describing Therapeutic Endpointsa
| Reference Citation(s) | Type of Study | Product Tested | Type(s) of Cancer | No. of Patients: Enrolled; Treated; Controlb | Strongest Benefit Reportedc | Concurrent Therapyd | Level of Evidence Scoree |
| No. = number. | |||||||
| a See text and theNCI Dictionary of Cancer Termsfor additional information and definition of terms. | |||||||
| b Number of patients treated plus number of patients controlled may not equal number of patients enrolled; number of patients enrolled = number of patients initially recruited/considered by the researchers who conducted a study; number of patients treated = number of enrolled patients who were administered the treatment being studiedAND for whom results were reported; historical control subjects are not included in number of patients enrolled. | |||||||
| c Strongest evidence reported that the treatment under study has anticancer activity or otherwise improves the well-being of cancer patients. | |||||||
| d Chemotherapy, radiation therapy, hormonal therapy, or cytokine therapy administered/allowed at the same time as mistletoe therapy. | |||||||
| e For information about levels of evidence analysis and an explanation of the level of evidence scores, seeLevels of Evidence for Human Studies of Cancer Complementary and Alternative Medicine. | |||||||
| [13] | Randomized controlled trial | PS76A (Lektin) | Breast | 352; 176; 176 | Improved quality of life | Yes | 1iC |
| [33] | Randomized trial | Isorel | Colorectal | 64; 50; 14 | Improved survival and tolerance to either adjuvant or palliative treatment | Yes | 1iiA |
| [34] | Nonrandomized controlled trial | Isorel | Digestive tract | 70; 40; 30 | Enhanced cellular immunity and improved quality of life | No | 2C |
| [41] | Nonrandomized controlled trial | Abnoba-viscumQuercus | Metastatic colorectal | 25; 25; none | None | Yes | 2Diii |
| [22] | Nonrandomized controlled trial | Viscum fraxini-2 | Hepatocellular carcinoma | 23; 23; none | Improved survival | No | 2Dii |
Current Clinical Trials
Check NCI's list of cancer clinical trials for cancer CAM clinical trials on mistletoe extract that are actively enrolling patients.
General information about clinical trials is also available from the NCI Web site.
References:
Adverse Effects
Although a number of different mistletoe extracts have been used in human studies, the reported side effects have generally been minimal and not life threatening. Common side effects include soreness and inflammation at injection sites, headache, fever, and chills. Reviewed in [1,2,3] A few cases of severe allergic reactions, including anaphylactic shock, have been reported.[2]
References:
Summary of the Evidence for Mistletoe Extracts
Mistletoe is one of the most widely studied complementary and alternative medicine therapies for cancer. In certain European countries, the preparations made from European mistletoe (Viscum album L.) are among the most prescribed drugs offered to cancer patients. Mistletoe extracts have been evaluated in numerous clinical studies and improvements in survival, quality of life, and/or stimulation of the immune system have been frequently reported. However, most clinical studies conducted to date have had one or more major weaknesses that raise doubts about the reliability of the findings. In addition, no evidence exists to support the notion that stimulation of the immune system by mistletoe leads to an improved ability to fight cancer. Because all patients in the reported clinical studies appear to have been adults, no information is available about the use of mistletoe as a treatment for children with cancer. At present, there is insufficient evidence to recommend the use of mistletoe as a treatment for people with cancer outside the context of well-designed clinical trials. Such trials will be valuable to determine more clearly whether mistletoe can be useful in the treatment of specific subsets of cancer patients.
Separate levels of evidence scores are assigned to qualifying human studies on the basis of statistical strength of the study design and scientific strength of the treatment outcomes (i.e., endpoints) measured. The resulting two scores are then combined to produce an overall score. For additional information about levels of evidence analysis, refer to Levels of Evidence for Human Studies of Cancer Complementary and Alternative Medicine.
Changes to This Summary (08 / 16 / 2012)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Editorial changes were made to this summary.
This summary is written and maintained by the PDQ Cancer Complementary and Alternative Medicine Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of mistletoe extracts in the treatment of people with cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Cancer Complementary and Alternative Medicine Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Mistletoe Extracts are:
- Lawrence B. Berk, MD, PhD (University of South Florida)
- John A. Beutler, PhD (National Cancer Institute)
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Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Cancer Complementary and Alternative Medicine Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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National Cancer Institute: PDQ® Mistletoe Extracts. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/cam/mistletoe/HealthProfessional. Accessed <MM/DD/YYYY>.
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Last Revised: 2012-08-16
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