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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:
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.
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[1,2,3,4,5,6,7,8,9,10] and to stimulate immune system cells both in vitro and in vivo.[10,11,12,13,14,15,16,17,18,19,20,21,22,23,24] Two components of mistletoe, namely viscotoxins, polysaccharides and lectins, may be responsible for these effects.[10,11,12,13,17,18,19,21,22,23,25,26,27,28,29,30,31,32] Viscotoxins are small proteins that exhibit cell-killing activity and possible immune-system-stimulating activity.[1,6,18,19,33,34] 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.[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. 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.
Preparations from mistletoe extracts are most frequently used in the treatment of cancer patients in German-speaking countries. Commercially available extracts are marketed under a variety of brand names, including Iscador (see explanation of suffixes below), Eurixor, Helixor, Isorel, Iscucin, Plenosol, and abnobaVISCUM. 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. Eurixor, Isorel, and Vysorel are no longer available on the market for sale.
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 cytotoxicity 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.[8,36,46,47,48,49]
Mistletoe extracts are prepared as aqueous solutions or solutions of water and alcohol, and they can be fermented or unfermented.[4,6,20,46,47,50,51,52,53] Some extracts are prepared according to homeopathic principles, and others are not. Accordingly, as homeopathic preparations, they are typically not chemically standardized extracts.[10,54] In addition, the commercial products can be subdivided according to the species of host tree, which is typically indicated in the product name by a suffix letter. Iscador, a fermented aqueous extract of Viscum album L. that is prepared as a homeopathic drug, is marketed as IscadorM (from apple trees; Malus domestica), IscadorP (from pine trees; Pinus sylvestris), IscadorQu (from oak trees; Quercus robur), and IscadorU (from elm trees; Ulmus minor). 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; Picea abies), HelixorM (from apple trees), and HelixorP (from pine trees; Pinus sylvestris). Eurixor (which is no longer available on the market for sale), 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). Some proponents contend the choice of extract should depend on the type of tumor and the gender of the patient.[49,51,55,56]
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.
Mistletoe extracts are usually given by subcutaneous injection, although administration by other routes (i.e., oral, intrapleural, intratumoral, and intravenous) has been described.[17,20,21,22,23,24,32,36,49,51,54,58,59,60,61,62,63] 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. 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).
In this summary, the mistletoe extract or product used in each study will be specified wherever possible.
Mistletoe has been used for centuries for its medicinal properties.[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. Most of the results of clinical studies have been published exclusively in German. Refer to the Human/Clinical Studies section of this summary for more information.
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.[7,8,9,10,11]
Mistletoe has been shown to stimulate increases in the number and the activity of various types of white blood cells.[2,3,9,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53] 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.[1,3,7,9,10,11,14,19,29,33,37,42,43,44,45,46,48,49,50,52,53,54] Other evidence suggests that mistletoe exerts its cytotoxic effects by interfering with protein synthesis in target cells [3,4,8,11,33,42,43,44,45,46,52,55,56,57,58,59,60,61,62,63] and by inducing apoptosis.[3,11,36,42,46,52,64,65,66] Mistletoe may also serve a bridging function, bringing together immune system effector cells and tumor cells.[18,67]
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; most research has focused on the lectins.[1,2,3,4,5,6,7,8,9] 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.[12,13,14] 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.[1,1,6,7,8,9,13,17,18] 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.[19,20,21]
Recombinant ML-1, rML (also known as rViscunim or aviscumin) appears to have the same efficacy as plant-based ML-1 in laboratory studies. 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. 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. 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. 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. [4,6,8,9,17,26,27,28,29,30,31,32,33] In addition, mistletoe extracts have demonstrated cytotoxic activity against a variety of mouse, rat, and human cancer cells in vitro.[1,8,23,34,35,36,37]
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. However, various other studies found that ML-1 and mistletoe extracts did not induce cell proliferation.[38,39]
A 2004 in vitro study of IscadorQu, 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 IscadorQu. IscadorQu showed early cell cycle inhibition followed by apoptosis in a dose-dependent manner.
Studies of the ability of mistletoe to inhibit cancer cell growth in animals have yielded mixed and inconsistent results.[5,6,7,8,9,36,41,42,43,44,45,46,47,48,49] 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. 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). 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. 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 (abnobaVISCUM Fraxini-2) demonstrated more antitumor activity than intravenous gemcitabine when injected into mouse xenografts of human pancreatic cancer.
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. 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.[36,54] In one study, IsorelM was used alone or in combination with local x-ray therapy in mice bearing mouse CMC-2 fibrosarcoma tumors. 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. 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.[5,8,48,55] In two of the studies, purified ML-1 was administered by subcutaneous injection.[5,8,55] 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.[8,48] 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.
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.[56,57,58,59] 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. In another study, IscadorM was shown to accelerate the recovery of hematopoietic tissue in the bone marrow and spleens of irradiated rats and mice. In another study, the mistletoe product Eurixor was shown to counteract the immunosuppressive effects of treatment with the drug cortisone. In this in vitro study, mistletoe (Viscum album L.) did not inhibit chemotherapy-induced cytostasis or cytotoxicity.
Mistletoe has been evaluated as a treatment for people with cancer in numerous clinical studies.[1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20]
The mistletoe extracts and products studied in clinical trials were Iscador, Eurixor, Helixor, Lektinol, Isorel, abnobaVISCUM, and recombinant lectin ML-1 (refer to the appropriate sections and tables at the end of this section for more information).
The findings from more than 50 clinical trials of mistletoe extracts in patients with cancer have been published, and several systematic reviews and meta-analyses of the results of these studies have been performed. Three of the most recent systematic reviews addressed quality of life (QOL), survival, and symptom relief in patients with various cancer types.[18,20,22] Most studies reported an improvement in QOL.
In one systematic review that examined 26 randomized controlled trials (RCTs), 22 trials reported an improvement in QOL. All 10 of the nonrandomized controlled trials also reported the same benefit. Improvement in fatigue, nausea and vomiting, depression, emotional well-being, and concentration were reported. Some of the studies were well designed, while others reported weaknesses.
Tumor response, QOL, and psychological distress were measured in a review of 21 RCTs of various cancers in which different mistletoe preparations were used either alone, with chemotherapy, or with radiation therapy. Survival times were included in 13 of the studies. Most of the studies reported benefits for patients, although this review was limited by small sample size and methodological weaknesses. Thus, the authors were unable to suggest practice guidelines for the use of mistletoe.
The oldest of these three reviews investigated the results of 10 RCTs that used a variety of mistletoe extracts in patients with various malignancies. There was no difference in survival or other benefits for cancer patients who received mistletoe. Therefore, mistletoe was not recommended as a curative or supportive care therapy.
A systematic review of all controlled clinical studies of mistletoe found consistent improvement in chemotherapy-associated fatigue as well as other QOL measures.
Although mistletoe was found to be therapeutically effective in most of the reported studies, many of the studies had one or more major design weaknesses as mentioned above 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 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. Eurixor, Isorel, and Vysorel are no longer available on the market for sale.
An interim analysis of a randomized phase III trial reported on 220 patients with locally advanced or metastatic pancreatic cancer. Patients received best supportive care and were randomly assigned to receive either IscadorQu or no antineoplastic therapy (control). Patients were stratified according to tumor stage, age, and performance status. Iscador was administered subcutaneously in a dose-escalating manner from 0.01 mg to 10 mg three times per week. Treatment with Iscador demonstrated a significant enhancement of overall survival (OS) (4.8 months vs. 2.7 months for IscadorQu patients vs. control patients, respectively; prognosis-adjusted hazard ratio [HR], 0.49; P < .0001). Patients were further stratified into two groups based on their expected prognostic factors:
Subgroup analysis demonstrated clinically relevant enhancement in the survival of both groups of patients who received Iscador. The median OS in patients who were classified as having a good prognosis was 6.6 months for the Iscador group versus 3.2 months for controls (HR, 0.43; P < .0001). Patients classified with a poor prognosis had a median OS of 3.4 months for the Iscador group versus 2.0 months for controls (HR, 0.55; P = .0031). For patients who received Iscador, the frequency and severity of post baseline disease-related symptoms were also significantly lower for the following:
The independent data monitoring committee that reviewed the interim analysis results recommended termination of the trial because of statistically significant superiority of survival in the treatment group, compared with the control group.
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. Patients were randomly assigned to one of the following treatments:
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. The interferon injections were administered every other day, whereas IscadorM was administered 3 times a week for up to 1 year. 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.
In another retrospective multicenter cohort study that determined the safety and efficacy of Iscador as an adjuvant long-term treatment after surgery for malignant melanoma, 686 patient records were examined (357 untreated controls and 329 treated with Iscador). Safety, efficacy, and a cluster of survival endpoints (tumor related, disease free, brain metastases free, and OS) were measured. The use of additional adjuvant chemotherapy was more frequent in the Iscador-treated group, while the use of immunotherapy was more frequent in the control group. Only mild to intermediate adverse drug reactions were seen in the treated group. The tumor-related mortality rate was 8.9% in the Iscador group, compared with 10.7% in the control group (P = .017).
Three other studies of mistletoe were described in a single published report. 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. 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.
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 matched 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 of 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.
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.[26,27]
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.
A randomized phase II study of Iscador combined with carboplatin-containing regimens was conducted in chemotherapy-naïve patients with advanced non-small cell lung cancer. Seventy-two patients were randomly assigned to receive either chemotherapy alone with carboplatin combined with gemcitabine or pemetrexed (39 patients) or chemotherapy plus Iscador (33 patients) 3 times a week until tumor progression. Time to progression (4.8 months vs. 6 months) and OS (11 months) were similar in both treatment groups. There were no differences in QOL observed between the treatment groups, although chemotherapy dose reductions, nonhematologic toxicities, and hospitalizations were less frequent in patients treated with Iscador in this nonblinded study.
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 but not yet published.
Other Mistletoe Preparations
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.[2,15] 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. The same dose of Eurixor, however, has been used in other clinical studies, including studies in which benefit was reported.[1,33] In addition, both the dose and the duration of Eurixor treatment in this trial are consistent with those recommended by the manufacturer.
A prospective, randomized phase II trial involved 45 patients who had noninvasive bladder cancer. 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.
Eurixor is no longer available on the market for sale.
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.
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.
Isorel is no longer available on the market for sale.
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. 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. The use of Helixor has also been examined in other studies.[37,38,39,40]
Most studies have been conducted in Europe, primarily in Germany and Austria. However, the National Center for Complementary and Alternative Medicine in cooperation with the National Cancer Institute (NCI) conducted 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, and no botanical-drug interactions were reported.
No tumor response was seen in any of the 25 patients in a phase ll trial that examined the effect of a mistletoe extract, known as abnobaVISCUM, in metastatic colorectal cancer resistant to standard treatment (5-fluorouracil and leucovorin chemotherapy). 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. A small, randomized, nonblinded trial of abnobaVISCUM, given postoperatively to 15 patients with resected stage IB or II gastric cancer, showed improved quality of life among patients who received the mistletoe extract compared with 16 untreated controls.
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.
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.[1,2,3]
One meta-analysis using Viscum album L. and isolated mistletoe lectins included both animal and human studies. Doses and application forms varied. No immunosuppressive effects were reported. Side effects included local reactions at the injection site and flu-like symptoms such as fever, chills, fatigue, mild gastrointestinal symptoms, and headache. High doses of mistletoe lectins resulted in reversible hepatotoxicity in some cases. Another review reported adverse reactions that included local reactions at the injection site, fever, increased intracerebral pressure, headache, circulatory problems, thrombophlebitis, swelling of lymph nodes, and allergic reactions.
A few cases of severe allergic reactions, including anaphylactic shock, have been reported.
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.
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.
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.
Added text to state that Eurixor, Isorel, and Vysorel are no longer available on the market for sale.
Added text to state that in this in vitro study, mistletoe did not inhibit chemotherapy-induced cytostasis or cytotoxicity (cited Weissenstein et al. as reference 60).
Added text about an interim analysis of a randomized phase III trial that reported on 220 patients with locally advanced or metastatic pancreatic cancer in whom treatment with Iscador demonstrated a significant enhancement of overall survival (cited Tröger et al. as reference 23).
Added text about a subgroup analysis that demonstrated clinically relevant enhancement in the survival of both groups of patients who received Iscador; for patients who received Iscador, the frequency and severity of post baseline disease-related symptoms were also significantly lower for pain, weight loss, fatigue, nausea and/or emesis, diarrhea, and anxiety.
Added text to state that the independent data monitoring committee that reviewed the interim analysis results recommended termination of the trial because of statistically significant superiority of survival in the treatment group as compared with the control group.
Revised text to state that the interferon injections were administered every other day, whereas IscadorM was administered 3 times a week for up to 1 year.
Added text to Table 1 about a randomized trial that found that treatment with Iscador improved survival in patients with advanced or metastatic pancreatic cancer.
Added text to state that Eurixor is no longer available on the market for sale.
Added text to state that Isorel is no longer available on the market for sale.
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.
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).
Board members review recently published articles each month to determine whether an article should:
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:
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
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.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
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>.
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
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Last Revised: 2015-01-13
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