This cancer 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 cancer information summaries may include links to external websites 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 websites, or of any treatment or product, by the PDQ Integrative, Alternative, and Complementary Therapies 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 [1-10] to down-regulate central genes involved in tumor progression, malignancy, and cell migration and invasion, such as TGF-beta and matrix-metalloproteinases.[11,12] Mistletoe extracts have been shown to do the following:[10-31]
Three components of mistletoe, namely viscotoxins, polysaccharides, and lectins, may be responsible for these effects.[10,13-15,19-21,23-25,32-39] Viscotoxins are small proteins that exhibit cell-killing activity and possible immune system–stimulating activity.[1,6,20,21,40,41] 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.[10,42-45]
In view of mistletoe’s ability to stimulate the immune system, it has been classified as a type of biological response modifier.[42] 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.[29]
Preparations from mistletoe extracts are most frequently used in the treatment of cancer patients in German-speaking countries.[46] 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 commercially available.
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.[47-51]
Mistletoe grows on several types of trees, and the chemical composition of extracts derived from it depends on the following:[8,43,52-55]
Mistletoe extracts are prepared as aqueous solutions or solutions of water and alcohol, and they can be fermented or unfermented.[4,6,22,52,53,56-59] Some extracts are prepared according to homeopathic principles, and others are not. Accordingly, as homeopathic preparations, they are typically not chemically standardized extracts.[10,60] 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 one of the following:[57]
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 one of the following:[57]
Eurixor (which is no longer commercially available), 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).[57] For more information, see the History section. Some proponents contend the choice of extract should depend on the type of tumor and the sex of the patient.[55,57,61,62]
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. Because this is not an extract of mistletoe, it is out of the purview of this summary.[63]
Mistletoe extracts are usually given by subcutaneous injection, although administration by other routes (i.e., oral, intrapleural, intratumoral, and intravenous) has been described.[19,22-26,39,43,55,57,60,64-70] 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.[71] 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, such as the mistletoe product described in this summary.
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.[1-6] 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. The use of mistletoe in the treatment of cancer is about 100 years old, and its use in the treatment of other indications is much older. 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. For more information, see the Human/Clinical Studies section.
Another reported activity of mistletoe 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.[7-11]
Mistletoe has been shown to stimulate increases in the number and the activity of various types of white blood cells.[2,3,9,11-53] 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.[1,3,7,9-11,14,19,29,33,37,42-46,48-50,52-54] Other evidence suggests that mistletoe exerts its cytotoxic effects by interfering with protein synthesis in target cells [3,4,8,11,33,42-46,52,55-63] and by inducing apoptosis.[3,11,36,42,46,52,64-66] 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.[1-9] Purified mistletoe lectins have demonstrated cytotoxic and immune system–stimulating activities. Four different lectins have been identified in mistletoe extracts as follows:
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. Iscador, and other fermented mistletoe extracts, contain only the mistletoe lectins ML-2 and ML-3, whereas the proteins of the ML-1 complex are missing.[12-14] 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.[1,6-9,13,17,18] 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.[19-21]
Recombinant ML-1, rML (also known as rViscumin or aviscumine) appears to have the same efficacy as plant-based ML-1 in laboratory studies.[22] Because 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.[4,6,8,9,17,26-33] In addition, mistletoe extracts have demonstrated cytotoxic activity against a variety of mouse, rat, and human cancer cells in vitro.[1,8,23,34-37]
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.[1] However, various other studies found that ML-1 and mistletoe extracts did not induce cell proliferation.[38,39]
Preclinical studies demonstrating biological effects on cancer cell lines and animal models are summarized in Table 1 and Table 2.
| IscadorQu = IscadorQ; ML-1 = mistletoe extracts with mistletoe lectins I. | ||
| aFor more information and definition of terms, see text and the NCI Dictionary of Cancer Terms. | ||
| Iscador | ||
| Cell Line | Outcome | Reference |
| Various human cancer cell lines | Iscador preparations containing a high lectin concentration (15 μg/mL) showed >70% growth inhibition in the mammary cancer cell line (MAXF 401NL) compared with untreated control cells; 30%–70% growth inhibition in three tumor cell lines (leukemia RPMI 8226, non-small cell lung LXFE 66NL, and uterine UXF 1138L) for IscadorM and in seven tumor cell lines (central nervous system SF268, gastric GXF 251L, non-small cell lung LXFE 66NL and LXFL 529L, prostate PC3M, renal RXF 944L, and uterine UXF 1138L) for IscadorQu | [35] |
| Human medulloblastoma cells Daoy, D341, D425, and UW 228-2 | Viscum album preparations (0.1–100 µg/mL) induced cell death through apoptosis. Growth-inhibition correlated with the lectin content of the used preparation | [37] |
| Various human cancer cell lines: SF268 (central nervous system); GXF 251 (gastric); H460, LXFA 629L, LXFE 66NL, LXFL 529L (lung); CCRFCEM, MOLT-4, HL-60, K562, U937, RPMI 8226 (leukemia and lymphoma); MCF7, MAXF 401NL (mammary); HT144, MALME-3M, SK-MEL28, MEXF 462NL, MEXF 514L (melanoma); PC3M (prostate); RXF 393NL, RXF 944L (renal); Hs729, SK-LMS-1, SK-UT-1B (sarcoma); and UXF 1138L (uterus) | IscadorM and IscadorQu with a high lectin content demonstrated antitumor activity in vitro at high test concentrations (15–150 µg/mL) | [38] |
| Human cell lines: HCC1937, HCC1143 (breast), PA-TU-8902 (pancreas), DU145 (prostate), NCI-H460 (lung) | Cell proliferation inhibition was detected with a mistletoe dose at 100 μg/mL in cell lines PA-TU-8902 and NCI-H460, and a dose at ≥10 μg/mL in cell lines HCC1937, HCC1143, and DU145 | [40] |
| Glioblastoma cells: LNT-229, LN-308 | Cell growth was reduced with IscadorQ and IscadorM at lectin concentrations of 100 µg/mL | [41] |
| Helixor | ||
| Cell Line | Outcome | Reference |
| Various human cancer cell lines | Helixor mistletoe preparations (15–150 µg/mL) and ML-1 (10–100 ng/mL) did not induce cell proliferation | [39] |
| abnobaVISCUM | ||
| Cell Line | Outcome | Reference |
| Human tumor cell lines: B-cell hybridomas, P815, EL-4, Ke37, MOLT-4, and U937 | Growth arrest was caused by the induction of apoptosis (50% of U937 cells at 100 ng/mL of ML-1 and 40% of B-cell hybridomas and EL-4 cells at concentrations as low as 1 ng/mL of ML-1) | [10] |
Studies of the ability of mistletoe to inhibit cancer cell growth in animals have yielded mixed and inconsistent results.[5-9,36,42-50] In most of these studies, mistletoe extracts were administered either by subcutaneous injection or by intraperitoneal injection; some of the differences in results may have resulted from the difference in route of administration. For example, IscadorM administration was associated with a prolonged survival of female Swiss mice when the route of administration was intraperitoneal [51] but not when the route was subcutaneous.[52] Other differences between these two studies were the number of cells used in the Ehrlich ascites inoculum and the doses of IscadorM administered.
| ALL = acute lymphoblastic leukemia; ME-A = mistletoe extracts (fir tree Abies); ME-M = mistletoe extracts (apple tree Malus); ML-1 = mistletoe extracts with mistletoe lectins I; ML-3 = mistletoe extracts with mistletoe lectins III; MT-A = mistletoe extracts obtained from fir trees; MT-P = mistletoe extracts obtained from pine trees; NK = natural killer. | ||
| aFor more information and definition of terms, see text and the NCI Dictionary of Cancer Terms. | ||
| Iscador | ||
| Animal Model | Outcome | Reference |
| Mice | Antiproliferative and antimetastatic effects in melanoma cell line MV3 were only achieved with low-dose ML-1 (30 ng/kg body weight) and not with higher doses (150 ng/kg and 500 ng/kg); increased number of infiltrating dendritic cells suggests stimulation of the immune system | [44] |
| Mice | Viscum album extract (20 µg/mouse/d) mediated inhibition of B16F1 melanoma cells tumor growth was associated with immunomodulation via induction of IL-12 secretion leading to enhanced T-cell and NK-cell functions | [45] |
| Mice | Organ colonization was investigated on day 14 after RAW 117 H 10 lymphosarcoma cell and L-1 sarcoma cell inoculation and demonstrated statistically significant (P < .05) reductions of experimental liver and lung metastases for standardized aqueous mistletoe extract–treated mice (2 µg, 20 µg, 100 µg, and 500 µg per mouse) | [47] |
| Mice (Nude and VMDk mice) | Glioblastoma tumor growth was reduced (cell lines LNT-229 and LN-308), the expression of genes associated with tumor progression was reduced, and NK cell mediated glioblastoma cell lysis was enhanced when IscadorQ and IscadorM 100 µg/mL was administered by an intratumoral injection | [41] |
| BDF and Swiss albino mice | Treatment with IscadorM (50 mg/kg/d and 100 mg/kg/d) 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 | [51] |
| Swiss albino mice | No antitumor effect or improvement in survival was observed when IscadorM (15.75 mg, 750 mg, 10.5 mg, 500 mg) was used to treat rats bearing chemically induced mammary carcinomas or tumors formed from rat Walker 256 carcinosarcoma cells; IscadorM (5 mg, 200 mg, 150 mg, 3.75 mg) was also not effective in treating mice that had been injected with Ehrlich ascites cells; in addition, IscadorP (135 mg) was found ineffective in treating rats with tumors formed from rat L5222 leukemia cells | [52] |
| Helixor | ||
| Animal Model | Outcome | Reference |
| SCID mice | Despite a considerably lower ML-3 content, MT-A (50 mg/kg and 100 mg/kg) was more effective and less toxic than MT-P (50 mg/kg) in a human acute lymphoblastic leukemia cell line (NALM-6); both were given intraperitoneally in mice inoculated with human ALL | [43] |
| Human ductal breast carcinoma cell line BT474 | As compared with tumors of control mice, tumors of the ME-A– and ME-M–treated groups (5 mg intratumoral injection) showed a decreased cell proliferation rate, as well as an increased cell necrosis and apoptosis rate | [46] |
| abnobaVISCUM | ||
| Animal Model | Outcome | Reference |
| Nude mice | Intratumoral injections of mistletoe extract (abnobaVISCUM Fraxini-2, 8 mg/kg body weight and lectin at 5.3 µg/kg body weight) demonstrated more antitumor activity than did intravenous gemcitabine when injected into mice bearing xenografts of human pancreatic adenocarcinoma cancer (PAXF 736) | [53] |
| Isorel | ||
| Animal Model | Outcome | Reference |
| Mice | In mice transplanted with fibrosarcoma (CMC-2), when IsorelM (140 mg/kg) was used alone, no effect on either tumor growth or animal survival was observed. When IsorelM (140 mg/kg) was combined with x-ray therapy of tumors, there was substantial improvements in survival of mice compared with survival of mice treated with x-ray therapy (43 Gy) alone | [54] |
| Eurixor | ||
| Animal Model | Outcome | Reference |
| Mice | Aqueous mistletoe extract (30 ng/mL or 300 ng/mL) showed antitumoral activity on urinary bladder carcinoma (MB49) in mice, which was considered to be mainly caused by the cytotoxic properties of mistletoe lectins | [6] |
| Lektinol | ||
| Animal Model | Outcome | Reference |
| Mice | Treatment with Lektinol (0.3, 3, 30, or 300 ng/mL/kg/d) slowed the growth of tumors formed in mice from implants of three types of mouse cancers (colon adenocarcinoma 38, Renca renal cell carcinoma, and F9 testicular carcinoma) but not from two other mouse cancers (B16 melanoma and Lewis lung carcinoma) | [7] |
Mistletoe has been evaluated as a treatment for people with cancer in numerous clinical studies.[1-20]
The mistletoe extracts and products studied in clinical trials were Iscador, Eurixor, Helixor, Lektinol, Isorel, abnobaVISCUM,[21] and recombinant lectin ML-1. For more information, see the appropriate subsections and tables in this section.
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, as did a noncontrolled, nonrandomized, real-world study that analyzed patient registry data.[23]
In one systematic review that examined 26 randomized controlled trials (RCTs), 22 trials reported an improvement in QOL. All 10 of the nonRCTs 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.[22]
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.[18] 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.[20]
A systematic review of all controlled clinical studies of mistletoe found consistent improvement in chemotherapy-associated fatigue as well as other QOL measures.[22]
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 the following:
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. 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.
A selection of studies is discussed below, organized by the type of mistletoe extract used. Studies on Iscador are summarized in Table 3. Studies on Helixor, abnobaVISCUM, Eurixor, Isorel, and Lektinol are summarized in Table 4. Eurixor, Isorel, and Vysorel are no longer available on the market for sale.
Although the quality of literature is limited by methodological flaws, prospective and controlled studies that explored the efficacy of Iscador use on QOL in patients with cancer generally report positive effects in favor of complementary treatment. A meta-analysis of several studies (RCTs: n = 9; non-RCTs: n = 4; patients n = 734) reported a statistically significant overall treatment effect in favor of Iscador application (standard mean deviation [SMD], 0.56; 95% confidence interval [CI], 0.41–0.71; P < .0001).[24] Tumor localization and study design were not significantly associated with a better or worse study outcome following multivariable regression.
A randomized study of postoperative early-stage breast cancer patients (T1, 3N0, 2M0) who received adjuvant chemotherapy with cyclophosphamide, Adriamycin, and fluorouracil found that patients who also received IscadorM treatment, a Viscum album extract harvested from apple (Mali) trees (n = 30), had significantly superior QOL ratings compared with patients who received chemotherapy alone (n = 31) (95% CI, P ≤ .017).[7] Significant improvements were noted in physical functioning, role functioning, emotional functioning, and social functioning. Improvements were also noted in appetite, nausea and vomiting, diarrhea, fatigue, pain, dyspnea, insomnia, and financial difficulties.[7]
At least two RCTs have assessed the QOL of patients with advanced NSCLC. Patients who received carboplatin/gemcitabine or carboplatin/pemetrexed and were randomly assigned to receive open-label IscadorQu treatment, a Viscum album extract harvested from oak (Quercus) trees, did not report statistically significant improvements in QOL when compared with NSCLC patients who received carboplatin-based combinations alone.[25] An assessment of QOL was performed in a study of patients with NSCLC who received adjuvant chemotherapy with IscadorQu and IscadorU (harvested from elm [Ulmi] trees) or a vitamin B mixture (control) over 2 years.[26] A subjective improvement in general well-being was more often seen in patients treated with Iscador.
QOL was assessed as a secondary endpoint in a small (n = 20) study of patients with osteosarcoma. Patients were free from disease after their second metastatic relapse and were randomly assigned to receive either open-label IscadorP therapy, a Viscum album extract harvested from pine (Pini) trees, or oral etoposide. Patients who received Iscador therapy experienced significant improvements in overall (global) and individual QOL domains when compared with baseline functioning (global health/QOL; 95% CI, 2.62–19.72; P = .013).[27] Improvements over baseline values were also reported in the following areas:
Ovarian cancer patients without metastases (n = 21 pairs) were randomly assigned to receive adjuvant Iscador (host tree unspecified) or no further treatment. Significant improvements in QOL were noted, as assessed by the degree of psychosomatic self-regulation, described as the capacity for autonomous regulation of emotional, social, and psychological factors, within 12 months of treatment (estimated median difference: 0.58; 95% CI, 0.30–0.90; P = .0002).[11]
Secondary endpoint analysis of uterine cancer patients without metastases (randomized: n = 30 pairs; nonrandomized: n = 103 pairs) who received adjuvant Iscador displayed significant improvements in psychosomatic self-regulation within 12 months of treatment when compared with women who received conventional oncological therapy alone (estimated median difference and 95% CI, 0.40 [0.15–0.70]; P = .0012; and 0.70 [0.25–1.15], P = .0037, respectively).[10]
In a study of postoperative early-stage breast cancer patients (T1, 3N0, 2M0) who were randomly assigned to receive open-label IscadorM therapy after chemotherapy (n = 30), a secondary endpoint analysis did not demonstrate statistically significant improvements in neutropenia (neutrophil count <1,000/µL) when compared with patients who received chemotherapy alone (n = 31).[7]
Another study (retrolective design) of postoperative early-stage breast cancer patients (T2, 4N0, 2M0) who received adjuvant conventional treatment (chemotherapy, radiation therapy, or hormonal therapy) (n = 710) compared the outcomes of patients who received Iscador with patients who did not receive any added therapy. Patients who received Iscador developed significantly less adverse drug reactions associated with conventional treatment compared with women treated with conventional therapy alone (n = 732) (16% vs. 54.0%, respectively; adjusted odds ratio [OR], 0.47; 95% CI, 0.32–0.67; P < .001).[28,29] Relief or significant reductions in nausea, vomiting, loss of appetite, headache, fatigue, depression, skin and mucosal reactions (including mucositis), disturbed concentration and memory, and irritability were observed.[29,30]
After surgery of squamous cell lesions of the larynx and pharynx, male patients who were randomly assigned to receive complementary IscadorQu treatment (n = 10) displayed significantly fewer adverse effects from chemotherapy and radiation therapy (radiation therapy with 50–60 Gy, chemotherapy with cisplatin and fluorouracil) on the microcirculation and immunological capacities of white blood cells compared with men who received conventional treatment alone (n = 10) (P = .05).[31] Patients who received adjuvant IscadorQu treatment also displayed significant accelerations in the restitution process when compared with the control group (P = .05).
Patients with advanced NSCLC who received carboplatin/gemcitabine or carboplatin/pemetrexed and were randomly assigned to receive open-label IscadorQu treatment (n = 33) displayed the following reactions when compared with patients who received chemotherapy alone (n = 39):[25]
The grades 3 and 4 hematological toxicity was not significantly different between the groups.
A systematic review and meta-analysis of several studies published from 1963 to 2014, including RCTs, found that adjuvant treatment with Iscador is associated with improved cancer survival outcomes when compared with conventional treatment alone.[32] Pooled analysis of controlled clinical studies (32 studies; total n = 13,745) that investigated overall survival (OS) and event-free survival (EFS) (i.e., disease-free survival [DFS], progression-free survival [PFS] or relapse-free survival, or the time until these events occurred in cancer patients), demonstrates a statistically significant hazard ratio (HR) of 0.59 (95% CI, 0.53–0.65; P < .0001) in favor of Iscador treatment. A significant difference in survival between cancer types was noted (P < .01), with the strongest association of Iscador use and general survival found in in patients with cervical cancer (HR, 0.43) and more modest outcomes in patients with lung cancer (HR, 0.84). In the meta-analysis, randomization was performed in only 14 studies. While subgroup analysis displayed a greater association between EFS and OS in patients who received Iscador in nonrandomized clinical trials (HR, 0.56; CI, 0.50–0.62) compared with patients who were randomized (HR, 0.68; CI, 0.55–0.83); this difference is not statistically significant (P = .13).[32] Many of the studies used study designs, analytical methods, and/or cancer treatment regimens that were outdated. While moderate heterogeneity between study results was noted (I2, 50.9%; P < .0001), neither differences in design, sample size, nor publication year demonstrated significant effects on these survival outcomes. The reviewed studies were blinded; therefore, they ran the risk of performance bias, given the knowledge of allocated interventions. It is unlikely that performance bias affected study outcomes associated with general survival (which is the reason why the U.S. Food and Drug Administration does not mandate blinding in survival studies); however, performance bias may exist for those reporting on EFS.
Primary breast cancer patients (without recurrences, lymphatic metastases, or distant metastases at the initiation of study observation; n = 84 pairs) who received Iscador therapy adjuvant to conventional treatment (surgery, chemotherapy, radiation therapy, or hormone therapy) displayed prolonged cancer-specific survival rates when matched to paired individuals with similar prognostic criteria who received conventional treatment alone (HR, 0.43; 95% CI, 0.27–0.68).[8] In the same report, patients with breast cancer who were randomly assigned to receive Iscador did not demonstrate a significant extension of OS when compared with their matched pairs.[8]
In another study, OS was evaluated as a secondary endpoint in patients with nonmetastatic breast cancer (T2, 4N0, 2M0) who underwent adjuvant treatment concomitant with regimented Iscador injections.[28,29] Women treated with subcutaneous Iscador therapy complementary to their conventional treatment regimen (n = 710) displayed significant extensions of overall mortality when compared with patients treated with conventional therapy alone (n = 732) (adjusted HR, 0.46; 95% CI, 0.22–0.96; P = .038).[28,29]
Patients with metastatic (n = 66) or local (n = 102) cervical cancer who elected to receive Iscador in addition to conventional oncological treatment demonstrated significant extensions of OS when compared with women with similar prognostic criteria who received conventional treatment alone (HR and 95% CI, 0.37 [0.17–0.80] and 0.23 [0.14–0.39], respectively).[9] However, this finding was not seen when women with metastatic cervical cancer were randomly assigned to receive open-label adjuvant Iscador.
Patients with surgically-treated, nonmetastatic colorectal cancer (CRC) (stages I–III) (n = 429) who received Iscador treatment with conventional aftercare displayed a statistically significant extension of DFS (HR, 0.60; P = .013) when compared with CRC patients who received conventional therapy alone (n = 375) after a median observation period of 58 months for patients who received Iscador and 51 months for patients who received conventional therapy alone.[33] A secondary analysis of this data was preformed specific to CRC patients who received IscadorQu extract, a Viscum album extract harvested from oak (Quercus) trees. Patients who had specifically received IscadorQu extract (n = 106) displayed an estimated 69% risk reduction in metastasis formation (HR, 0.31; 95% CI, 0.13–0.711; P = .006) relative to conventionally-treated controls (n = 212).[34]
A phase III study of melanoma patients (n = 102) with high-risk primary disease (stage II, Breslow thickness >3mm) or regional lymph node metastasis (stage III, after curative dissection) treated with IscadorM found no clinical benefit of low-dose adjuvant therapy in the disease-free interval when compared with the control group (n = 102) after one year of treatment (or until tumor progression).[5]
Lymph node–positive NSCLC patients (n = 87) who were randomly assigned to receive Iscador therapy (without concurrent treatment) displayed significant extensions in median survival rates when compared with untreated controls.[35] Clinical benefit in median survival was not observed in patients with nonmetastatic NSCLC.[35] Similarly, a three-arm comparison with a sheep spleen glycopeptide, reported to be an immunostimulant and an inhibitor of tumor cell glycolysis, and a vitamin B preparation (placebo) (n = 107), found no clinical benefit in median survival above placebo in patients with advanced NSCLC who were randomly assigned to receive IscadorQu and IscadorU (n = 105) after two years of open-label treatment.[26]
Osteosarcoma patients who underwent a complete surgical resection after a second relapse were randomly assigned to receive IscadorP maintenance therapy (subcutaneous injections three times a week) (n = 9) for 1 year. After a follow-up period of 12 years, patients displayed a 71% reduced risk of relapse (measured as postrelapse DFS; HR, 0.287; 95% CI, 0.076–0.884; P = .03) when compared with patients who received 6 months of oral etoposide treatment (50 mg/m2 a day for 21 days, every 28 days) (n = 10).[36]
Primary ovarian cancer patients without distant metastases (n = 21 pairs) who received Iscador therapy after conventional treatment (surgery and chemotherapy) displayed prolonged OS rates when compared with patients with similar prognostic criteria who received conventional treatment alone (HR, 0.47; 95% CI, 0.31–0.69; P = .0002).[11] Patients who were randomized to receive Iscador treatment did not display a significant difference in OS when compared with matched controls. Patients with metastatic ovarian cancer, randomly assigned to receive complementary Iscador therapy (n = 20 pairs), also demonstrated a significant extension of OS when compared with matched pairs (HR, 0.33; 95% CI, 0.12–0.92; P = .033), although a significant extension in OS was not observed in the nonrandomized arm.[11]
Patients with locally advanced or metastatic pancreatic cancer (UICC stage III or stage IV) who were randomly assigned to receive open-label Iscador therapy as an adjuvant to best supportive care methods (n = 110) demonstrated prolonged survival when compared with patients under similar prognostic criteria who received supportive care alone (n = 110). The median OS was 4.8 months for patients who received Iscador and 2.2 months for patients who received supportive care alone (prognosis-adjusted HR, 0.49; 95% CI, 0.36–0.65; P < .0001).[37]
A retrospective analysis investigated the effects of mistletoe and chemotherapy with hyperthermia versus mistletoe and chemotherapy in the palliative treatment of patients with pancreatic cancer. The results of the analysis found a significant improvement in survival rates for patients who received all three treatments. Weaknesses of the analysis include the retrospective nature of the study, multiple types of chemotherapy (gemcitabine/nab-paclitaxel, 34%; FOLFIRINOX, 36%; gemcitabine, 30%) and mistletoe (e.g., Iscador, Abnoba viscum, or Helixor) regimens used, and the lack of a study arm for hyperthermia and chemotherapy.[38] Furthermore, the study was not stratified despite enrolling patients who were previously treated with 1 to 3 lines of therapy, making the group median survival rates clinically insignificant.
In a retrospective analysis of patients with stages I to IV pancreatic cancer (n = 292) who received Iscador (host tree unspecified) therapy alone or adjuvant to conventional treatment (surgery, chemotherapy, radiation therapy, hormone therapy, or a combination) (n = 61), a median survival of 6.58 months was reported.[39]
Patients with corpus uteri cancer without distant metastases (n = 30 pairs) were randomly assigned to receive Iscador therapy adjuvant to conventional treatment (surgery or radiation therapy). Patients had longer OS (time from initial diagnosis to tumor-related death) than matched pairs of patients with similar prognostic criteria who received conventional treatment alone (HR, 0.36; 95% CI, 0.16–0.82; P = .014).[10] However, corpus uteri cancer patients with distant metastases randomly assigned to receive adjuvant Iscador did not display a significant difference in OS when compared with matched controls who were randomly assigned to conventional oncologic care only. In the nonrandomized portion of the study, corpus uteri cancer patients, with (n = 95 pairs) or without (n = 103 pairs) distant metastases, who previously received the complementary therapy, demonstrated a significant extension of OS when compared with matched pairs of similar prognostic criteria who received conventional treatment alone (prognosis-adjusted HR and 95% CI, 0.61 [0.39–0.93], P = .023 and 0.41 [0.26–0.63], P < .0001, respectively).[10]
| Reference | Trial Design | Condition or Cancer Type | Treatment Groups (Enrolled; Treated; Placebo or No Treatment Control)b | Results | Concurrent Therapy Usedc | Level of Evidence Scored |
|---|---|---|---|---|---|---|
| DFS = disease-free survival; LN+ = lymph node–positive disease; No. = number; OS = overall survival; QOL = quality of life. | ||||||
| aFor more information and definition of terms, see text and the NCI Dictionary of Cancer Terms. | ||||||
| bNumber 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 studied and for whom results were reported; historical control subjects are not included in number of patients enrolled. | ||||||
| cChemotherapy, radiation therapy, hormonal therapy, or cytokine therapy administered/allowed at the same time as mistletoe therapy. | ||||||
| dFor information about levels of evidence analysis and scores, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies. | ||||||
| eControl 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. | ||||||
| fRadiation 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. | ||||||
| gAmong 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. | ||||||
| hPatients were strictly matched according to sex, year of birth ± 3 years, year of diagnosis ± 3 years, type of tumor, stage of disease, and conventional therapy received. | ||||||
| [26] | Randomized trial | Lung, non-small cell, inoperable | 408; 105; 107e | Subjective improvement in QOL | Yesf | 1iiA |
| [35] | 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 | 204; 102; 102 | No improvement in DFS or OS rates | No | 1iiA |
| [37,40] | Randomized trial | Pancreatic, advanced or metastatic | 220; 110; 110 | Improved OS | No | 1iiA |
| [27] | Randomized trial | Osteosarcoma, second metastatic relapse | 20; 9 (viscum); 11 (etoposide) | Improved DFS compared with etoposide group | No | 1iiDii |
| [41] | Randomized trial | Breast | 95; 30 (IscadorM) and 34 (HelixorA); 31 | No differences in the primary outcome between groups | Yes | 1iiC |
| [29] | Comparative, retrolective, cohort study | Breast, stages I–IV | 1,442; 710; 732 | Fewer adverse drug reactions with mistletoe | Yes | 2B |
| [28] | Comparative, retrolective, cohort study | Melanoma, stages II–III | 686; 329; 357 | Improved overall disease-specific survival | Unknown | 2A |
| [4] | Cohort study | Breast, stage III | 8,475g; 17h; 17h | Improved mean survival | Yes | None |
| [4] | Cohort study | Various types, stages I–IV | 8,475g; 39h; 39h | Improved mean survival | Yes | None |
| [4] | Cohort study | Various types, stages I–IV | 10,226g; 396h; 396h | Improved mean survival | Yes | None |
| [33] | Retrospective, observational, cohort study | Nonmetastatic colorectal | 804; 429; 375 | Lower incidence of diarrhea, nausea, loss of appetite, dermatitis, fatigue, and mucositis | Yes | 2C |
| [38] | Retrospective analysis study | Pancreatic | 206 (subgroup of 142 using survival data on 124); 25 (chemotherapy alone); 48 (chemotherapy and mistletoe), 50 (chemotherapy, mistletoe, and hyperthermia); 1 (chemotherapy and hyperthermia) | Improved survival was reported in the triplet arm | Yes | 2A |
| [39] | Nonconsecutive case series | Pancreatic | 292; 292; various historical controls | Improved median survival | Yes | 3iiiA |
The first intravenous (IV) trial of mistletoe (HelixorM) is completed.[42] A standard 3 + 3 phase I design was used. The study included 21 patients with heavily pretreated metastatic solid tumors. A dose of 600 mg IV 3 times a week was determined to be the maximum tolerated dose recommended for future phase II trials. Three patients had tumor shrinkage, though none met RECIST criteria for a partial response. The disease control rate was 23.8% and the median stable disease was 15 weeks. Two patients had stable disease for almost 6 months. The most common treatment-related adverse events were fatigue (28.6%), nausea (9.5%), and chills (9.5%). A secondary endpoint analysis found that QOL was significantly improved during treatment as measured by the Functional Assessment of Cancer Therapy-General assessment, with a change in score from 79.7 to 93 between week 1 and week 4.[42] Future research should be conducted to examine the effect of mistletoe on chemotherapy tolerability and to gather more information about its effect on QOL, PFS, and OS.
Patients with cancer (breast, n = 67; ovarian, n = 66; NSCLC, n = 91) were randomly assigned to receive open-label treatment with HelixorA (viscum album abietis) concurrent with standard chemotherapy (n = 115). These patients demonstrated significant improvements in QOL (as assessed by Functional Living Index-Cancer, Karnofsky Performance Index, and Traditional Chinese Medicine Index questionnaires) when compared with patients in the control group, who received conventional oncologic treatment and Lentinan, an immunomodulating agent derived from the shiitake mushroom (n = 109) (P < .05).[43] Patients who received HelixorA also experienced fewer adverse events (AEs) from chemotherapy when compared with the control group (52 AEs reported in the HelixorA and chemotherapy group vs. 90 AEs in the control group).
Pleurodesis with HelixorM (Viscum album mali) may be an effective procedure to control malignant pleural effusions (MPE) in patients with advanced lung cancer.[44] Over half (52%) of lung cancer patients treated with HelixorM pleurodesis (n = 42) were free from recurrence of MPE one month after the procedure. Neither patient characteristics (including age, gender, histopathology, or systemic treatment), nor MPE characteristics (including location and chemistry) was deemed significantly associated with the outcome of HelixorM pleurodesis in this study.[44]
Patients with breast cancer (T1–3, N0–3, M0; local recurrence) were randomly assigned to receive Helixor adjuvant to conventional therapy (i.e., surgery and radiation therapy) (n = 192). These patients demonstrated a significant extension in 5-year survival when compared with patients who received conventional treatment alone (n = 274) (5-year survival rates, 69.1% vs. 59.7%, respectively) (P = .048).[45]
Patients with metastatic CRC were randomly assigned to receive Helixor adjuvant to chemotherapy (n = 20). These patients demonstrated significant extensions in mean survival (26.7 ± 11.9 months in complete/partial responders) when compared with patients randomly assigned to receive chemotherapy alone (n = 20) (13.6 ± 4.4 months in complete/partial responders).[46]
As per QLQ-C30 function scales, health-related QOL in patients with breast cancer (stages I–III) who received abnobaVISCUMM concurrent with chemotherapy (n = 270) remained stable throughout the course of chemotherapy and significantly improved 4 weeks after treatment (P < .0001) when compared with the initial visit.[47] Patients also showed significant improvements above baseline in all parameters of the QLQ-BR23 function scale (a QOL module specific to breast cancer) at final examination (P < .0001).
Postoperative patients with gastric cancer (stage IB or stage II) were randomly assigned to receive abnobaVISCUMQ adjuvant to oral chemotherapy (n = 15). These patients demonstrated a significant improvement in global health status (a parameter constructed by totaling scores on two questions from the QLQ-C30 questionnaire) at week 16 and at completion of treatment (week 24), when compared with patients who received oral chemotherapy alone (n = 14) (P = .0098).[48] All other function and symptom scales of the QLQ-C30 and the QLQ-STO22 (a QOL module specific to stomach cancer) did not show statistical significance when abnobaVISCUMQ treatment was added.[48]
Patients with advanced cancer were treated with abnobaVISCUM pleurodesis for MPE (n = 62). These patients demonstrated a significant improvement in mean response rate (P < .0001) when compared with reference values (97% and 64%, respectively).[49] Forty-nine patients (79%) demonstrated a complete response (no recurrence of MPE at least 4 weeks after treatment) and 11 patients (18%) demonstrated partial response (reaccumulation of pleural effusion under 50% of the pretreatment volume), while 2 patients (3.23%) did not respond (recurrence of pleural effusion within 4 weeks after treatment) to mistletoe-mediated pleurodesis with abnobaVISCUM.[49]
Symptomatic relief was reported by 40% of patients with metastatic CRC who were resistant to fluorouracil and leucovorin (5-FU/LV)-based chemotherapy and received abnobaVISCUMQ therapy (n = 25). Symptomatic relief was assessed as a secondary endpoint measure for a median duration of 14 weeks.[50] Relief of the following symptoms was reported:
In one study, postoperative patients with gastric cancer (stage IB or stage II) were randomly assigned to receive abnobaVISCUMQ adjuvant to oral chemotherapy (n = 15). The secondary endpoint analyses demonstrated a significant improvement in leukocyte (P = .01) and eosinophil (P = .0036) counts when compared with patients who received oral chemotherapy alone (n = 14) after a 24-week treatment cycle.[48]
A marker tumor remission rate of 55.6% (95% CI, 38.1–72.1) was achieved in 20 of 36 patients with nonmuscle-invasive bladder cancer (Ta G1/G2 or T1 G1/G2) 12 weeks after beginning bladder instillation therapy with abnobaVISCUMF (once a week for 6 weeks).[51] Of the 19 evaluable patients, 14 (73.7%) did not have recurrent tumor at 1 year after initiation of treatment (95% CI, 48.8%–90.9%), corresponding to a 1-year recurrence rate of 26.3% (95% CI, 9.1%–51.2%).
Objective tumor response was not observed in a phase II study of patients with metastatic CRC who were resistant to 5-FU/LV-based chemotherapy and received abnobaVISCUMQ therapy for a median time period of 14 weeks. Stable disease was noted in 21 of 25 patients (84%), lasting for a median of 2.5 months (range; 1.5–7 months).[50]
Eurixor is no longer available on the market for sale.
Patients with metastatic CRC were randomly assigned to receive Eurixor adjuvant to standard cancer treatment (n = 38). These patients demonstrated improved QOL (P = .0001) when compared with patients randomly assigned to receive standard treatment alone (n = 41).[52,53]
Patients with breast cancer (UICC stages I–IIIB) underwent postoperative chemotherapy, radiation therapy, or hormone therapy, and received complementary treatment with Eurixor (n = 219) for a median time period of 270 days. These patients demonstrated significant improvements in disease- or therapy-induced adverse reactions (P < .0001) when compared with patients who received standard cancer therapy alone (n = 470) at up to 285 days of follow-up.[54] Significant improvements in nausea, appetite reduction, stomach pain, fatigue, depression, memory, and irritability/restlessness were reported (P < .0001, in each subgroup).
Patients with bladder cancer (pTa G1/G2) (n = 45) received subcutaneous Eurixor injections after transurethral resection. These patients did not demonstrate differences in time-to-first recurrence, total number of recurrences, or recurrence-free outcomes at up to 18 months after primary treatment compared with patients who were randomly assigned to receive no adjuvant treatment.[3]
Patients treated with Eurixor before and after resection of squamous cell carcinomas of the head and neck, with or without follow-up radiation therapy, demonstrated no difference in DFS when compared with patients who received surgery alone or surgery followed by radiation therapy, without adjuvant Eurixor treatment.[2]
Isorel is no longer available on the market for sale.
Perioperative use of Isorel in patients with cancer of the digestive tract (esophageal, stomach, pancreatic, ileac, colorectal) has been shown to increase the lymphocyte count in patients within 14 days of administration.[55]
Patients with advanced CRC (Dukes C and D) were randomly assigned to receive Isorel along with adjuvant postoperative chemotherapy with 5-FU (6 cycles) (n = 29). These patients demonstrated prolonged survival (P < .05) when compared with patients who received postoperative chemotherapy only (n = 21) and patients who received surgery only (n = 14) without postoperative chemotherapy or Isorel treatment (n = 14).[56]
Patients with breast cancer were randomly assigned to receive open-label PS76A (an aqueous mistletoe extract standardized to the galactoside-specific mistletoe lectin [ML]) adjuvant to chemotherapy (n = 176). These patients demonstrated improved QOL when compared with patients who received chemotherapy alone.[13]
In a double-blind study, patients with breast cancer (stages II–III) were randomly assigned to receive PS76A2 (Lektinol; 30 ng ML/mL) adjuvant to cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy (4 cycles) for a period of 15 consecutive weeks (n = 65). These patients demonstrated statistically significant improvements in self-assessments of QOL (P = .0121 and P = .0021 for GLQ-8 and Spitzer’s uniscale, respectively) when compared with patients who were randomly assigned to receive chemotherapy treatment alone (n = 66).[57] Only the medium dose (30 ng ML/mL) indicated a significant preventative effect against placebo; no treatment effect of low- or high-dose Lektinol (10 ng ML/mL or 70 ng ML/mL) was established against the placebo. In a second confirmatory study, superiority of complementary Lektinol (30 ng ML/mL) (n = 176) over the placebo (n = 176) was observed according to three FACT-G subscales (physical, emotional, and functional well-being) assessed during the fourth CMF cycle (P < .0001).[58]
Some systematic reviews have found that studies of better methodological quality typically show that Viscum album extracts (VAEs) have few beneficial effects on QOL in cancer,[18,20,59] while others studies suggest that mistletoe extracts produce a significant, though medium-sized, effect on QOL in cancer patients (mean difference = 0.61; 95% CI, 0.41–0.81, P < .00001).[60]
However, another systematic review reached different conclusions. In a review consisting of 26 RCTs, 22 reported a benefit of mistletoe therapy (supplied with or without concomitant surgery, chemotherapy, or radiation therapy), whereas 3 reported no difference, and 1 did not indicate a result.[22] All 10 nonRCTs reported a benefit of VAE treatment, whether it was supplied with or without concomitant therapy.[22] Among the studies designated as higher in methodological quality, most reported a benefit of VAE treatment, whereas one reported no difference from standard oncological treatment. Most consistently, studies reported improvements regarding the following:[22]
Systematic reviews reported inconsistent results regarding the efficacy of mistletoe treatment on survival outcomes on the basis of methodological quality of the study.[61] In a review that consisted of 28 publications (n = 2,639) investigating a wide range of cancers (bladder, breast, cervix, lungs, uterus, ovaries, colon, stomach, pancreas, gliomas, head and neck cancers, melanomas, and osteosarcomas), most studies did not show that adjuvant mistletoe had an effect on survival, especially those of high methodological quality.[62] This finding is consistent with other review articles. In an investigation of 13 RCTs, 6 showed evidence of a survival benefit, but none of these studies were of high methodological quality.[18]
In another review of 23 controlled clinical studies (16 randomized, 2 quasi-randomized, and 5 nonrandomized) that investigated the use of VAE in patients with cancers of the breast, lung, stomach, colon, rectum, head and neck, kidney, genitals, bladder, melanomas, and gliomas, positive effects on survival were indicated in 8 studies and tumor remission was supported by 1 study.[16] Four studies reported no effect on survival, one indicated no effect on DFS, two reported no benefit of treatment on tumor recurrence, and three indicated no effect on cancer remission.
| Reference | Trial Design | Product Tested | Condition or Cancer Type | Treatment Groups (Enrolled; Treated; Placebo or No Treatment Control)b | Results | Concurrent Therapy Usedc | Level of Evidence Scored |
|---|---|---|---|---|---|---|---|
| DFS = disease-free survival; No. = number; QOL = quality of life. | |||||||
| aFor more information and definition of terms, see text and the NCI Dictionary of Cancer Terms for additional information and definition of terms. | |||||||
| bNumber 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 studied and for whom results were reported; historical control subjects are not included in number of patients enrolled. | |||||||
| cChemotherapy, radiation therapy, hormonal therapy, or cytokine therapy administered/allowed at the same time as mistletoe therapy. | |||||||
| dFor information about levels of evidence analysis and scores, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies. | |||||||
| eThis 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 QOL, 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 | Eurixor | Bladder, noninvasive | 45; 23; 22 | DFS did not vary between groups | No | 1iiDi |
| [1,63] | Randomized trial | Eurixor | 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 |
| [52,53] | Randomized trial | Eurixor | Colorectal, metastatic | 107; 38; 41 | Improved QOL | Yes | 1iiC |
| [2] | Randomized trial | Eurixor | Head and neck, squamous cell, stages I–IV | 495; 235e; 242e | No differences in DFS between groups | Yese | 1iiDi |
| [45] | Randomized trial | Helixor | Breast, stages I–III | 692; 192 (Helixor) and 177 (chemotherapy); 274 | Improved survival | Yes | 1iiA |
| [46] | Randomized trial | Helixor | Colorectal, metastatic | 60; 20; 20 | Improved mean survival | Yes | 1iiA |
| [43] | Randomized trial | Helixor | Breast, ovarian, and non-small cell lung | 224; 115; 109 | Improved QOL | Yes | 1iiC |
| [41] | Randomized trial | HelixorA, IscadorM | Breast | 95; 34 (HelixorA) and 30 (IscadorM); 31 | No differences in the primary outcome between groups | Yes | 1iiC |
| [13] | Randomized controlled trial | PS76A (Lektin) | Breast | 352; 176; 176 | Improved QOL | Yes | 1iC |
| [57] | Randomized trial | Lektinol | Breast | 261; 195; 66 | Improved QOL | Yes | 1iC |
| [58] | Randomized trial | Lektinol | Breast | 352; 176; 176 | Improved QOL | Yes | 1iC |
| [56] | Randomized trial | Isorel | Colorectal | 64; 50; 14 | Improved survival and tolerance to either adjuvant or palliative treatment | Yes | 1iiA |
| [55] | Nonrandomized controlled trial | Isorel | Digestive tract | 70; 40; 30 | Enhanced cellular immunity and improved QOL | No | 2C |
| [50] | Nonrandomized controlled trial | abnobaVISCUM Quercus | Metastatic colorectal | 25; 25; none | No objective tumor response | Yes | 2Diii |
| [21] | Nonrandomized controlled trial | Viscum fraxini-2 | Hepatocellular carcinoma | 23; 23; none | Improved survival | No | 2Dii |
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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 the following:[1-4]
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 recombinantly-produced mistletoe lectins (not available in commercial products) resulted in reversible hepatotoxicity in some cases.[5] 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.[6]
A few cases of severe allergic reactions, including anaphylactic shock, have been reported.[2]
Although from an observational cohort study, three types of mistletoe (Iscador, Helixor, and abnobaVISCUM) that were given intratumorally, intravenously, or subcutaneously were found to be safe in a small group of cancer patients with autoimmune diseases such as Graves disease, Hashimoto thyroiditis, ulcerative colitis, psoriasis, and some rheumatic diseases.[7]
To assist readers in evaluating the results of human studies of integrative, alternative, and complementary therapies for cancer, the strength of the evidence (i.e., the levels of evidence) associated with each type of treatment is provided whenever possible. To qualify for a level of evidence analysis, a study must:
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 an explanation of the scores and additional information about levels of evidence analysis for cancer, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.
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 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.
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 Integrative, Alternative, and Complementary Therapies 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® Cancer Information for Health Professionals pages.
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 in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
This summary is reviewed regularly and updated as necessary by the PDQ Integrative, Alternative, and Complementary Therapies 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.
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The preferred citation for this PDQ summary is:
PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ Mistletoe Extracts. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/treatment/cam/hp/mistletoe-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389489]
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