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Mistletoe Extracts (PDQ®)

Health Professional Version
Last Modified: 04/11/2014

Human/Clinical Studies

Iscador
Other Mistletoe Preparations
        Eurixor
        Isorel
        Helixor
        abnobaVISCUM
Current Clinical Trials

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 (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.[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 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.

Iscador

A three-arm, randomized phase III trial that involved 408 patients with previously untreated, inoperable non-small cell lung cancer was conducted between 1978 and 1987.[23] Patients were randomly assigned to one of the following treatments: (1) subcutaneous injection 3 times a week with IscadorU or IscadorQ (refer to the General Information section of this summary for more information); the concentration of mistletoe was increased during a seven-injection sequence or cycle, followed by a 3-day pause, and then the process was repeated; IscadorU was administered for two cycles, followed by two cycles of IscadorQ; both mistletoe preparations contained mercury); (2) intramuscular injection once a week with Polyerga Neu, which is a sheep spleen glycopeptide that is reported to be an immunostimulant and an inhibitor of tumor cell glycolysis; and (3) intramuscular injection once a week with a vitamin B mixture, which served as a placebo. Complete follow-up information was available for 337 patients, and 312 patients (105 Iscador treated, 100 Polyerga Neu treated, and 107 placebo treated) were included in the survival analysis. No statistically significant differences in survival were found between the three groups. Median survival for the Iscador group was 9.1 months; for the Polyerga Neu group, it was 9.0 months; and for the placebo group, it was 7.6 months. The researchers reported that 11.5% of the patients in the Iscador group survived 2 years from the time they entered the trial; the corresponding survival values for the Polyerga Neu and the placebo groups were 13.9% and 10.1%, respectively. In addition, no differences were found between the three groups with respect to tumor response, median body weight, blood chemistry values, Karnofsky Performance Status, and quality of life. However, more patients in the Iscador group than in the Polyerga Neu or the placebo groups reported subjective improvement in feelings of well-being (59.4% vs. 43.2% and 44.8%, respectively).

Another randomized phase III trial of mistletoe as a treatment for people with cancer involved 830 patients with high-risk melanoma (i.e., a primary tumor >3 mm in diameter and no regional lymph nodes positive for cancer or a primary tumor of any size, one or two regional lymph nodes positive for cancer, and no distant metastases) who were randomly assigned to one of the following four groups after potentially curative surgery: (1) treatment with low-dose interferon -alpha, (2) treatment with low-dose interferon-gamma, (3) treatment with IscadorM, or (4) no further treatment. Both types of interferon and IscadorM were administered by subcutaneous injection for a period of 1 year.[5] The interferon injections were administered every other day, whereas IscadorM was administered 3 times a week. After 8 years of follow-up, no increase in survival time or increase in time until melanoma recurrence was demonstrated for mistletoe treatment or treatment with either type of interferon.

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 overall survival) 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).[24]

Three other studies of mistletoe were described in a single published report.[4] One of the three studies was a large cohort study on the effectiveness of Iscador as a treatment for people with rectal cancer, colon cancer, breast cancer, stomach cancer, or lung cancer.[4] The second and third studies were small, prospective, randomized, matched-pair studies (one randomized, one nonrandomized) that involved patients who were selected from a group of 8,475 individuals who had not been treated with mistletoe.[4]

These studies are summarized in Table 1. The overall conclusion of the authors in the report of these three studies was that Iscador treatment can produce a clinically significant increase in survival in cancer patients. However, there were several weaknesses in the design and execution of these studies. In a large cohort study, the investigators were unable to find 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.[25,26]

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.[27]

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.[28] 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 overall survival (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.

Table 1. Use of Iscador in Cancer Treatment: Clinical Reports Describing Therapeutic Endpointsa
Reference Citation(s)  Type of Study  Type(s) of Cancer  No. of Patients: Enrolled; Treated; Controlb Strongest Benefit Reportedc Concurrent Therapyd Level of Evidence Scoree 
[23]Randomized trialLung, non-small cell, inoperable408; 105; 107fSubjective improvement in quality of lifeYesg1iiA
[29]Randomized trialLung, non-small cell, stages I–IV218; 87; 96Improved median survival, LN+ patients onlyNo1iiA
[5]Randomized trialMelanoma, stages II–III204; 102; 102NoneNo1iiA
[25]Comparative, retrolective, cohort studyBreast, stages I–IV1,442; 710; 732Improved survivalYes2B
[24]Comparative, retrolective, cohort studyMelanoma, stages II–III686; 329; 357Improved survivalUnknown2A
[4]Cohort studyBreast, stage III8,475h; 17i; 17iImproved mean survivalYesNone
[4]Cohort studyVarious types, stages I–IV8,475h; 39i; 39iImproved mean survivalYesNone
[4]Cohort studyVarious types, stages I–IV10,226h; 396i; 396iImproved mean survivalYesNone
[27]Retrospective, observational cohort studyNonmetastatic colorectal804; 429; 375Lower incidence of diarrhea, nausea, loss of appetite, dermatitis, fatigue, and mucositisYes2C
[30]Nonconsecutive case seriesPancreatic 292; 292; various historical controlsImproved median survivalYes3iiiA
[31]Case report Lung, small cell, stage IV1; 1; NonePartial responseYesNone

LN+ = lymph node–positive disease; No. = number.
aRefer to 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.
cStrongest evidence reported that the treatment under study has anticancer activity or otherwise improves the well-being of cancer patients.
dChemotherapy, radiation therapy, hormonal therapy, or cytokine therapy administered/allowed at the same time as mistletoe therapy.
eFor information about levels of evidence analysis and an explanation of the level of evidence scores, refer to Levels of Evidence for Human Studies of Cancer Complementary and Alternative Medicine.
fControl 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.
gRadiation 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.
hAmong 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.
iPatients were strictly matched according to gender, year of birth ± 3 years, year of diagnosis ± 3 years, type of tumor, stage of disease, and conventional therapy received.

Other Mistletoe Preparations

Eurixor

Five randomized controlled trials of Eurixor have been published as peer-reviewed articles. The largest of these studies involved 477 patients with squamous cell carcinoma of the head and neck.[2,15] These patients were randomly assigned to treatment with surgery or surgery and radiation therapy, and they were randomly assigned again to either no additional treatment or treatment with Eurixor. This double randomization produced the following four groups: (1) 105 patients treated with surgery alone; (2) 97 patients treated with surgery and Eurixor; (3) 137 patients treated with surgery and radiation therapy; and (4) 138 patients treated with surgery, radiation therapy, and Eurixor. Eurixor was administered in four treatment cycles over a 60-week period. Each treatment cycle lasted 12 weeks and was followed by a 4-week break period. During each cycle, Eurixor was administered by subcutaneous injection twice a week. Each injection contained enough standardized mistletoe extract to yield a dose of 1 nanogram of ML-1 lectin per kilogram of body weight. The results of this randomized trial showed that treatment with Eurixor did not improve either 5-year disease-free survival or 5-year disease-specific survival. In addition, no stimulation of the immune system or improvement in quality of life was found with Eurixor treatment.

It has been suggested that a less-than-optimum dose of mistletoe was administered to patients in this trial.[4] The same dose of Eurixor, however, has been used in other clinical studies, including studies in which benefit was reported.[1,32] In addition, both the dose and the duration of Eurixor treatment in this trial are consistent with those recommended by the manufacturer.[2]

A prospective, randomized phase II trial involved 45 patients who had noninvasive bladder cancer.[3] After surgery, the patients were randomly assigned to receive either three cycles of treatment with Eurixor or no further therapy. The goal of the study was to determine whether Eurixor treatment could reduce bladder cancer recurrence. Twenty-three patients were randomly assigned to the treatment group, and 22 were randomly assigned to the control group. Each cycle of Eurixor treatment consisted of 3 months of subcutaneous injections, administered twice a week, followed by a 3-month break period. One milliliter of Eurixor was administered at each injection. After 18 months of follow-up, 11 recurrences were observed in the treatment group, and 8 were observed in the control group. The average time of recurrence for the treatment group was 6.3 months; for the control group, it was 6.4 months. The median disease-free interval for the treatment group was 9 months; for the control group, it was 10.5 months. None of these differences was considered significant.

A major concern about this study, however, is that the dose of lectin ML-1 administered to patients was not adjusted for body weight.

Isorel

Only two trials of Isorel have been reported in the publicly available, online indexed peer-reviewed medical literature. In one study, 64 patients with advanced colorectal cancer (Dukes C and D) were randomly assigned to three groups: (1) surgery and chemotherapy; (2) surgery and chemotherapy plus Isorel; and (3) surgery alone. Patients receiving treatment with Isorel had a significantly better median survival advantage and a better cumulative survival advantage than patients in the other two groups. In addition there were no side effects to treatment in the Isorel group.[33]

Another study showed that perioperative use of Isorel in patients with cancer of the digestive tract resulted in an increase in lymphocytes through 14 days of drug administration.

Helixor

In a three-arm randomized trial, breast cancer patients were randomly assigned to one of the following groups after surgery: Helixor, chemotherapy, or control. Some patients in each group were also treated with local radiation therapy. The number of evaluable patients in the chemotherapy group was 177, with survival in the chemotherapy group superior to that in the control group and equivalent to that in the Helixor group.[34] 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.[35] The use of Helixor has also been examined in other studies.[36-39]

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.[40]

abnobaVISCUM

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.[41] 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.[42]

Table 2. Use of Other Mistletoe Products in Cancer Treatment: Clinical Reports Describing Therapeutic Endpointsa
Reference Citation(s) Type of Study Product Tested Type(s) of Cancer No. of Patients: Enrolled; Treated; Controlb Strongest Benefit Reportedc Concurrent Therapyd Level of Evidence Scoree 
[3]Randomized trialEurixorBladder, noninvasive45; 23; 22NoneNo1iiDi
[1,32]Randomized trialEurixorBrain, glioma; 74% of patients, stages III–IV; 26% of patients, no stage information47; 20; 18Improved survival, stages III–IV patients onlyYes1iiA
[43,44]Randomized trialEurixorColorectal, metastatic107; 38; 41Improved quality of lifeYes1iiA
[2]Randomized trialEurixorHead and neck, squamous cell, stages I–IV495; 235f; 242fNoneYesf1iiA
[34]Randomized trialHelixorBreast, stages I–III692; 192; 274Improved survivalYes1iiA
[35]Randomized trialHelixorColorectal, metastatic60; 20; 20Improved mean survivalYes1iiA
[13]Randomized controlled trialPS76A (Lektin)Breast352; 176; 176Improved quality of lifeYes1iC
[33]Randomized trialIsorelColorectal64; 50; 14Improved survival and tolerance to either adjuvant or palliative treatmentYes1iiA
[45]Nonrandomized controlled trialIsorelDigestive tract70; 40; 30Enhanced cellular immunity and improved quality of lifeNo2C
[41]Nonrandomized controlled trialabnobaVISCUM QuercusMetastatic colorectal25; 25; noneNoneYes2Diii
[21]Nonrandomized controlled trialViscum fraxini-2Hepatocellular carcinoma23; 23; noneImproved survivalNo2Dii

No. = number.
aRefer to 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.
cStrongest evidence reported that the treatment under study has anticancer activity or otherwise improves the well-being of cancer patients.
dChemotherapy, radiation therapy, hormonal therapy, or cytokine therapy administered/allowed at the same time as mistletoe therapy.
eFor information about levels of evidence analysis and an explanation of the level of evidence scores, refer to Levels of Evidence for Human Studies of Cancer Complementary and Alternative Medicine.
fThis trial was a four-arm trial; patients were randomly assigned to surgery only or to surgery plus radiation therapy, followed by a second randomization to no mistletoe treatment or to treatment with Eurixor; the resulting treatment groups contained the following numbers of evaluable patients: surgery only = 105, surgery plus Eurixor = 97, surgery plus radiation therapy = 137, and surgery plus radiation therapy plus Eurixor = 138; radiation therapy and Eurixor treatment overlapped; no treatment approach was superior in terms of disease-free survival, disease-specific survival, improvement in quality of life, or stimulation of the immune system; in the table, mistletoe-treated and nontreated (control) patients were grouped (i.e., number treated = 97 + 138 = 235, and number control = 105 + 137 = 242).

Current Clinical Trials

Check NCI’s list of cancer clinical trials for cancer CAM clinical trials on mistletoe extract that are actively enrolling patients.

General information about clinical trials is also available from the NCI Web site.

References
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  2. Steuer-Vogt MK, Bonkowsky V, Ambrosch P, et al.: The effect of an adjuvant mistletoe treatment programme in resected head and neck cancer patients: a randomised controlled clinical trial. Eur J Cancer 37 (1): 23-31, 2001.  [PUBMED Abstract]

  3. Goebell PJ, Otto T, Suhr J, et al.: Evaluation of an unconventional treatment modality with mistletoe lectin to prevent recurrence of superficial bladder cancer: a randomized phase II trial. J Urol 168 (1): 72-5, 2002.  [PUBMED Abstract]

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