Mistletoe has been evaluated as a treatment for cancer in numerous clinical studies.[1-32] Reviewed in [33-37] All studies reported to date were conducted in Europe, primarily in Germany and Austria. Results of most of these studies were published exclusively in German. The mistletoe extracts/products tested were Iscador, Eurixor, Helixor, Lektinol, and recombinant lectin ML-I (see the tables at the end of this section).

Approximately half of the reported studies were controlled studies, and a majority of these were randomized clinical trials. Survival was the principal endpoint measured in most reported studies; however, other endpoints included tumor response, tumor recurrence, and quality of life.

Although mistletoe was found to be therapeutically effective in most of the reported studies, almost all of the studies had one or more major weaknesses that raised doubts about the reliability of the findings. These weaknesses include registration of small numbers of patients; presence of large numbers of patients who either were not evaluable or were otherwise excluded from the analyses; failure to adequately document mistletoe use, mistletoe dose, and/or interruptions of mistletoe use; absence of control subjects or use of historical control subjects; use of inadequate randomization procedures; absence of treatment blinding; extensive use of subset analysis; and the measurement of mean as opposed to median survival. (Note: In studies with small numbers of patients, the mean survival time, i.e., the average survival time can be greatly exaggerated if one or more patients exhibit unusually long survival; median survival, therefore, is a better 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.

Seven of the most completely documented studies are discussed below.

One of the 7 studies was a three-arm, randomized phase III trial that involved 408 patients with previously untreated, inoperable non-small cell lung cancer.[21] These patients were randomly assigned to one of the following treatments: (1) subcutaneous injection 3 times a week with IscadorU or IscadorQ (see General Information section); 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. The trial was initiated at the beginning of 1978 and was completed at the end of June 1987. 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 carefully measured 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 phase III trial involved 477 patients with squamous cell carcinoma of the head and neck.[4] Reviewed in [36] These patients were randomly assigned to treatment with surgery or surgery and radiation therapy, and then 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 given 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-I 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.[7] The same dose of Eurixor, however, has been used in other clinical studies, including studies in which benefit was reported.[1,3,22] In addition, both the dose and the duration of Eurixor treatment in this trial are consistent with those recommended by the manufacturer.[4]

A third randomized phase III trial of mistletoe as a treatment for cancer involved 830 patients with high-risk melanoma (i.e., a primary tumor larger than 3 millimeters in diameter and no regional lymph nodes positive for cancer or a primary tumor of any size, 1 to 2 regional lymph nodes positive for cancer, and no distant metastases) who were randomly assigned to 1 of the following 4 groups after potentially curative surgery: (1) treatment with low-dose interferon -alfa, (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.[24] The interferon injections were given every other day, whereas IscadorM was administered 3 times a week. After 8 years of follow-up, no increase in survival time or increase in time until melanoma recurrence was demonstrated for mistletoe treatment or treatment with either type of interferon. A nonrandomized, case-control study of long-term mistletoe extract for patients with melanoma, however, showed a survival advantage among patients with high-risk disease.[38]

Three other studies of mistletoe were described in a single published report.[7] The patients in these studies were drawn from 10,226 cancer patients who were participants in a prospective study of the influence of self-regulation (i.e., the ability of a person to achieve a sense of well-being, inner equilibrium, a feeling of competence, and an ability to control stressful situations) on the incidence and course of cancer. Among these individuals, 1,668 patients who had been treated with Iscador and 8,475 patients who had received no mistletoe therapy were identified.

One of the 3 studies was a retrospective matched-pair study of the effectiveness of Iscador as a treatment for cancer.[7] Among the patients who had been treated with Iscador and those who had not, 396 pairs of individuals were identified who were closely matched according to criteria of gender; year of birth ±3 years; year of cancer diagnosis ±3 years; type of cancer; stage of disease; type of metastasis, if present; and type(s) of conventional therapy received. These individuals had rectal cancer, colon cancer, breast cancer, stomach cancer, or lung cancer. It was reported that the mean survival time of the Iscador-treated patients was 39% longer than the mean survival time of the patients who had not been treated with mistletoe (mean survival times = 4.23 years and 3.05 years, respectively). This difference in survival was statistically significant. However, the retrospective nature of this study is a major weakness. Another weakness is the fact that Iscador use was incompletely ascertained. Only the actuality of mistletoe use (yes/no) and its overall duration of use were documented. No information was collected about the type of Iscador used (i.e., the host tree), the dose used, and whether there were any interruptions in use.

The second and third studies were prospective, randomized matched-pair studies (i.e., similar to randomized trials) that involved patients who were drawn from the group of 8,475 individuals who had not been treated with mistletoe.[7] From this group, 2 sets of matched pairs were created. One set contained 49 pairs of patients who had rectal cancer, colon cancer, stomach cancer, breast cancer, or lung cancer. The other set contained 17 pairs of individuals who had stage II or stage III breast cancer. These studies used the same matching criteria as the retrospective study. In the 2 sets, one member of each pair was randomly selected as a candidate for mistletoe therapy. These patients were advised to ask their doctor for Iscador treatment. Ultimately, only 39 individuals in the 49-pair set were treated with Iscador. Therefore, only 39 pairs of this 49-pair set were eligible for analysis. All 17 pairs in the second set were eligible for analysis.

The mean survival time of the Iscador-treated patients in the 39-pair set was 42% longer than the mean survival time of the patients who were not treated with mistletoe (mean survival times = 3.49 years and 2.45 years, respectively). The mean survival time of the Iscador-treated patients in the 17-pair set was approximately twice that of the patients who did not receive mistletoe therapy (mean survival times = 4.79 years and 2.41 years, respectively). Both differences in survival were statistically significant.

These 2 randomized studies, however, had major weaknesses, including the recruitment of small numbers of patients and insufficient documentation of mistletoe use. As in the case of the retrospective study, only the actuality of mistletoe use (yes/no) and the overall duration of mistletoe treatment were ascertained. No information was collected on the type of Iscador used, the dose of Iscador used, and whether there were any interruptions in Iscador therapy.

The seventh study was a prospective, randomized phase II trial that involved 45 patients who had noninvasive bladder cancer.[5] 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, given 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 eight 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-I administered to patients appears to have varied with body weight. If different batches of Eurixor were used for individual patients, the patients may not have received uniform doses throughout the trial. Each milliliter of Eurixor has been reported to contain 50 to 70 nanograms of ML-I. Reviewed in [1,3,34] Therefore, the dose of lectin administered to a person weighing 120 pounds (approximately 55 kilograms) could have ranged from 0.91 nanograms per kilogram body weight to 1.27 nanograms per kilogram body weight. For a person weighing 160 pounds (approximately 73 kilograms), the dose of lectin could have ranged from 0.68 nanograms per kilogram body weight to 0.96 nanograms per kilogram body weight. As indicated above, the manufacturer of Eurixor recommends a dose of 1 nanogram per kilogram body weight. Since 33 of the 45 patients in this trial were men and men tend to weigh more than women, it is conceivable that a substantial fraction of the patients were treated with lower-than-recommended doses of ML-I.

Refer to the NCI Web site for a list of active clinical trials evaluating the use of mistletoe in cancer treatment.

References

1. Lenartz D, Stoffel B, Menzel J, et al.: Immunoprotective activity of the galactoside-specific lectin from mistletoe after tumor destructive therapy in glioma patients. Anticancer Res 16 (6B): 3799-802, 1996 Nov-Dec.  [PUBMED Abstract]
   
   
2. Gabius HJ, Gabius S, Joshi SS, et al.: From ill-defined extracts to the immunomodulatory lectin: will there be a reason for oncological application of mistletoe? Planta Med 60 (1): 2-7, 1994.