List of References
Mistletoe in Cancer
Prospective Comparative Trials
48 prospective comparative trials investigated the influence of mistletoe therapy on tumour diseases, 30 of which are randomised controlled trials (RCT Review Table) and 18 are non-randomised studies (N-RCT Review Table). Most of the non-randomised studies employed specific methods to control for confounding: Patients were alternately allocated to the test or control groups in two studies; prospective matched patient pairs were recruited from a large pool of patients in nine studies; patients were matched for evaluation in one study; there was a prognostic disadvantage for the mistletoe group in one study; and in another study an independent senior hospital physician allocated patients to the mistletoe group and control groups respectively.
30 RCTs enrolled 3396 patients, 18 N-RCTs enrolled more than 4068 patients (the size of one control group was not specified). The studies have been carried out in university hospitals, other academic hospitals, large communal hospitals and specialist oncology clinics.
Diagnoses 
These prospective comparative trials investigated mistletoe therapy in the treatment of: breast carcinoma (n = 14), lung carcinoma (n = 8), colon and rectum carcinoma (n = 6), stomach carcinoma (n = 4), gastrointestinal cancer (n = 1), bladder carcinoma (n01), melanoma (n = 4), ovarian carcinoma (n = 6), genital carcinoma (n = 1), uterus carcinoma (n=4), cervical carcinoma (n = 4), cervical dysplasia (n=2), head and neck tumours (n = 1), osteosarcoma (n=1), malignant pleural effusion (n = 1). The stage of tumour disease varied in each study, ranging from early diagnosis tumours to advanced tumour disease.
Endpoints
The following endpoints were identified for the trials: Survival time (n = 34); tumour remission or tumour recurrence (n = 15); quality of life and coping behaviour (n = 16), reduction in side effects of conventional therapies such as chemotherapy, radiotherapy or surgery (n = 10).
Therapy
Iscador® was administered in 37 studies, Helixor in eight studies, Isorel® and Abnobaviscum® in two studies each. Dosage mostly followed recommendations of the manufacturer - i.e. low dosage at the beginning of therapy; thereafter gradually increasing to the maximum well-tolerated dosage. In one study, mistletoe extracts were also administered according to lectin content (1ng/kg bodyweight) [3]. The mistletoe extracts were administered by subcutaneous injection, with the exception of five studies where administration was by infusion [4, 5, 34], intrapleural [22], or intravesical [17a]. The control group either received no further treatment (n = 27), treatment with an additional placebo (n = 3), Lentinan (n = 1), BCG (n = 2), Doxycyxlin (n = 1), Etoposide (n=1), or partly hormone treatment (n = 1).
In 13 trials mistletoe therapy was administered concurrently with conventional treatments (chemotherapy, radiotherapy, surgery) [1, 4, 4a, 5, 7, 8, 8a, 9, 24, 26, 34, 35, 37]. Four of these studies at least partially involved patients with advanced metastatic disease [5, 7, 8, 26]. Ten studies assessed reduction of side effects of the conventional cytoreductive therapies (including surgery) [1, 4, 4a, 5, 9, 24, 26, 34, 36, 37]. In 32 trials mistletoe treatment was administered, at least partially, in an adjuvant setting following primary surgery or radiotherapy [1, 4, 5, 8a, 10, 11, 13-17, 17a, 23, 25, 26, 28-33, 35-37].
Results (RCT-Review Table and N-RCT-Review Table)
- Altogether 35 studies showed a statistically significant favourable result in at least one clinically relevant parameter [1, 3-7, 8a, 9-11, 13-17, 22, 24, 26, 29, 31-34, 36, 37], a further 10 studies showed a positive trend [8, 15b, 16a, 24b, 25, 28, 30, 35], one study found no difference [15a], and one study showed a negative trend. [23]. In one study standard medication showed better results than mistletoe treatment [17a].
- Survival time has been investigated in 34 studies: Sixteen trials found a statistically significant benefit to using mistletoe therapy [5, 10, 11, 13-15b, 17, 29, 31-33], 16 studies showed a positive trend [6-8, 13-15, 15b, 16, 16a, 25, 28, 30, 35] and two studies found no effect [15a, 23]. One study reported that survival advantage increased according to duration of mistletoe treatment [11].
- Disease-free intervals, time to even, and recurrences were investigated in 11studies: Five studies found a statistically significant benefit in favour of mistletoe treatment [13-15, 16], two showed a positive trend [16a], one study found no effects [30] and the last reported a negative trend [23]. An interim analysis indicated a positive trend [24b]. In one study standard medication showed better results than mistletoe treatment [17a].
- Tumour remission was investigated in four studies: Two studies reported a statistically significant favourable effect [7, 22], one study showed a positive trend [6], and one study found no effect [8].
- Quality of life and coping behaviour (self-regulation) were investigated in 16 studies, 13 of which showed a statistically significant favourable advantage [3, 6, 8a, 11, 13-16], two a positive trend [11, 24b] and one study did not report its results pertaining to these endpoints [23]. One study suggested that good coping behaviour (self-regulation) and mistletoe therapy have a positive synergistic influence on each other. [11, 12]
- Reduction of the side effects of chemotherapy, radiotherapy, surgery and related improvement in quality of life was investigated in ten trials, seven of which reported a statistically significant benefit arising from mistletoe therapy [4, 9, 24, 26, 34, 36, 37]. An eighth trial found a reduction of chemotherapy-related side effects but no benefit using well-established quality of life-questionnaires; this study, however, was only published as an abstract and presented little information on study details and results. [4a] A ninth, very small pilot study had mixed results (no positive effect on quality of life, a significant reduction of suppression of activated CD56+/CD69+/CD45+NK-cells, no further effects on other immune cells) [1]. The tenth study mentioned less frequent side effects of 5-FU and an improvement in quality of life without giving details [5]. Furthermore, one study reported that a higher dosage of cisplatin and holoxan could be given during treatment with mistletoe therapy as fewer and especially less serious side effects occurred. [24]
- Tolerance of mistletoe therapy was mostly good. One case of urticaria and an angio-oedema was described [26]. No further major side effects were reported. Reactions at the injection site (swelling, induration, redness, itching, pain) and mild influenza-like symptoms or fever were considered to be minor, spontaneously-subsiding effects. One of the studies, on malignant pleural effusion, observed less side effects (pain, fever, burning sensation) after the instillation of mistletoe extracts than after instillation of Doxycyclin, Meperidin and Lidocain. [22]
Methodological quality of the studies
The methodological quality of the studies varied considerably. The quality of several trials—design, execution and documentation—is in some respects far below the standards deemed necessary or optimal today, especially in some of the older studies. However, during recent years the quality has improved and a number of recent studies have been well executed. For a detailed evaluation of study quality see [18-21]; some of the most important studies have been comprehensively described: Piao 2004, Grossarth 2001, 2006, 2007 and 2008, Kleeberg 2004.
Summary and comments
The prospective comparative randomised trials predominantly show benefits of mistletoe therapy with respect to survival time, quality of life and reduction in the side effects of conventional therapies. While the quality of the studies varies widely, the overall conclusions do not essentially change if only the good quality studies are taken into consideration. A reduction in side effects of conventional therapies and improvement of quality of life appears to be best substantiated. In this regard, the study is easier to conduct and less complicated, mainly due to a shorter study duration—that is, if the issue of blinding is excluded (which can only be carried out pro forma because of the high rates of unblinding [1, 27] with subcutaneous administration). Survival benefit has been shown, but not beyond critique. Survival time is possibly dependent on the duration of therapy [2, 11] and on additional factors such as good coping behaviour (self-regulation) [11, 12]. It is not possible to make reliable statements regarding tumour remission and disease-free intervals due to methodological weaknesses in the prospective comparative trials. 18 of the studies were embedded in the same large epidemiological cohort study (details, see Grossarth et al. ).
RCT-Table in English as PDF-download
N-RCT-Table in English as PDF-download
Gunver S. Kienle, MD
Last modified:
May 2010
References 
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