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Efficacy and safety of the long-term treatment of melanoma with a mistletoe preparation (Iscador)
Abstract
Background: Mistletoe preparations such as Iscador are in common use as complementary medication for solid cancers. Efficacy and safety of this therapy is still controversial. Objective: Does the long-term application of the mistletoe preparation Iscador show any effect in prospective controlled studies on survival, tumor progression, and psychosomatic self-regulation of patients with melanoma? Patients and Methods: Prospective recruitment and long-term follow-up of two controlled cohort studies: (1) Randomised matched-pair study (22 pairs): patients with melanoma, treated with conventional therapies who had never used any kind of mistletoe therapy were matched for prognostic factors. By pairwise random allocation, a mistletoe therapy was suggested to one of the patients. (2) Non-randomised matched-pair study (32 pairs): patients with melanoma, treated with conventional therapies who already received mistletoe (Iscador) therapy were matched by the same criteria to control patients without Iscador therapy. Results: For overall survival, neither study shows a significant effect in favour of the Iscador therapy. The overall assessment of the effect of long-term Iscador therapy on tumor progression, however, is significant in favour of the Iscador group in both studies, hazard ratio estimate and 95% confidence interval (CI): 0.49 (0.32, 0.75) and 0.72 (0.54, 0.97) respectively. In the randomised study, the psychosomatic self-regulation improves within 12 months on a scale from 1 (low) to 6 (high) significantly in the Iscador group relative to the control group: estimate of the median of differences with CI: 0.55 (0.15, 0.85). Conclusion: The mistletoe preparation Iscador shows in these studies a clinically relevant and significant therapeutic effect on the progression of melanoma. In the short term, self-regulation rises more under Iscador therapy than under conventional therapy alone.
... Systematic search of the literature de-novo: [375,[377][378][379] Strength of consensus: 95 % ...
... Thus, this study does not constitute a comparative therapeutic study of two therapies actually performed. The effect of mistletoe therapy on survival therefore cannot be assessed [379]. ...
... Corroborating these data, the in vitro effect was good or moderate depending on the investigated parameter. No positive impact on survival, but a significant decrease in tumor progression was found in VAE-treated human melanoma patients [135,136]. One clinical study was conducted with adjuvant VAE treatment after radiation of canine oral melanomas, and a marked prolongation of survival time was found. ...
Cancer is a common disease in humans and in companion animals and treatment is challenging. The aim of this systematic review was to identify and assess the potential use of Viscum album L. extracts (VAE) for treatment of neoplastic diseases in companion animals. Peer-reviewed animal, in vivo and in vitro studies were included, considering the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement and a measurement tool to assess systematic reviews (AMSTAR). Overall, 6,148 references were identified. Following a predefined protocol, 114 full-text references were assessed. Ultimately, 61 references were included for further assessment, 25 references included in vitro experiments, 26 included in vivo and clinical experiments and 10 references included both in vitro and in vivo experiments. These 61 references comprised data of 193 in vitro and 67 in vivo and clinical experiments. Most of the 67 in vivo and clinical experiments were conducted with mice (59), followed by rats (4), dogs (3) and horses (1). So far, oral melanomas, mammary tumors and sticker sarcomas in dogs, as well as sarcoids in horses, have been investigated in controlled clinical trials. A scoring system was established to evaluate the outcomes of each study based on defined effect levels. The efficacy of VAE treatment was most pronounced for melanomas, sarcomas, mammary carcinoma and equine sarcoids. The limited number and quality of published studies on VAE treatment in companion animals impedes to draw definitive conclusions regarding the efficacy of VAE in the treatment of cancer. Thus, further research is needed to elucidate the impact of VAE on the treatment of cancer in companion animals and possible underlying mechanisms.
... Clinical studies on the effect of mistletoe on mortality in tumour patients are inconclusive. On the one hand, there are studies showing a longer average survival in the mistletoe arm [103][104][105][106][107][108], on the other hand, there are studies that found no influence of mistletoe on the mortality of tumour patients [109][110][111][112][113][114][115]. The influence of mistletoe on progression-free survival of tumour patients has also been investigated in some studies. ...
Modern phytotherapy is part of today’s conventional evidence-based medicine and the use of phytopharmaceuticals in integrative oncology is becoming increasingly popular. Approximately 40% of users of such phytopharmaceuticals are tumour patients. The present review provides an overview of the most important plants and nature-based compounds used in integrative oncology and illustrates their pharmacological potential in preclinical and clinical settings. A selection of promising anti-tumour plants and ingredients was made on the basis of scientific evidence and therapeutic practical relevance and included Boswellia, gingko, ginseng, ginger, and curcumin. In addition to these nominees, there is a large number of other interesting plants and plant ingredients that can be considered for the treatment of cancer diseases or for the treatment of tumour or tumour therapy-associated symptoms. Side effects and interactions are included in the discussion. However, with the regular and intended use of phytopharmaceuticals, the occurrence of adverse side effects is rather rare. Overall, the use of defined phytopharmaceuticals is recommended in the context of a rational integrative oncology approach.
... Apart from these risks, several other important risks of bias in the studies must be noted. First of all, another risk of bias in 13 studies was the very small sample size (per arm less than 30 patients) independently from power analysis (Cazacu et al. 2003;El-Kolaly et al. 2016;Gaafar et al. 2014;Goebell et al. 2002;Grossarth-Maticek and Ziegler 2006b, 2007a, b, c, 2008Kim et al. 2012;Lenartz et al. 2000;Longhi et al. 2014). On the one hand this makes statistical calculations less reliable or even impossible and on the other hand it reduces significantly the generalizability of results. ...
Purpose
Mistletoe treatment of cancer patients is discussed highly controversial in the scientific literature. Aim of this systematic review is to give an extensive overview about current state of research concerning mistletoe therapy of oncologic patients regarding survival, quality of life and safety.
Methods
In September and October 2017 Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), PsycINFO, CINAHL and “Science Citation Index Expanded” (Web of Science) were systematically searched.
Results
The search strategy identified 3647 hits and 28 publications with 2639 patients were finally included in this review. Mistletoe was used in bladder cancer, breast cancer, other gynecological cancers (cervical cancer, corpus uteri cancer, and ovarian cancer), colorectal cancer, other gastrointestinal cancer (gastric cancer and pancreatic cancer), glioma, head and neck cancer, lung cancer, melanoma and osteosarcoma. In nearly all studies, mistletoe was added to a conventional therapy. Patient relevant endpoints were overall survival (14 studies, n = 1054), progression- or disease-free survival or tumor response (10 studies, n = 1091). Most studies did not show any effect of mistletoe on survival. Especially high quality studies do not show any benefit.
Conclusions
With respect to survival, a thorough review of the literature does not provide any indication to prescribe mistletoe to patients with cancer.
Purpose
Mistletoe treatment is discussed controversial as a complementary treatment for cancer patients. Aim of this systematic analysis is to assess the concept of mistletoe treatment in the clinical studies with respect to indication, type of mistletoe preparation, treatment schedule, aim of treatment, and assessment of treatment results.
Methods
In the period from August to December 2020, the following databases were systematically searched: Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), PsycINFO, CINAHL, and “Science Citation Index Expanded” (Web of Science). We assessed all studies for study types, methods, endpoints and mistletoe preparations including their ways of application, host trees and dosage schedules.
Results
The search concerning mistletoe therapy revealed 3296 hits. Of these, 102 publications and at total of 19.441 patients were included. We included several study types investigating the application of mistletoe in different groups of participants (cancer patients of any type of cancer were included as well as studies conducted with healthy volunteers and pediatric patients). The most common types of cancer were breast cancer, pancreatic cancer, colorectal cancer and malignant melanoma. Randomized controlled studies, cohort studies and case reports make up most of the included studies. A huge variety was observed concerning type and composition of mistletoe extracts (differing pharmaceutical companies and host trees), ways of applications and dosage schedules. Administration varied e. g. between using mistletoe extract as sole treatment and as concomitant therapy to cancer treatment. As the analysis of all studies shows, there is no relationship between mistletoe preparation used, host tree and dosage, and cancer type.
Conclusions
Our research was not able to deviate transparent rules or guidelines with respect to mistletoe treatment in cancer care.
Background:
Mistletoe extracts are used as an adjunct therapy for cancer patients, but there is dissent as to whether this therapy has a positive impact on quality of life (QoL).
Methods:
We conducted a systematic review searching in several databases (Medline, Embase, CENTRAL, CINAHL, PsycInfo, Science Citation Index, clinicaltrials.gov, opengrey.org ) by combining terms that cover the fields of "neoplasm", "quality of life" and "mistletoe". We included prospective controlled trials that compared mistletoe extracts with a control in cancer patients and reported QoL or related dimensions. The quality of the studies was assessed with the Cochrane Risk of Bias tool version 2. We conducted a quantitative meta-analysis.
Results:
We included 26 publications with 30 data sets. The studies were heterogeneous. The pooled standardized mean difference (random effects model) for global QoL after treatment with mistletoe extracts vs. control was d = 0.61 (95% CI 0.41-0.81, p < 0,00001). The effect was stronger for younger patients, with longer treatment, in studies with lower risk of bias, in randomized and blinded studies. Sensitivity analyses support the validity of the finding. 50% of the QoL subdomains (e.g. pain, nausea) show a significant improvement after mistletoe treatment. Most studies have a high risk of bias or at least raise some concern.
Conclusion:
Mistletoe extracts produce a significant, medium-sized effect on QoL in cancer. Risk of bias in the analyzed studies is likely due to the specific type of treatment, which is difficult to blind; yet this risk is unlikely to affect the outcome.
Prospero registration:
CRD42019137704 .
Purpose
One important goal of any cancer therapy is to improve or maintain quality of life. In this context, mistletoe treatment is discussed to be highly controversial. The aim of this systematic review is to give an extensive overview about the current state of evidence concerning mistletoe therapy of oncologic patients regarding quality of life and side effects of cancer treatments.
Methods
In September and October 2017, Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), PsycINFO, CINAHL and “Science Citation Index Expanded” (Web of Science) were systematically searched.
Results
The search strategy identified 3647 articles and 28 publications with 2639 patients were finally included in this review. Mistletoe was used in bladder cancer, breast cancer, other gynecological cancers (cervical cancer, corpus uteri cancer, and ovarian cancer), colorectal cancer, other gastrointestinal cancer (gastric cancer and pancreatic cancer), glioma, head and neck cancer, lung cancer, melanoma and osteosarcoma. In nearly all studies, mistletoe was added to a conventional therapy. Regarding quality of life, 17 publications reported results. Studies with better methodological quality show less or no effects on quality of life.
Conclusions
With respect to quality of life or reduction of treatment-associated side effects, a thorough review of the literature does not provide any indication to prescribe mistletoe to patients with cancer.
Resection margins of melanomas in the head and neck region often have to be adapted according anatomical circumstances. In the case of thicker primary tumors or after complete resection of locoregional lymph node metastases, adjuvant therapy with interferon-α can be performed; in some cases, adjuvant radiotherapy may also be indicated. In the case of inoperable lymph node or distant metastases, systemic treatment is required. Beside well-established mono- or polychemotherapy regimens, newer targeted therapies with BRAF inhibitors (vemurafenib, dabrafenib), mitogenic-activated protein kinase (MEK) inhibitors (trametinib, binimetinib, and cobimetinib), and kinase inhibitors (imatinib, sunitinib, nilotinib, dasatinib) are also available.
This first German evidence-based guideline for cutaneous melanoma was developed under the auspices of the German Dermatological Society (DDG) and the Dermatologic Cooperative Oncology Group (DeCOG) and funded by the German Guideline Program in Oncology. The recommendations are based on a systematic literature search, and on the consensus of 32 medical societies, working groups and patient representatives. This guideline contains recommendations concerning diagnosis, therapy and follow-up of melanoma. The diagnosis of primary melanoma based on clinical features and dermoscopic criteria. It is confirmed by histopathologic examination after complete excision with a small margin. For the staging of melanoma, the AJCC classification of 2009 is used. The definitive excision margins are 0.5 cm for in situ melanomas, 1 cm for melanomas with up to 2 mm tumor thickness and 2 cm for thicker melanomas, they are reached in a secondary excision. From 1 mm tumor thickness, sentinel lymph node biopsy is recommended. For stages II and III, adjuvant therapy with interferon-alpha should be considered after careful analysis of the benefits and possible risks. In the stage of locoregional metastasis surgical treatment with complete lymphadenectomy is the treatment of choice. In the presence of distant metastasis mutational screening should be performed for BRAF mutation, and eventually for CKIT and NRAS mutations. In the presence of mutations in case of inoperable metastases targeted therapies should be applied. Furthermore, in addition to standard chemotherapies, new immunotherapies such as the CTLA-4 antibody ipilimumab are available. Regular follow-up examinations are recommended for a period of 10 years, with an intensified schedule for the first three years.
A prospective epidemiologic cohort study of long duration with 10'226 cancer patients was able to show that treatment with the mistletoe preparation Iscador had a significant effect on survival time. For the 2 × 622 patients of a prospective matched-pair study within this cohort, the mean survival time for patients with the 8 cancer types considered (breast carcinoma without metastases, breast carcinoma with axillary metastases, breast carcinoma with remote metastases, rectum carcinoma, colon carcinoma, stomach carcinoma, small-cell and non-small-cell lung carcinoma) was up to 40% longer than in the group without Iscador. Two studies with randomised matched pairs essentially confirmed these results. In this paper we single out from the overall complex of possible influencing factors the interaction between therapy with Iscador and self-regulation in each patient. Self-regulation according to Grossarth-Maticek comprises activities of the individual self which satisfy basic needs and harmonise physical, emotional and spiritual functions. A self-regulated person in this sense has the capacity, through creating certain conditions within the physical body, soul and spirit, and in the the social environment, to bring about specific stimuli and challenges to enhance his or her overall well-being. Self-regulation can be measured on an ordinal scale from 1 to 6 using questionnaires specifically designed for this purpose. Measuring the degree of self-regulation gives a tool to determine the link between psychosocial factors (quality of life) and disease/health status and physical risk factors. Several studies have shown that greater self-regulation is associated with a smaller risk of contracting a disease (i.e. physical and psychosocial risk factors have less impact), as well as with a longer survival time if the disease, particularly cancer, has already begun. Treatment with Iscador as well as a higher self-regulation score both seemed - independently of each other - to contribute to a longer survival time for cancer patients. In addition, there was a positive interaction and synergy effect. On the one hand, patients with high self-regulation benefited more from Iscador treatment (+ 51% relative to the control group) than did patients with low self-regulation. It seems that Iscador exerted its positive effect in particular when self-regulation was high, or where self-regulation could be increased. On the other hand, Iscador treatment of cancer patients was associated with increased self-regulation and a corresponding enhancement of quality of life.
The aim was to study the perceived quality of life/life satisfaction in a sample of women with breast cancer who were treated in a hospital with alternative/complementary care and the same variables in individually matched patients who received only conventional medical treatment. A non-randomized controlled trial design with repeated measurements was used. Sixty women with breast cancer treated with anthroposophic medicine (ABCW) and 60 with conventional medicine (CBCW) were included and 36 matched pairs took part on all occasions. The quality of life was measured by the EORTC QLQ-C30 and the Life Satisfaction Questionnaire (LSQ). The comparisons were calculated as effect sizes (ES). The women in the ABCW group reported small or moderate effects, expressed as ES, on their quality of life/life satisfaction compared to their matched "twins" in the CBCW group at the 1-year follow-up in 15 out of 21 scales/factors. It was concluded that the women who had chosen anthroposophic care increased their perceived quality of life/life satisfaction according to the methodology of the study.
Many patients with cancer, women more often than men, use complementary and alternative medicine (CAM) and care. Our aim was to examine coping over 5 years (November 1995 to January 1999) in two samples of women with breast cancer who were treated with anthroposophic care or conventional medical treatment. The present study is part of a larger study of the outcome of anthroposophic care for women with breast cancer.
A nonrandomized controlled trial design was used with individual matching and repeated measurements on six occasions (at admission, 1 month, 3 months, 6 months, 1 year, and 5 years). The matching was based on the following variables: stage of disease at entry, age, treatment during the 3 months before entering the study, and prognosis.
An anthroposophic hospital and conventional hospitals in Sweden.
Sixty (60) women treated with anthroposophic medicine and 60 women from an oncology outpatient department participated. Forty-nine (49) women in anthroposophic care and 51 in the outpatient group survived 1 year; 26 women in anthroposophic care and 31 in the outpatient group survived 5 years.
An anthroposophic care program.
Coping was measured using the Mental Adjustment to Cancer scale. Repeat measures of analysis of variance (ANOVA) were used for within-group comparisons, and effect size (ES) was used for between-group comparisons.
The women in anthroposophic care showed more passive and anxious coping on admission, but this decreased over time. In the women in anthroposophic care, there were small ES improvements in fighting spirit and passive, anxious coping at 4 of the measured timepoints compared to admission.
The choice of anthroposophic care could be seen as a possible way to cope with emotional distress in this group of women with breast cancer.
Mistletoe preparations such as Iscador (Weleda, Schwäbisch Gmünd, Germany) are commonly used in complementary and alternative / anthroposophic medicine for many cancer indications, particularly for solid cancers. Efficacy of this complementary therapy is still controversial.
Does long-term therapy with Iscador show any effect on survival, tumor progression and psychosomatic self-regulation of patients with breast cancer?
Prospective recruitment and long-term follow-up of two controlled cohort studies: (1) Randomized matched-pair study (38 pairs): breast cancer patients without any recurrences or metastases and no mistletoe therapy were matched for prognostic factors. By pairwise random allocation, one of the patients was suggested mistletoe therapy to be applied by the attending physician. (2) Non-randomized matched-pair study (84 pairs): breast cancer patients without recurrences or metastases that already received mistletoe therapy were matched to control patients without Iscador therapy.
For overall survival, the nonrandomized study shows significant effects in favor of Iscador therapy: hazard ratio HR estimate and 95% confidence interval CI: 0.43 (0.27-0.68). The effect of long-term Iscador therapy on tumor progression as measured by the time to local recurrences, lymphatic or distant metastases in breast cancer patients without any such events at first diagnosis, is in most cases significant in favor of the Iscador group, in the randomized as well as in the non-randomized study. Psychosomatic self-regulation in the Iscador group improves significantly within 12 months compared with the control group in the randomized as well as in the non-randomized study: estimate of the median difference and 95% CI: 0.35 (0.05-0.60), respectively 0.20 (0-0.35).
Iscador shows a clinically relevant effect on breast tumor progression as measured by overall survival as well as by the time to recurrences, lymphatic or distant metastases. In the short term, psychosomatic self-regulation increases more markedly under complementary Iscador therapy than under conventional therapy alone.
This article introduces a new personality inventory dealing with self-regulation. This is in some ways the opposite of neuroticism, and measures personal autonomy or independence, particularly as far as emotional dependence is concerned. Our concern was the relation between self-regulation and health, and large samples of healthy men and women were tested and followed up to demonstrate high predictability of mortality from cancer, coronary heart disease and other causes of death from scores on the questionnaire. It was also demonstrated that psychological risk factors were largely independent from physical risk factors, and could be changed by behavioural-cognitive treatment, reducing mortality.
The key difference between randomised (RCTs) and non-randomised studies (NRS) is their susceptibility to selection bias. Unlike RCTs, groups in non-randomised cohort studies are unlikely to be balanced because of the reasons leading patients to receive one or another treatment, giving rise to "confounding by clinical indication" (CCI). Researchers can try to minimise the susceptibility of NRS to selection bias both at the design stage, e. g. by matching participants on key prognostic factors, and during data analysis, e. g. by regression modeling. Nevertheless, because of i) logistical difficulties in matching, ii) imperfect knowledge about the relationships between prognostic factors and between prognostic factors and outcome, and iii) because of measurement limitations, it is inevitable that estimates of effect size derived from NRS will be confounded to some extent. Researchers and users of evidence alike need to be aware of the consequences of residual confounding. CCI need not necessarily lead to systematic bias in favour of one treatment but, if CCI acts in an unpredictable way, it will still give rise to additional, non-statistical "uncertainty bias" around the estimate of effect size.