According to a definition by the German Federal Ministry of Education and Research (BMBF), health services research describes the "reality of medical care, providing information on the use, success and risks of diagnostic and therapeutic procedures and health care concepts under everyday conditions" and "answers questions that neither basic biomedical research nor classical clinical research can answer" .
Over the course of the past two decades, health services research has contributed significantly to the understanding and definition of high quality cancer care , now representing a key element of modern oncology for long-term evaluation of patient-related endpoints .
Health services research studies or real-world data (RWD) studies are becoming increasingly important in modern oncology and are also gaining international recognition [251, 252, 253, 254]. The results of the RWD studies on mistletoe therapy can be summarised as follows:
Implementation and safety
Integrative oncological therapies are well accepted by oncological patients of different age groups and can be implemented in the daily care routine of cancer centres certified by the German Cancer Society [16, 19].
Subcutaneous mistletoe therapy, as well as intravenous and intratumoural application (off-label) in combination with other tumour therapies, is safe and has a mild to moderate side effect profile [93, 94, 95, 96].
A multicentre pharmaco-epidemiological cohort study shows that the use of a mistletoe extract (Iscador Qu) in colorectal cancer reduces the side effects of standard therapy (chemo-/radiotherapy), alleviates cancer-related symptoms and has a potential for improving metastasis-free survival .
If autoimmune diseases such as Hashimoto's thyroiditis, psoriasis, ulcerative colitis, Graves’ disease or Sjögren's syndrome are present concurrently with cancer, additional mistletoe therapy is possible .
Mistletoe extracts given in combination with monoclonal antibodies [65, 67], targeted therapy  or PD-1 and CTLA-4 inhibitors do not increase or exacerbate the side effect profile of these therapies. In fact, the side effect rate of an antibody therapy with additional mistletoe therapy is reduced by a factor of 5 in comparison to antibody therapy without mistletoe therapy ; in the case of a targeted therapy in combination with mistletoe therapy the discontinuation rate of treatment with conventional cancer drugs can be reduced by 50%. Furthermore, side effect rates are significantly lower compared to targeted therapy alone .
Quality of life
Additional mistletoe therapy is also useful to reduce pain and other cancer-related symptoms in the long term (for about five years), to alleviate symptoms associated with conventional treatment such as fatigue, and to improve HRQL in non-metastatic breast cancer . Financial worries have been shown to be significantly associated with tumour-related emotional and physical disorders in individuals with breast and lung cancer [306, 308].
The evaluation of the European Organization for Research and Treatment Quality of Life questionnaire (EORTC-QLQ-C30) showed improvements in emotional, social and role functioning after additional mistletoe therapy in patients with non-metastatic breast cancer . Two further studies – also in patients with non-metastatic breast cancer – showed a sustainable improvement in the sensation of warmth after additional mistletoe therapy [98, 99, 310].
Regarding the positive impact on thermo-coherence, data of a real-world-study (RWD) also revealed improvement of fatigue, insomnia and physical performance in non-metastatic breast cancer patients .
In a multicentre pharmaco-epidemiological cohort study, it was shown for the first time that supportive mistletoe therapy (Iscador Qu) in addition to chemo-/radiotherapy significantly improved fatigue syndrome in patients with non-metastatic colorectal cancer .
An observational study in patients with lymphocytic non-Hodgkin's lymphoma (CLL) revealed that mistletoe extracts (Helixor A) can be safely used  and can improve quality of life and immune competence .
In a qualitative study, 35 physicians specialised in integrative medical anthroposophic therapies were asked about their experience with mistletoe therapy in oncological patients. It was demonstrated that mistletoe therapy stabilizes the course of disease, improves patient’s general condition, increases vitality and strength, reduces dyspnoea and cachexia, improves the feeling of warmth as well as appetite and sleep and reduces pain caused by bone metastases along with therapy-related fatigue symptoms as well as the side effects of chemotherapy .
A multicentre pharmaco-epidemiological study in patients with pancreatic cancer (n = 396) showed that additional mistletoe therapy (Iscador) in combination with chemotherapy (mainly with gemcitabine) or as part of best supportive care is suitable for reducing tumour-related symptoms and prolonging life .
A prospective real-world data study of the Network Oncology Registry showed that 30 percent of a total of 87 patients with lung cancer with a median age of 68 years at diagnosis reported financial difficulties even before oncological treatment, which were particularly associated with pain (p=0.03) and younger age (p=0.02) according to adjusted multivariable regression analysis. The study highlights that the emotional and physical needs of patients with lung cancer should be considered before and during early treatment, as recommended in integrative and supportive tumour therapy concepts .
In a Real-World Data longitudinal study of the Network Oncology, patients with primary, non-metastatic breast cancer (n=319) received standard oncological therapy combined with Viscum album L. (VA) applications in 40 percent of the patients. Data evaluated included tumour-associated fatigue at baseline and 6, 12, and 24 months later. After 6 and 12 months, worsening of fatigue was observed in patients treated with chemotherapy (Ctx). Significant positive effects on thermocoherence, fatigue and in seven EORTC QLQ-C30 scales were observed 24 months later in patients who received VA applications but not Ctx. An adjusted multivariable long-term subgroup regression analysis (n=106) showed that Ctx, immunological and endocrine therapies caused a worsening of 17, 17, and 6 points, respectively, in the EORTC QLQ-C30 Fatigue scale (p=0.0004), while VA therapy caused an improvement of 12 points. In the present study, additional VA treatment had a supportive effect on tumour-related fatigue, insomnia, physical functioning, and thermocoherence .
Another Real-World Data longitudinal study of the Network Oncology in patients with primary, non-metastatic breast cancer (n=231) showed that, in addition to mistletoe therapy, non-pharmacological interventions such as nursing compresses (p=0.0002; R² = 28%) or detailed counselling sessions and biography work (p=0.0002; R² = 25%) led to an improvement of tumour-associated fatigue. Thus, breast cancer patients benefit from a hospital-based integrative medicine program and an extension of this concept should be developed in the future to alleviate fatigue symptoms during oncologic therapy .
In two health services research studies conducted by the German Network Oncology a prolongation of survival was observed in patients with metastatic non-small cell lung cancer (NSCLC)  and in patients with advanced metastatic pancreatic cancer  receiving mistletoe therapy in addition to the standard therapy according to the respective guidelines (see also the information under clinical studies).
An earlier health care research study conducted by the Network Oncology using the example of a clinic with an anthroposophic concept (Öschelbronn Clinic) had already shown the median survival of patients with stage III/IV pancreatic cancer, of which 91 percent had received mistletoe therapy, to be significantly longer at 12.4 months compared to previously published study results (6 to 9 months) .
Another Real-World Data study from the Network Oncology Registry indicates a positive effect of add-on treatment with Viscum album L (VA) on survival in 275 patients with stage I to IIIA NSCLC (mean age 67.6 years, 57.2 percent male patients). Although no statistically significant difference in survival was observed between the two groups, a positive clinical effect in survival was observed for a subgroup of non-surgical patients with stage I NSCLC (adenocarcinoma or squamous cell carcinoma) with the combined therapy compared with standard oncological therapy alone. Furthermore, the results suggest a possible survival-prolonging effect of additional VA therapy in non-operated patients .
In patients with metastatic pancreatic cancer, a cost-effectiveness analysis study revealed that combined standard oncological treatment plus mistletoe compared to standard treatment alone resulted in lower hospital costs per mean month of overall survival . This could also be confirmed for patients with metastatic non-small cell lung cancer [286, 305].
Last update: November 25th, 2021/AT1