Immunotherapy with PD-1/PD-L1 inhibitors has been shown to significantly improve the survival rates of non-small-cell lung cancer (NSCLC) patients in advanced or metastasised stages. Therefore, the overall survival data of these patients were analysed in this Real-World Data (RWD) study in order to assess the influence of add-on mistletoe therapy to treatment with PD-1/PD-L1 inhibitors on the clinical outcome [332]. IA total of 415 patients were included in the study, 193 receiving anti-PD-1/PD-L1 therapy combined with mistletoe extracts and 222 receiving anti-PD-1/PD-L1 therapy alone (control group). The patients in the combinatorial group lived seven months longer (median overal survival 13.8 months) in comparison to the control group (median overal survival 6.8 months) and the adjusted hazard of death was reduced significantly by 40 percent. It was reduced by further 16 percent in patients with PD-L1-positive tumours (tumour cell proportion value ≥ 1%) who received first-line anti-PD-1/PD-L1 therapy and add-on mistletoe therapy.

Despite advances in treatment, pancreatic cancer remains associated with poor survival rates. Therefore, in this monocentric retrospective analysis conducted at the Medical Faculty of Heidelberg University, the influence of mistletoe therapy and hyperthermia in addition to chemotherapy in patients with advanced or metastatic pancreatic cancer was investigated [331]. Of a total of 206 patients, 142 were included in the survival analysis. Twenty-five of these received chemotherapy alone, 48 received combined chemotherapy/mistletoe therapy, 50 received combined chemotherapy/mistletoe therapy plus hyperthermia and 1 chemotherapy plus hyperthermia. The median survival times with additional mistletoe therapy of 11.2 months (p = 0.02) and with additional mistletoe and hyperthermia of 18.9 months (p < 0.001) were significantly longer compared to treatment with chemotherapy alone (8.6 months). While the survival times of the group treated only with chemotherapy compare well with data from pivotal trials and register data, the results of the study suggest that the additional use of mistletoe therapy and hyperthermia could significantly improve survival in advanced pancreatic cancer compared to chemotherapy alone. However, due to the retrospective study design and the limited sample size, further prospective studies are needed to confirm these results.

This monocentric real-world data study included patients with histologically confirmed primary lung cancer who had evaluable data sets on self-reported quality of life available at least at the time of initial diagnosis (T0) and 12 months later (T1) [320]. A total of 112 patients were included, with 27 patients who received neither radiotherapy nor mistletoe therapy serving as the reference group, 29 patients who received mistletoe therapy without radiotherapy, 32 patients who received radiotherapy but no mistletoe therapy and 24 patients who received both radiotherapy and mistletoe therapy. The assessment of changes in quality of life (EORTC-QLQ C30) after 12 months showed a significant improvement of 27 points for pain ( p = 0.006) and 17 points for nausea/vomiting (p = 0.005) in patients who received radiotherapy and mistletoe therapy. Significant improvements of 15 to 21 points for role function (p = 0.03) as well as physical (p = 0.02), cognitive (p = 0.04) and social functioning (p = 0.04) were also observed in patients who received mistletoe therapy but no radiotherapy. Further information can be found under Clinical studies/Lung cancer.

With breast cancer being the most common type of cancer in women, this meta-analysis investigated for the first time whether mistletoe extracts, which are already listed in several cancer guidelines, can also improve the quality of life of breast cancer patients. For this purpose, randomised clinical trials (RCTs) and non-randomised studies of intervention (NRSIs) were included to compare the quality of life of breast cancer patients treated with standard of care plus add-on mistletoe extracts to control groups treated with standard of care only. Nine RCTs with 833 and seven NRSIs with 2,831 patients were included. A medium effect size on the quality of life of breast cancer patients with low heterogeneity between the studies was found, with an effect size comparable to or even larger than other interventions such as physical activity. Further information can bei found under Meta-analyses and systematic reviews oder Clinical studies/Breast cancer.

A first clinical experience with additive mistletoe therapy (Helixor) to targeted therapy in 242 patients with breast cancer or other gynecologic cancer entities is now available (216). In a Real-World Data study (RWD study) from the Network Oncology Registry, in which one group of patients received only targeted therapies (n=160) and the other additionally mistletoe therapy (n=82), the side effect rate as well as dose reduction adjustments and therapy discontinuations of the targeted therapy including monoclonal antibodies, tyrosine kinase inhibitors, checkpoint inhibitors, CDK4/6 inhibitors or PARP inhibitors were determined in both groups. It was found that the additional mistletoe therapy did not change the side effect rate of the targeted therapy. Furthermore, no adverse events and a trend towards better adherence to targeted therapy were observed in the group receiving the combined therapy (targeted therapy plus mistletoe extracts). This RWD study is the first of its kind to also highlight the safety profile of newer targeted therapy groups such as CDK 4/6 inhibitors as well as PARP inhibitors in combination with mistletoe extracts. Overall, the data indicate that additional mistletoe therapy with Viscum album L. extracts does not alter the safety profile of targeted therapy in breast cancer and other gynecologic tumors. Further studies involving combined therapy in additional tumor entities are planned.

A 56-year-old female patient with diabetes mellitus, chronic B-virus hepatitis, and subclinical hypothyroidism was diagnosed with a well-differentiated, resectable adenocarcinoma in the pancreatic head and so-called at ampulla of Vater (317). After robot-assisted pylorus-preserving pancreatic head resection, the pathologic findings of the tumor (2.2 x 1.8 cm) revealed a moderately differentiated infiltrating adenocarcinoma of the pancreas with lymphatic and perineural invasion. After surgery, the patient recovered well and was discharged. On day 19 after surgery, the patient was re-admitted to the hospital for chylous ascites as a result of a surgically induced lymphatic vessel injury. During the course of the examinations, the drainage fluid had a milky straw color with a serum ascites albumin ratio of 1.3 g/dL. Ascitic drainage, albumin substitution, and the administration of diuretics and lipid-lowering agents was started. Furthermore, the administration of octreotide and parenteral nutritional adjustments with the aim to improve portal pressure was performed. After initial worsening of ascites, the patient was returned to a general diet on day 89 after surgery. In addition, on days 94, 97, 110, 115, 126, 129, and 132 after surgery, extracts of abnobaVISCUM in increasing doses were injected intraperitoneally through the drainage for lymphatic sclerosis ("Viscum shooting"). At this stage surgical management was excluded due to a predicted morbidity risk of the patient. While ascitic fluid turned a serous color on day 94 after surgery, the amount of drained ascitic fluid also decreased during subsequent mistletoe injections until day 132. The patient was discharged from the hospital in good general condition and showed no signs of recurrence even on day 156 after surgery and at 3-month follow-up. This is the first published case on the treatment of chylous ascites and off-label injection with abnobaVISCUM extracts as a minimally invasive sclerotherapy with only minor side effects.

Patient recruitment of the Swedish prospective, randomised, double-blind, multicentre, placebo-controlled clinical investigator-initiated trial (IIT) in a parallel group design on the efficacy of mistletoe extracts as an add-on to standard therapy for advanced pancreatic cancer has been completed (MISTRAL, n=290, NCT02948309). In addition to efficacy (overall survival, primary endpoint) and safety (side effect profile, secondary endpoint), the participants' self-reported quality of life will be measured and evaluated using the two internationally standardised questionnaires EORTC-QLQ-C30 and EORTC-PAN-26 (secondary endpoint). ATreatment of the last participant(s) in the study is scheduled to end in September 2022, according to information posted on clinicaltrials.gov. Funding for the MISTRAL study is provided by Karolinska Hospital Stockholm. For more information on the methodology and subgroup analyses, see the following page.

A cancer-related fatigue syndrome (CRF) develops as a result of cancer or therapy, is characterized by tiredness or exhaustion (being not proportional to recent physical activity) and represents one of the most burdensome symptoms in cancer patients. Tiredness and exhaustion do not diminish even with sufficient sleep and can have a strong impact on life. The first-line therapy includes physical activity and psychosocial interventions. According to the S3-Guideline on Complementary Medicine in Oncological Patients, physical activity and sports, tai chi and qigong as well as yoga are recommended as non-pharmacological interventions. Sports and physical activities are not always manageable by oncological patients, e.g. by cachectic patients. Currently, methylphenidate is the only pharmacological treatment with evidence in improving CRF, however consensus on its recommendation against cancer-related fatigue seems to be unclear. Thus, further pharmacological and non-pharmacological solutions are needed. Although a large number of studies have documented positive effects of mistletoe extracts (Viscum album L) in the treatment of cancer-related fatigue, no meta-analysis has so far analysed their results in relation to clinical trials, including non-randomised intervention studies and all types of CRF questionnaires.

Recently (March 2022) a systematic review was published in the journal “Supportive Care in Cancer” on the effect of mistletoe therapy on cancer-related fatigue by Florian Pelzer, Martin Loef, David D. Martin and Stephan Baumgartner [314]. Two random-effect meta-analyses (one with 12 randomised controlled trials and one with 7 non-randomised studies of intervention) were performed. The effect sizes analysed were moderate (randomized: SMD=-0.48, p=0.006) and moderate to large (non-randomised: OR=0.36, p=0.0008). Sensitivity analyses were performed revealing robust results but high inter-study heterogeneity, possibly driven by variances in study population and methodology. Analyses reveal as well that the risk of bias was high for 11 of 12 randomised and serious for all non-randomised trials (confounding risk).

Despite a risk of bias in the included studies, the results of the systematic review and the meta-analyses indicate that mistletoe therapy can statistically significantly reduce cancer-related fatigue compared to the control group. Mistletoe therapy can be recommended as an add-on to physical activity.

In this retrospective monocentric observational study the influence of an oak mistletoe extract on the response to neoadjuvant chemoradiotherapy (NCRT) was investigated in 52 patients with locally advanced rectal cancer [318]. Fifteen patients additionally received mistletoe therapy and 37 only chemotherapy. A significantly better tumour response in terms of complete tumor remission was observed in the group with NCRT and add-on mistletoe therapy compared to the group with NCRT only (53.3 % vs. 21.6 %, p = 0.044). In addition, the downstaging was significantly higher in the group with the NCRT plus add-on mistletoe therapy (86.7% vs. 56.8%, p = 0.040). More detailed information you can find under mistletoe therapy for colorectal cancer.