A useful list of recent research papers including reviews, safety studies and case studies / series.

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Produced by a research team at the University of Witten/Herdecke, this paper summarises all the recent evidence on Mistletoe Therapy with regards to safety, effectiveness and impact on Quality of Life and Life Expectancy.

This is useful reading for those who wish to gain an oversight of mistletoe evidence available.

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Jeong-Heum B, Youngbae J, Kyoung-Won H, Dong Hae J, Kyung-Ok K
World Journal of Surgical Oncology. 2021; Volume 219: 178.

ABSTRACT
Background: Mistletoe extract, used as a complementary chemotherapeutic agent for cancer patients, has anticancer effects against various malignancies. The aim of the present study was to evaluate the effect of mistletoe extract (Abnoba Viscum Q®) on tumor responses to neoadjuvant chemoradiotherapy (NCRT) for locally advanced rectal cancer.
Methods: This study included patients with rectal cancer who underwent NCRT between January 2018 and July 2020. In the mistletoe group (MG), the patients were administered Abnoba Viscum Q® subcutaneously during chemoradiotherapy—maintained just before surgery. Patient demographics, clinical outcomes, histopathological outcomes, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) assay results were compared between the MG and non-mistletoe group (NMG). Two rectal cancer cell lines (SNU-503 and SNU-503R80Gy) were treated with Abnoba Viscum Q® to assess its mechanistic effects in vivo.
Conclusion: Patients treated with chemoradiation combined with mistletoe extract showed better outcomes than patients not treated with mistletoe extract in terms of tumor responses. This diversity in treatment may improve the
efficacy of NCRT, leading to better oncologic outcomes. Prospective and randomized studies with long-term follow-up are warranted to confirm and extend these results.

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Reynel M, Villegas Y, Werthmann PG, Kiene H, Kienle GS
Integrative Cancer Therapies. 2021; Volume 20: 1-9.

ABSTRACT
Background: Retroperitoneal sarcomas are rare. Dedifferentiated liposarcomas (DDLs) are high-grade tumors with a high propensity for local recurrence and metastasis and are associated with reduced survival. Radical resection remains the standard treatment of sarcomas. Meanwhile, Viscum album L. extract (VAE) is used in cancer patients owing to its cytostatic and immunomodulating effects and to its ability to improve patients’ quality of life.
Case Presentation: A 68-year-old male patient underwent a resection of a DDL (T2 N0 M0, FNCLCC grade 2, stage IIIA) in the retroperitoneum. Three months after this first surgery, a recurrence occurred, and was treated with neoadjuvant and adjuvant doxorubicin plus ifosfamide and surgery (resection). A second recurrence—11 months after the second surgery—was treated with surgery and radiotherapy. The patient then began to undergo VAE treatment (0.2 mg-2 mg, subcutaneously, thrice a week). After
the VAE treatment was initiated, the patient reported improved quality of life. A third recurrence—12 months after the third surgery—was treated with surgery, radiotherapy, and with an increased dose of VAE (20 mg). Sixty-nine months (5.8 years) after the fourth surgery a fourth recurrence occurred. It was again treated with surgery, along with a month of intravenous VAE infusions and subsequent subcutaneous VAE (20 mg) treatment. Finally, a fifth recurrence—5 months after the fifth surgery—was treated with subcutaneous and intravenous VAE applications and eribulin. The patient died 11 months after the last recurrence; he received a total of 103 months (8.6 years) of VAE treatment and achieved 10.5 years of survival.
Conclusion: The case presented herein shows a long-time survival and a prolonged recurrence-free interval in a patient with retroperitoneal DDL treated with surgery, chemotherapy, radiotherapy, and VAE injections. On the basis of the antitumoral and immunomodulating effects of VAE and on the reported prolonged survival of VAE-treated patients with other types of tumors, the adjunct VAE treatment is presumed to have contributed to the favorable outcome. Regarding the clinical relevance of VAE treatment, further investigations are needed.

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Reynel M, Villegas Y, Werthmann PG, Kiene H, Kienle GS
Medicine, December 2019.

ABSTRACT
Rationale/strong>: Thymic neuroendocrine tumor (TNET) is very rare and characterized by a tendency to invade adjacent structures, frequent metastasis, resistance to therapy, and a poor prognosis. Viscum album extracts (VAE) have shown immunological, apoptogenic, and cytotoxic properties.
Outcomes: Quality of Life (QoL) improved substantially. The patient returned to work and the tumor remained stable for 71 months. Thereafter, the tumor progressed and the patient died 90 months after initial diagnosis. Besides self-limited local skin reactions around the application site, no side effects occurred.
Conclusion / Lessons: This is an exceptionally good course of disease of an inoperable, large, obstructing and invasive TNET with a reduced baseline condition due to pronounced symptoms. Given the considerable reduction of symptoms and improved QoL following the onset of VAE therapy and other reports describing long disease stability and improvement of the QoL using VAE in different cancer types, we presume that the VAE treatment was supportive in this case. As TNETs are rare and few trials are available, future treatments of TNETs using VAE should be carefully documented and published to help determine whether further investigation of the use of VAE in TNET treatment is worthwhile.

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Reynel M, Villegas Y, Kiene H, Werthmann PG, Kienle GS
Anticancer Research. Sep 2019; 39: 5597-5604.

ABSTRACT
Background: Bilateral asynchronous renal cell carcinoma (RCC) is infrequent. Immunotherapy is the first-line treatment for advanced RCC not controlled by locoregional therapy. Viscum album extracts (VAE) have been shown to improve quality of life as well as immunological and antineoplastic properties in different types of cancers.
Case Report: A 67-year-old man was diagnosed with Fuhrman grade 3/4 RCC, stage pT1bN0M0 in the right kidney. During the subsequent 6 years, he underwent a right nephrectomy and two metastasectomies (lung). Then an RCC lesion of the left kidney was detected. The patient refused a second nephrectomy and was treated solely with high-dose intravenous and subsequent subcutaneous VAE. A central necrotic area and a peritumoral halo were seen on an ultrasound follow-up from month 7. The patient showed no further progression of RCC during the next 2.5 years.
Conclusion: As far as we are aware of, this is the first report of a patient with metastatic RCC with an RCC lesion of the second kidney treated solely with highdose intravenous and subcutaneous VAE, associated with 2.5 years of progression-free survival and a good quality of life. The use of VAE in RCC should be carefully documented and published to determine future research.

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Werthmann PG, Hintze A, Kienle GS
Medicine. Oct 2017; 96:46(e8731).

ABSTRACT
Introduction: Metastatic malignant cutaneous melanoma (MCM)-a highly immunogenic cancer-typically has a poor prognosis. Viscum album extracts (VAEs) have strong immune-stimulating, apoptogenic, and cytotoxic effects.
Case Presentation: A 66-year-old MCM patient with newly diagnosed lymph node metastases opted for sole VAE treatment. VAEs were initially applied subcutaneously, and then later in exceptionally high, fever-inducing doses, both intravenously and intralesionally. The metastases shrunk over the following months, and after 2 years, all lesions had completely remitted (regional and hilar lymph nodes). The patient has been tumor free for 3.5 years at the time of publication (and for 5 years since initiation of intensified VAE treatment). Besides fever and flu-like symptoms, no side effects occurred.
Discussion: We presume that VAE triggered an increased release of tumor-associated antigens, enhanced immunologic recognition, and increased immune response against the tumor tissue and induced tumor remission.

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Shakeel M, Trinidade A, Geider S, Ah-See KW
The Journal of Laryngology & Otology. March 2014; 128: 302–306.

ABSTRACT
Introduction: Complementary and alternative medicine usage, though rising, remains largely devoid of a sound scientific basis; however, there is increasing evidence to support its use in cancer therapy.
Aim: To present the case of a patient with laryngeal carcinoma who made a full recovery following mistletoe therapy, despite failing to respond to chemoradiotherapy and salvage laryngectomy.
Design: Case report with relevant literature review.
Results: The patient developed extensive, unresectable stomal recurrence, and it was deemed appropriate to supply palliative care only. Following treatment with mistletoe extract injections after palliative radiotherapy, he recovered fully and was eventually discharged from care.
Conclusion: The benefit of mistletoe in laryngeal cancer treatment requires further investigation, and might be considered in selected patients, as an adjunct or when other conventional therapies have failed.

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Orange M, Lace A, Fonseca MP, von Laue BH, Geider S & Kienle GS.
Global Advances in Health and Medicine. March 2012 1(1): 18-25

ABSTRACT
Background: Mistletoe is a complementary cancer treatment that is widely used, usually in addition to and alongside recommended conventional cancer therapy. However, little is known about its use, effectiveness, and safety in the treatment of cutaneous lymphoma.
Case Report: Two patients with primary cutaneous B-cell lymphoma (pT2bcNxM0 follicle center and pT2ac-NxM0 marginal zone) either declined or postponed recommended conventional treatment and received high-dose, fever-inducing mistletoe treatment; a combination of intratumoral, subcutaneous, and intravenous application was given; and one patient also underwent whole-body hyperthermia. The lymphoma regressed over a period of 12 and 8 months, respectively, and after administration of a cumulative dose of 12.98 g and 4.63 g mistletoe extract, respectively. The patients are in remission to date, 3.5 years after commencement of treatment. Neither patient received conventional cancer treatment during the entire observation period.

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Orange M, Fonseca A, Lace A, von Laue HB & Geider S
European Journal of Integrative Medicine, June 2010; 2(2): 63–69

ABSTRACT
Introduction: Viscum album L. extracts (VAEs) are widely used in the complementary treatment of cancer, to improve quality of life of cancer patients, commonly using subcutaneous application of low doses of VAEs.
Case presentations: Two patients were treated with VAE (AbnobaViscum®) alone, using a combination of intratumoural, subcutaneous and in one case intravenous administration. A 75-year-old lady with relapsed Merkel cell cancer – a rare and aggressive neuro-endocrine cancer of the skin – declined radiotherapy, and was treated with VAE alone over 9.8 months, using a total of 5.8G VAE, averaging 592 mg/VAE/month (>300,000 ng mistletoe lectin (ML)/month; >2300 μg viscotoxin (VTX)/month); the 3 cm tumour was impalpable after 4 months and she continues to be in complete remission after 3 years. A 50-year-old postmenopausal woman with asynchronous bilateral breast cancer (right breast: grade 1, hormone sensitive; left breast: grade 3, hormone insensitive and HER2-positive ductal carcinoma), declined all conventional cancer treatment. She was treated with VAE alone for 2.6 years, with a total of 8.9G VAE, averaging 290 mg/month (>150,000 ng ML/month; >1200 μg VTX/month); she had complete responses of both tumours after 31 months of intratumoural and subcutaneous VAE application, and remains in remission after 4 years.
Conclusions: Durable tumour regression occurred in 2 patients following treatment with VAE, used in higher than generally used doses and combining different applications. Both patients had no other established cancer therapies. Further studies are required to define the strategic role of VAE and its different applications, safety and efficacy.

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Schad F, Steinmann D, Oei SL et al.
Radiation Oncology Volume 18, 47. March 2023

ABSTRACT
Background: Lung cancer (LC) is associated with high mortality and poor quality of life (QoL). The disease as well as oncological treatments such as radiation and chemotherapy with adverse effects can impair the QoL of patients. Add-on treatment with extracts of Viscum album L. (white-berry European mistletoe, VA) has been shown to be feasible and safe and to improve the QoL of cancer patients. The aim of this study was to analyze the changes in QoL of LC patients being treated with radiation according to oncological guidelines and add-on VA treatment in a real-world setting.
Methods: A real-world data study was conducted using registry data. Self-reported QoL was assessed by the evaluation of the European Organization of Research and Treatment Health-Related Quality of Life Core Questionnaire scale (EORTC QLQ-C30). Adjusted multivariate linear regression analyses were performed to analyze factors associated with changes in QoL at 12 months.
Conclusions:Add-on VA therapy reveals supportive effects for the QoL of LC patients. Particularly in combination with radiation a significant reduction in pain and nausea/ vomiting has been observed.

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Channing J.P. et al
American Association for Cancer Research Journals, February 2023

ABSTRACT
Purpose: Mistletoe extract (ME) is widely used for patients with cancer to support therapy and to improve quality of life (QoL). However, its use is controversial due to suboptimal trials and a lack of data supporting its intravenous administration.
Materials and Methods: This phase I trial of intravenous mistletoe (Helixor M) aimed to determine the recommended phase II dosing and to evaluate safety. Patients with solid tumor progressing on at least one line of chemotherapy received escalating doses of Helixor M three times a week. Assessments were also made of tumor marker kinetics and QoL.
Results: Twenty-one patients were recruited. The median follow-up duration was 15.3 weeks. The MTD was 600 mg. Treatment-related adverse events (AE) occurred in 13 patients (61.9%), with the most common being fatigue (28.6%), nausea (9.5%), and chills (9.5%). Grade 3+ treatment related AEs were noted in 3 patients (14.8%). Stable disease was observed in 5 patients who had one to six prior therapies. Reductions in baseline target lesions were observed in 3 patients who had two to six prior therapies. Objective responses were not observed. The disease control rate (percentage of complete/partial response and stable disease) was 23.8%. The median stable disease was 15 weeks. Serum cancer antigen-125 or carcinoembryonic antigen showed a slower rate of increase at higher dose levels. The median QoL by Functional Assessment of Cancer Therapy-General increased from 79.7 at week 1 to 93 at week 4.
Conclusions: Intravenous mistletoe demonstrated manageable toxicities with disease control and improved QoL in a heavily pretreated solid tumor population. Future phase II trials are warranted.
Significance: Although ME is widely used for cancers, its efficacy and safety are uncertain. This first phase I trial of intravenous mistletoe (Helixor M) aimed to determine phase II dosing and to evaluate safety. We recruited 21 patients with relapsed/refractory metastatic solid tumor. Intravenous mistletoe (600 mg, 3/week) demonstrated manageable toxicities (fatigue, nausea, and chills) with disease control and improved QoL. Future research can examine ME’s effect on survival and chemotherapy tolerability.

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Tröger W, Galun D, Reif M, Schumann A, Stankovic N, Milicevic M
European Journal of Cancer. Dec 2013; 49(18): 3788-97

ABSTRACT
Background: The unfavourable side-effects of late-stage pancreatic cancer treatments call for non-toxic and effective therapeutic approaches. We compared the overall survival (OS) of patients receiving an extract of Viscum album [L.] (VaL) or no antineoplastic therapy.
Methods: This is a prospective, parallel, open label, monocentre, group-sequential, randomised phase III study. Patients with locally advanced or metastatic cancer of the pancreas were stratified according to a binary prognosis index, composed of tumour stage, age and performance status; and were evenly randomised to subcutaneous injections of VaL extracts or no antineoplastic therapy (control). VaL was applied in a dose-escalating manner from 0.01 mg up to 10mg three times per week. Patients in both groups received best supportive care. The primary end-point was 12-month OS, assessed in a group-sequential analysis.
Findings: We present the first interim analysis, including data from 220 patients. Baseline characteristics were well balanced between the study arms. Median OS was 4.8 for VaL and 2.7 months for control patients (prognosis-adjusted hazard ratio, HR=0.49; p<0.0001). Within the 'good' prognosis subgroup, median OS was 6.6 versus 3.2 months (HR=0.43; p<0.0001), within the 'poor' prognosis subgroup, it was 3.4 versus 2.0 months respectively (HR=0.55; p=0.0031). No VaL-related adverse events were observed.
Conclusion: VaL therapy showed a significant and clinically relevant prolongation of OS. The study findings suggest VaL to be a non-toxic and effective second-line therapy that offers a prolongation of OS as well as less disease-related symptoms for patients with locally advanced or metastatic pancreatic cancer.

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Axtner J, Steele M, Kröz M, Spahn G, Matthes H, Schad F
BMC Cancer 2016; 16: 579

ABSTRACT:
Background: Pancreatic cancer has a dire prognosis and is associated with a high mortality. Palliative patients have special needs and often seek help in integrative oncological concepts (IO) that combine conventional and complementary therapies. Nevertheless there are few recommendations regarding IO in current cancer guidelines. The aims of this study were to report on implementation of IO in everyday palliative care and to analyze patient survival in advanced pancreatic cancer.
Methods: This multicenter observational study investigates the implementation of IO and length of survival of patients suffering from advanced pancreatic cancer (stage IV). We analyzed patient’s survival by employing multivariable proportional hazard models using different parametric distribution functions and compared patients receiving chemotherapy only, a combination of chemotherapy and Viscum album (VA) treatment, and VA treatment only.
Results: Records of 240 patients were analyzed. Complementary therapy showed high acceptance (93 %). Most frequent therapy was VA treatment (74 %) that was often administered concomitantly to chemotherapy (64 %). Both therapies had positive effects on patient survival as they had significant negative effects on the hazard in our log-normal model. A second analysis showed that patients with combined chemotherapy and VA therapy performed significantly better than patients receiving only chemotherapy (12.1 to 7.3 month). Patients receiving only VA therapy showed longer survival than those receiving neither chemotherapy nor VA therapy (5.4 to 2.5 months). Our data demonstrates that IO can be implemented in the everyday care of patients without disregarding conventional treatment. Patients combining VA with chemotherapy showed longest survival.
Conclusions: Our data demonstrate the importance and potential of health services research showing that IO treatment can be successfully implemented in the every-day care of patients suffering from advanced pancreatic cancer. Patients combining VA with chemotherapy showed longest survival. To address patients’ needs adequately, future cancer guidelines might increasingly include comments on complementary treatment options in addition to conventional therapies. Further studies should investigate the effect of complementary treatments on survival and quality of life in more detail.

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Tröger W, Galun D, Reif M, Schumann A, Stankovic N, Milicevic M
Dtsch Arztebl Int 2014; 111(29-30): 493-502

ABSTRACT
Background: The treatment of cancer patients with mistletoe extract is said to prolong their survival and, above all, improve their quality of life. We studied whether the quality of life of patients with advanced pancreatic cancer could be improved by mistletoe extract.
Methods: An open, single-center, group-sequential, randomized phase III trial (ISRCTN70760582) was conducted. From January 2009 to December 2010, 220 patients with locally advanced or metastatic pancreatic cancer who were receiving no further treatment for pancreatic cancer other than best supportive care were included in this trial. They were stratified by prognosis and randomly allocated either to a group that received mistletoe treatment or to one that did not. Mistletoe extract was given in escalating doses by subcutaneous injection three times a week. The planned interim evaluation of data from 220 patients indicated that mistletoe treatment was associated with longer overall survival, and the trial was terminated prematurely. After termination of the study, the results with respect to quality of life (assessed with the QLO-C30 scales of the European Organisation for Research and Treatment of Cancer) and trends in body weight were evaluated.
Results: Data on quality of life and body weight were obtained from 96 patients treated with mistletoe and 72 control patients. Those treated with mistletoe did better on all 6 functional scales and on 7 of 9 symptom scales, including pain (95% confidence interval [CI] −29 to –17), fatigue (95% CI –36.1 to –25.0), appetite loss (95% CI −51 to −36.7), and insomnia (95% CI –45.8 to –28.6). This is reflected by the trend in body weight during the trial.
Conclusion: In patients with locally advanced or metastatic pancreatic carcinoma, mistletoe treatment significantly improves the quality of life in comparison to best supportive care alone. Mistletoe is an effective second-line treatment for this disease.

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Cogo E, Elsayed M, Bhardwaj S, et al.
Current Oncology Volume 30 (9): 8196-8219. 6 Sep 2023.

Background
We aim to evaluate the safety and efficacy of mistletoe extract (ME) use during the oncological perioperative period. Methods: Details registered a priori on PROSPERO (CRD42018086168). Results: Seven RCTs (comprising 663 participants in nine reports) and three nonrandomized studies were included. In five RCTs, ME was evaluated as adjunctive care and the control group had no additional intervention, whereas in two RCTs, ME was compared head-to-head against common cancer treatments (i.e., etoposide or bacillus Calmette-Guérin) with the intervention groups not receiving standard care. Meta-analyses found no evidence for a difference between ME and no added therapy for mortality and recurrence (RR, 95% CI: 1.00, 0.79–1.27; and 1.03, 0.79–1.33, respectively). Two RCTs reported beneficial effects of ME on immune cells, specifically natural killer cells, in colorectal cancer, and one RCT reported quality of life improvement. Two RCTs reported ME discontinuations due to adverse events and grade 3/4 toxicities. Nevertheless, no safety signals were detected from these 10 studies. Quality appraisal revealed a substantial risk of bias. Conclusions: Preliminary data are encouraging for mistletoe extracts, particularly in the context of colorectal cancer. However, the evidence is limited by the number of studies, an evaluation of different outcomes, and methodological limitations. Further high-quality research is warranted.
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Li Oei, Thronicke & Schad.
Hindawi Evidence-Based Complementary and Alternative Medicine
April 2019. Volume 2019, Article ID 5893017

ABSTRACT
In early tumor development, cancer cells develop a plethora of strategies to escape surveillance from the adaptive and innate immune system. Cancer immunotherapies, in particular immune checkpoint inhibitors, are becoming a highly promising cancer therapeutic approach that has remarkable increased progress in combating various cancer types. Unfortunately, their mechanisms of action induce some complications, such as inflammatory reactions and immune-related adverse events. In the management of side effects during anticancer therapy, complementary and integrative therapy approaches are becoming of growing interest.
Particularly, mistletoe, Viscum album L. (VA), has a long traditional history of about 100 years as an add-on therapy of cancer treatment in German-speaking countries. Besides antitumoral and quality of life-promoting activities, VA applications reduce side effects ofmodern conventional anticancer therapies and exert immunomodulatory characteristics.As these propertiesmay provide a good basis for a combination with modern oncological therapies, the biological activities of VA applications and mechanisms involved have to be understood. In this review, the impact of VA compounds on different cellular pathways and immunological reactions in the fight against cancerous cells is discussed.

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Horneber M, Bueschel G, Huber R, Linde K, Rostock M.
Cochrane Database of Systematic Reviews. April 2008, (2): CD003297

ABSTRACT
Background: Mistletoe extracts are commonly used in cancer patients. It is claimed that they improve survival and quality of life (QOL) in cancer
patients.
Objectives: To determine the effectiveness, tolerability and safety of mistletoe extracts given either as monotherapy or adjunct therapy for patients
with cancer.
Main Results: Eighty studies were identified. Fifty-eight were excluded for various reasons, usually as there was no prospective trial design with randomised treatment allocation. Of the 21 included studies 13 provided data on survival, 7 on tumour response, 16 on measures of QOL or psychological outcomes, or prevalence of chemotherapy-related adverse effects and 12 on side effects of mistletoe treatment; overall comprising 3484 randomised cancer patients. Interventions evaluated were 5 preparations of mistletoe extracts from 5 manufacturers and one commercially not available preparation. The general reporting of RCTs was poor. Of the 13 trials investigating survival, 6 showed some evidence of a benefit, but none of them was of high methodological quality. The results of two trials in patients with melanoma and head and neck cancer gave some evidence that the used mistletoe extracts are not effective for improving survival. Of the 16 trials investigating the efficacy of mistletoe extracts for either improving QOL, psychological measures, performance index, symptom scales or the reduction of adverse effects of chemotherapy, 14 showed some evidence of a benefit, but only 2 of them including breast cancer patients during chemotherapy were of higher methodological quality. Data on side effects indicated that, depending on the dose, mistletoe extracts were usually well tolerated and had few side effects.
Author's Conclusions: The evidence from RCTs to support the view that the application of mistletoe extracts has impact on survival or leads to an improved ability to fight cancer or to withstand anticancer treatments is weak. Nevertheless, there is some evidence that mistletoe extracts may offer benefits on measures of QOL during chemotherapy for breast cancer, but these results need replication. Overall, more high quality, independent clinical research is needed to truly assess the safety and effectiveness of mistletoe extracts. Patients receiving mistletoe therapy should be encouraged to take part in future trails.

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Kienle GS, Kiene H.
Integrative Cancer Therapy. June 2010; 9(2):142-157.

ABSTRACT
Objective: To evaluate controlled clinical studies on the efficacy and effectiveness of Viscum album for quality of life (QoL) in cancer.
Materials & methods: The authors conducted a search of 7 electronic databases and reference lists and had extensive consultations with experts. They carried out a criteria-based assessment of methodological study quality.
Results: The authors identified 26 randomized controlled trials (RCTs) and 10 non-RCTs that investigated the influence of V album extracts (VAEs) on QoL in malignant diseases; 26 studies assessed patient-reported QoL. Questionnaires were mostly well established and validated. Half of the studies investigated VAEs concomitant with chemotherapy, radiotherapy, or surgery. Some studies were well designed, whereas others had minor or major methodological weaknesses. Among the 26 RCTs, 22 reported a QoL benefit, 3 indicated no difference, and 1 did not report any result. All the non-RCTs reported a QoL benefit. Of the studies with higher methodological quality, most reported a benefit, whereas 1 found no difference. Improvements were mainly in regard to coping, fatigue, sleep, exhaustion, energy, nausea, vomiting, appetite, depression, anxiety, ability to work, and emotional and functional well-being in general and, less consistently, in regard to pain, diarrhea, general performance, and side effects of conventional treatments. VAEs were well tolerated.
Conclusions: VAEs seem to have an impact on QoL and reduction of side effects of conventional therapies (chemotherapy, radiation) in experimental trials as well as in routine daily application. The influence on fatigue especially should be investigated further.

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Kienle GS, Kiene H.
European Journal of Medical Research. March 2007; 12(3):103-119.

ABSTRACT
Background: Anthroposophic Mistletoe therapy is a widely used complementary cancer treatment.
Objective: To evaluate prospective clinical trials on the effectiveness of anthroposophic mistletoe therapy for cancer.
Design: Systematic review.
Material & methods: Search of 9 electronic databases, reference lists and extensive expert consultations. Criteria-based assessment of methodological study quality.
Results: 16 randomized (RCT) and 9 non-randomized (N-RCT) controlled trials were identified that investigated mistletoe treatment of malignant diseases. Statistically significant benefit for survival was reported in 8 of 17 trials (in 5 of 10 RCTs), for disease-free survival and tumour recurrence in none of 2 RCTs, for remission of tumour and malignant effusion in 1 RCT and 1 N-RCT of 4 controlled trials, for quality of life (QoL) in 3 of 5 RCTs, and for QoL and reduction of side effects of cytoreductive therapies (chemotherapy, radiation or surgery) in 5 of 7 trials (3 of 5 RCTs). Methodological quality of the controlled trials differed substantially; some had major limitations while others were reasonably well conducted. 12 single-arm cohort studies were identified. 5 of 7 studies found substantial tumour remission in various cancers, one study reported remission of CIN, and 4 studies remission of malignant pleural effusion or ascites. Quality of reporting in cohort studies was mostly reasonably good. Mistletoe application was well tolerated.
Conclusions: Regarding quality of studies and consistency of results, the best evidence for efficacy of mistletoe therapy exists for improvement of QoL and reduction of side effects of cytotoxic therapies (chemotherapy, radiation). Survival benefit has been shown but not beyond critique. Tumour remissions are described in cohort studies that investigate the application of high dose or local mistletoe extracts. As several reasonably well-conducted studies indicate beneficial effects, further properly designed trials should be encouraged to investigate clinical efficacy and its possible dependency on the mode of application.

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Thronicke A., Li Oei S., Merkle A., Matthes H., Schad F.
Medicines. Sep 2018

ABSTRACT
Background: Despite improvement of tumor response rates, targeted therapy may induce toxicities in cancer patients. Recent studies indicate amelioration of adverse events (AEs) by add-on mistletoe (Viscum album L., VA) in standard oncological treatment. The primary objective of this multicenter observational study was to determine the safety profile of targeted and add-on VA therapy compared to targeted therapy alone.
Methods: Demographic and medical data were retrieved from the Network Oncology registry. Allocation to either control (targeted therapy) or combinational group (targeted/add-on VA) was performed. Safety-associated variables were evaluated by adjusted multivariable analyses.
Results: The median age of the study population (n = 310) at first diagnosis was 59 years; 67.4% were female. In total, 126 patients (40.6%) were in the control and 184 patients (59.4%) in the combination group. Significant differences were observed between both groups with respect to overall AE frequency (2 = 4.1, p = 0.04) and to discontinuation of standard oncological treatment (2 = 4.8, p = 0.03) with lower rates in the combinational group (20.1%, 35% respectively) compared to control (30.2%, 60.5%, respectively). Addition of VA to targeted therapy significantly reduced the probability of oncological treatment discontinuation by 70% (Odds ratio (OR) 0.30, p = 0.02).
Conclusions: Our results indicate a highly significant reduction of AE-induced treatment discontinuation in all-stage cancer patients when treated with VA in addition to targeted therapy.

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Thronicke A., Steele M., Grah C., Matthes B., Schad F.
BMC Complementary and Alternative Medicine. 2017

ABSTRACT
Background: Despite improvement of tumour response rates in patients with progressive and metastatic cancer, immune checkpoint inhibitors (ICM) induce toxicities in cancer patients. Viscum album L. (VA, mistletoe) extracts are applied as add-on cancer therapy especially in German speaking countries and within integrative and anthroposophical concepts with the goal to improve quality of life. The primary objective of this pilot observational cohort study was to determine the rate of adverse events (AE) related to ICM therapy with and without VA in patients with advanced or metastatic cancer in a certified Cancer Center.
Methods: ICM or combined ICM/VA therapies were applied in patients with progressive or metastatic cancer. AE rates of both therapy groups were compared.
Results: A total of sixteen cancer patients were treated with ICM: nivolumab (75%), ipilimumab (19%) or pembrolizumab (6%). The median age of the study population was 64 years (IQR 57.8; 69.3); 44% were male. Of the sixteen patients receiving ICM, nine patients received additional VA (56%; ICM/VA group) and seven did not (44%; ICM group). No statistically significant differences were seen between groups with respect to AE-rates (67% ICM/VA versus 71% ICM). Adjusted multivariate regression analysis revealed that concomitant application of VA did not alter the AE rate in ICM treated patients. 85% of AEs were expected ICM reactions. No AEs of grade 3 or greater were documented for the total study cohort.
Conclusions: This is the first study evaluating the clinical safety profile of ICM in combination with VA in patients with advanced or metastatic cancer. The overall AE rate of the study cohort is comparable to AE rates of ICM treatment in the literature. Our data indicate a first impression that concomitant VA application may not alter ICM-induced AE rates. However, the nature of this study does not allow excluding possible immunological interactions between ICM and VA. Further prospective trials in larger study cohorts should focus on the assessment of safety aspects, clinical efficacy and health related quality of life in patients with combined ICM/VA therapy.

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Schad F., Thronicke A., Merkle A., Matthes H., Steele M.
Phytomedicine 36. 2017, p54-58

ABSTRACT
Background: Immune-related adverse drug reactions (ADRs) to immunotherapy agents have been associated with beneficial clinical outcomes in oncology. Viscum album L. (VA, European mistletoe) is frequently used as an immunomodulatory agent alongside conventional cancer treatment in Europe. VA has been associated with
improved quality of life and a reduction in chemotherapy-related ADRs. Beneficial effects of VA are believed to be related to its immunomodulatory properties. Current guidelines recommend commencing with a low dose and increasing slowly overtime, however, off-label prescribing of high initial doses is common.
Purpose: We investigated ADR profiles related to subcutaneous VA therapy commencing with low, recommended doses versus higher than recommended doses.
Study Design: Retrospective cohort study.
Methods: Medical records of 1361 cancer patients treated between 2003 and 2013 were assessed. Patients were divided into two groups based on whether the dose of their first VA injection adhered to current guidelines. Patient characteristics and suspected VA-related ADRs were compared between dose groups.
Results: Of 1361 cancer patients, 516 (38%) started with a recommended, low dose of VA(≤0.02 mg) and 845 (62%) started with a higher dose(>0.02 mg). Groups did not differ by age or gender, but significant differences were observed for type (p<0.001) and stage of cancer (p=0.05). Starting with a high dose of VA was significantly
associated with a higher incidence of VA-related ADRs compared to starting with a low dose (20.7% versus 0.8%, p<0.001). Adjusting for age, gender, tumour type and stage of disease, produced an odds ratio of 37.5 (95% CI=15.7–122.8, p<.001). Almost all ADRs, irrespective of the initial VA dose, were of mild or moderate intensity. Most ADRs were immune-related, general disorders and administration site conditions, many of which are desired reactions, such as pyrexia and local reactions. Overall, no serious ADRs occurred. 
Conclusions: Starting VA therapy with a higher than recommended dose was associated with a high frequency of ADRs, however, nearly all ADRs were expected, of mild to moderate intensity and most were desired reactions. Future research is necessary to investigate whether higher incidences of immune-related events are indicators of beneficial immunomodulation and better clinical outcomes.

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Mascher A, Pelzer F, Duncan LJ, Martin DD, Baumgartner S, Berger B.
Integrative Cancer Therapies Volume 22. 20 September 2023

ABSTRACT
Introduction: The introspective experience of cancer patients using mistletoe therapy has received little scientific interest, although it is crucial for a holistic understanding of this therapy. This study contributes to patient-centered research and treatment by documenting the subjective experiences of individuals undergoing mistletoe therapy.
Methods: In this qualitative, explorative study, 20 outpatients with a history of various cancer types were recruited from Arlesheim Hospital (Arlesheim, Switzerland). All patients received subcutaneous mistletoe therapy for at least 2 years (median 7.5 years). Data was collected through 2 semi-structured, in-depth interviews per patient. Qualitative content analysis was applied to examine the data. The individual experience of mistletoe therapy was analyzed in relation to 6 predefined levels of human experience: physical, vital, emotional, mental, spiritual and social. In addition, 3 further aspects, considered as cross-dimensional perspectives, emerged out of the material: warmth, immune strengthening, and general wellbeing.
Conclusions: Prior to this study it had not been shown that cancer patients using mistletoe therapy do have observations on different levels of experience. These results may lead to a deeper understanding of patients receiving mistletoe therapy, enabling them to be supported in a more holistic way both during mistletoe treatment and on their life path. Further investigations into the effects of mistletoe therapy on the emotional, mental, and spiritual level are warranted.

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Nicoletti M.
Plants 12(7):1460. 27 March 2023

ABSTRACT
The therapeutic story of European mistletoe (Viscum album L.) presents a seesawing profile. In ancient times, this hemiparasitic plant was considered a panacea and even to be endowed with exceptional beneficial properties. In more recent times, despite its multiple uses in traditional medicines, some parts of the plant, in particular the berries, were considered poisonous and dangerous, including concerns of cytotoxicity, which spread serious suspicion on its medicinal utility. However, since the last century, medical interest in mistletoe has come back in force due to its utilization in clinical cancer treatments, based on its selective action on tumor cells. In Central Europe, the hydro-alcoholic extracts of European mistletoe register a relevant and continuous utilization in anthroposophic medicine, which is a holistic system that includes the utilization of phytomedicinal substances. In Switzerland and Germany, most physicians and patients use these products as complementary therapy in oncological treatments. However, despite its increasing use in this field, the results of mistletoe’s use are not always convincing, and other aspects have appeared. Nowadays, products that contain mistletoe are utilized in several fields, including diet, phytotherapy, veterinary medicine and homeopathy, but in particular in cancer therapies as coadjuvant factors, in consideration of several positive effects including effects in the improvement of quality-of-life conditions and reinforcement of the immune system. In this review, based on the understanding of the association between cancer and inflammation, we propose a relationship between these recent uses of mistletoe, based on its antioxidant properties, which are supported by phytochemical and pharmacological data. The unicity of mistletoe metabolism, which is a direct consequence of its hemiparasitism, is utilized as a key interpretation element to explain its biological properties and steer its consequent therapeutic uses.

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Li Oei et al.
Integrative Cancer Therapies Volume 18(1): 1–10. January 2019

ABSTRACT
Background: Viscum album L (VA, mistletoe) extracts are commonly used in integrative oncology. Here the clinical safety profile of additional VA-treatments to standard care in cancer patients with preexisting autoimmune diseases was analyzed.
Methods: In this observational cohort study medical data and recorded adverse events (AEs) of treated patients were retrieved from the Network Oncology registry and a safety analysis was performed.
Results: A total of 106 patients (median age 63 years) treated with add-on VA-extracts were analyzed. Most frequent autoimmune diseases were Hashimoto’s thyroiditis (27%), psoriasis (19%), and ulcerative colitis (15%). Seventeen patients (16%) experienced VA-related AEs, but neither long-term side effects nor VA-therapy discontinuations were recorded. In a subgroup of 30 patients receiving long-term VA-therapy no exacerbations or flares of underlying autoimmune diseases were recorded. Additionally, a significant halving of overall AE-rates was observed during VA-treatment periods (p= 0.019).
Conclusions: Our findings suggest that add-on VA-therapy in cancer patients with preexisting autoimmune diseases as Hashimoto’s thyroiditis, psoriasis, ulcerative colitis, Grave’s disease, and some rheumatic diseases is safe. No higher rates of VAassociated AEs were observed and the overall AE-rates were significantly lowered in VA-therapy periods. However, results should be interpreted with caution in light of the study’s observational character.

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Schad et al.
PLOS ONE. August 2018

ABSTRACT
Background:Stage IV non-small cell lung cancer (NSCLC) is associated with a five-year survival rate of around 1%. Treatment with Viscum album L. (VA) extracts has been shown to reduce chemotherapy (CTx)-related adverse events, decrease CTx dose reductions and improve quality of life in a number of cancers. Recent data suggest a beneficial effect of add-on treatment with Viscum album L. (VA, European mistletoe) on survival in cancer patients. The objective of this study was to evaluate the effect of VA in addition to chemotherapy on survival in stage IV NSCLC patients.
Methods: The observational study was conducted using data from the Network Oncology clinical registry which is an accredited conjoint clinical registry of German oncological hospitals, practitioners and out-patient centers.Patients were included if they had stage IV NSCLC at diagnosis, lived at least for four weeks post-diagnosis and received chemotherapeutic treatment. Patients with EGFR mutations as well as patients receiving tyrosine kinase inhibitors or immune checkpoint inhibitors were not included. Overall survival and impact on hazard in patients with chemotherapy (CTx) to patients receiving CTx plus VA were compared. To identify factors associated with survival and to address potential sources of bias a multivariate analyses using Cox proportional hazard model was performed.
Results: The median age of the population was 64.1 years with 55.7% male patients. The highest proportion of patients had adenocarcinoma (72.2%) and most of the patients were current or past smokers (70.9%). Of 158 stage IV NSCLC patients, 108 received CTx only and 50 additional VA. Median survival was 17.0 months in the CTx plus VA group (95%CI: 11.0± 40.0) and was 8.0 months (95%CI: 7.0±11.0) in the CTx only group (χ2 = 7.2, p = .007). Overall survival was significantly prolonged in the VA group (HR 0.44, 95%CI: 0.26±0.74, p = .002). One-year and three-year overall survival rates were greater with CTx plus VA compared to CTX alone (1y: 60.2% vs. 35.5%; 3y: 25.7% vs. 14.2%).
Conclusions: Our findings suggest that concomitant VA is positively associated with survival in stage IV NSCLC patients treated with standard CTx. These findings complement pre-existing knowledge of add-on VA's clinical impact, however, results should be interpreted with caution in light of the study's observational character.

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