There is a long tradition, going back to the fourth century BC, of using mistletoe as a remedy. This evergreen plant has been used over the ages for menstruation complaints, epilepsy, ulcers, cardiac insufficiency, hypertension and oedema (Ramm 2015).

Based on research by Dr. Rudolf Steiner (1861–1925), the founder of anthroposophy, the white-berried mistletoe (Viscum album L.) was first specifically used in cancer therapy at the beginning of the 20th century. At the end of 1916, he suggested to Dr. Ita Wegman, a physician closely collaborating with him, that mistletoe has specific potential for cancer treatment. Working with an experienced pharmacist, she developed an injection preparation (Iscar), and first treated cancer patients with mistletoe in the summer of 1917 (Selg 2016) . The preparation was further developed in the following years and registered under the name ISCADOR in 1926. Today, after almost a century of clinical and practical experience, ISCADOR is the most frequently prescribed mistletoe preparation in complementary tumour therapy, with the longest and most thorough research history.

ISCADOR, which is manufactured from the leaves, stems and berries of the plant, is a fermented aqueous extract of the white-berried mistletoe (Viscum album L.) originating from the host trees of apple (ISCADOR M = Mali), oak (ISCADOR Qu = Quercus), pine (ISCADOR P = Pini) and elm (ISCADOR U = Ulmi). In Switzerland, fir mistletoe ISCADOR is also available (ISCADOR A = Abietis).

This brochure gives a full account of the constituents of mistletoe, their effects and immunological properties, and current ISCADOR study findings. ISCADOR treatment is also described here in more detail.

BACKGROUND: Advanced pancreatic cancer (aPC) has a poor prognosis with limited survival benefit from current standard treatment. Viscum album extracts (VAE) are used by many cancer patients, showing immune-stimulating effects, improved quality of life, and a survival benefit in patients with aPC.

CASE SUMMARY: A 59-year-old architect developed epigastric pain. A cystic lesion of the pancreas of 45-mm diameter was detected. In a follow-up magnetic resonance imaging, about one year later, multiple lesions were seen in the corpus and the tail of the pancreas; CA-19-9 was elevated to 58.5 U/mL. A distal pancreatectomy with splenectomy was performed, and a tumor of 7 cm × 5 cm × 3.5 cm was excised. Histologic investigation showed an intraductal papillary mucinous neoplasm-associated invasive adenocarcinoma with invasion of the lymph vessels, perineural invasion, and positive nodes (2/27); surgical margins showed tumor cells, and the tumor was classified as pT3 N1 M0 R1. The patient was treated with radiation of the tumor bed and capecitabine/oxaliplatin followed by gemcitabine and FOLFIRINOX. Seven months after surgery, a liver metastasis was detected and treatment with FOLFIRINOX was started. Four months after detection of the metastasis, the patient opted for additional treatment with VAE. Another month later, the metastasis was treated with radiofrequency ablation (RFA). Eight months later, the hepatic lesion recurred and was again treated with RFA. The continuous VAE treatment was increased in dose, and the patient stayed
recurrence-free for the next 39 mo in good health and working full-time (as of the time this case report was written).

CONCLUSION: We present the case of a patient with aPC with R1-resection with development of liver metastasis during the course of treatment who showed an overall survival of 63 mo and a relapse-free survival of 39 mo under increasing VAE therapy. The possible synergistic effect on tumor control of RFA treatment and immune-stimulatory effects of VAE should be further investigated.

Key words: Pancreatic cancer; Integrative medicine; Viscum album extract; Radiofrequency ablation; Case report

Citation: Werthmann, P. G., Kempenich, R., Lang-Avérous, G., & Kienle, G. S. (2019). Long-term survival of a patient with advanced pancreatic cancer under adjunct treatment with Viscum album extracts: A case report. World Journal of Gastroenterology, 25(12), 1524–1530. https://doi.org/10.3748/wjg.v25.i12.1524

Background: The unfavourable side-effects of late-stage pancreatic cancer treatments call for non-toxic and effective therapeutic approaches. We compared the overall sur-vival (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 noantineoplastic therapy (control). VaL was applied in a dose-escalating manner from 0.01 mg up to 10 mg 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.

Citation: Tröger, W., Galun, D., Reif, M., Schumann, A., Stanković, N., & Milićević, M. (2013). Viscum album [L.] extract therapy in patients with locally advanced or metastatic pancreatic cancer: A randomised clinical trial on overall survival. European Journal of Cancer, 49(18), 3788–3797. https://doi.org/10.1016/j.ejca.2013.06.043

Rationale: Metastatic pancreatic cancer has a dismal prognosis. Many patients seek integrative care as an add-on to their conventional cancer treatment. Viscum album extracts (VAE)—widely used as an adjunct to cancer treatment—have cytotoxic, apoptogenic, and immune stimulatory properties. A statistically significant survival benefit has been demonstrated for VAE in advanced pancreatic cancer. Patient concerns and diagnosis: A 28-year old patient presented with painless jaundice and was subsequently diagnosed as pancreatic adenocarcinoma with liver metastases.

Interventions: He was treated with FOLFIRINOX/Mitomycin, hyperthermia and fever-inducing VAE.

Outcomes: Subsequently, the liver metastases regressed. Surgical intervention involved successful R0-resection of the primary tumor, as well as an atypical liver resection. A relapse was again treated with FOLFIRINOX/Mitomycin and hyperthermia. As of publication of this report, 49 months after initial diagnosis, the patient exhibits good condition, and is unrestricted in quality of life (till publication).

Lessons: This case demonstrates the favorable outcome of a patient with metastatic pancreatic cancer following treatment with chemotherapy, integrative medicine, and surgical excision. As other positive outcomes in pancreatic cancer patients are related to inflammatory events, we presume the immunologic effects of VAE to have contributed to the favorable outcome here. Based on this case, and the other positive results of VAE use in pancreatic cancer, further investigations seem highly worthwhile. Abbreviations: CT = computed tomography, FOLFIRINOX = folinic acid, fluorouracil, irinotecan, oxaliplatin, FOLFOX = folinic acid, fluorouracil, oxaliplatin, ML = mistletoe lectin, PC = pancreatic cancer, UICC = Union for International Cancer Control, VAE = viscum album axtracts.

Keywords: fever, integrative medicine, mistletoe, pancreatic cancer, Viscum album

Citation: Werthmann, P. G., Inter, P., Welsch, T., Sturm, A.-K., Grützmann, R., Debus, M., Sterner, M.-G., & Kienle, G. S. (2018). Long-term tumor-free survival in a metastatic pancreatic carcinoma patient with FOLFIRINOX/Mitomycin, high-dose, fever inducing Viscum album extracts and subsequent R0 resection: A case report. Medicine, 97(49), e13243. https://doi.org/10.1097/MD.0000000000013243

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.

Method: 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.

Citation: Tröger, W., Galun, D., Reif, M., Schumann, A., Stanković, N., & Milićević, M. (2014). Quality of Life of Patients With Advanced Pancreatic Cancer During Treatment With Mistletoe. Deutsches Ärzteblatt Int., 2014(111), 493–502. https://doi.org/10.3238/arztebl.2014.0493