{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T01:13:39Z","timestamp":1777511619242,"version":"3.51.4"},"reference-count":29,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,1,31]],"date-time":"2023-01-31T00:00:00Z","timestamp":1675123200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Iscador AG Arlesheim, Switzerland"},{"name":"ABNOBA GmbH Pforzheim, Germany"},{"name":"Astrazeneca GmbH"},{"name":"Helixor GmbH Rosenfeld, Germany"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>Background: Newer personalized medicines including targeted therapies such as PARP inhibitors and CDK 4\/6 inhibitors have been shown to improve the survival of breast and gynaecological cancer patients. However, efficacy outcomes may be ham5pered by treatment discontinuation due to targeted therapy-related adverse drug reactions or resistance. Studies have suggested that add-on mistletoe (Viscum album L., VA) improves the quality of life and ameliorates the cytotoxic side effects of standard oncological therapy in cancer patients. The primary objective of this real-world data study was to determine the safety profile of targeted therapy in combination with add-on Helixor\u00ae VA therapy compared to targeted therapy alone in breast and gynecological cancer patients. Methods: The present study is a real-world data observational cohort study utilizing demographic and treatment data from the accredited national Network Oncology (NO) registry. The study has received ethics approval. The safety profile of targeted therapies with or without Helixor\u00ae VA therapy and safety\u2014associated variables were evaluated by univariate and adjusted multivariable regression analyses. Results: All stages of breast and gynecological cancer patients (n = 242) were on average 54.5 \u00b1 14.2 years old. One hundred and sixty patients (66.1%) were in the control (CTRL, targeted therapy) and 82 patients (33.9%) were in the combinational (COMB, targeted plus Helixor\u00ae VA therapy) group. The addition of Helixor\u00ae VA did not hamper the safety profile (\u03c72 = 0.107, p-value = 0.99) of targeted therapy. Furthermore, no adverse events and a trend towards an improved targeted therapy adherence were observed in the COMB group. Conclusions: The present study is the first of its kind showing the applicability of Helixor\u00ae VA in combination with targeted therapies. The results indicate that add-on Helixor\u00ae VA does not negatively alter the safety profile of targeted therapies in breast and gynaecological cancer patients.<\/jats:p>","DOI":"10.3390\/ijerph20032565","type":"journal-article","created":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T02:29:03Z","timestamp":1675218543000},"page":"2565","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Safety of Combined Targeted and Helixor\u00ae\u00a0Viscum album L. Therapy in Breast and Gynecological Cancer Patients, a Real-World Data Study"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6928-6209","authenticated-orcid":false,"given":"Friedemann","family":"Schad","sequence":"first","affiliation":[{"name":"Network Oncology, Research Institute Havelh\u00f6he, Kladower Damm 221, 14089 Berlin, Germany"},{"name":"Oncological Center, Department of Interdisciplinary Oncology and Palliative Care, Hospital Gemeinschaftskrankenhaus Havelh\u00f6he, Kladower Damm 221, 14089 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6421-8290","authenticated-orcid":false,"given":"Anja","family":"Thronicke","sequence":"additional","affiliation":[{"name":"Network Oncology, Research Institute Havelh\u00f6he, Kladower Damm 221, 14089 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,31]]},"reference":[{"key":"ref_1","unstructured":"National Cancer Institute (2022, November 11). Targeted Therapy to Treat Cancer, Available online: https:\/\/www.cancer.gov\/about-cancer\/treatment\/types\/targeted-therapies."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1158\/1078-0432.CCR-20-2766","article-title":"PARP Inhibitors in Cancer Diagnosis and Therapy","volume":"27","author":"Chan","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1007\/s40265-020-01461-2","article-title":"Inhibiting CDK4\/6 in Breast Cancer with Palbociclib, Ribociclib, and Abemaciclib: Similarities and Differences","volume":"81","author":"Braal","year":"2021","journal-title":"Drugs"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"j4530","DOI":"10.1136\/bmj.j4530","article-title":"Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: Retrospective cohort study of drug approvals 2009-13","volume":"359","author":"Davis","year":"2017","journal-title":"BMJ"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1992","DOI":"10.1001\/jamainternmed.2015.5868","article-title":"Cancer Drugs Approved on the Basis of a Surrogate End Point and Subsequent Overall Survival: An Analysis of 5 Years of US Food and Drug Administration Approvals","volume":"175","author":"Kim","year":"2015","journal-title":"JAMA Intern Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e2033004","DOI":"10.1001\/jamanetworkopen.2020.33004","article-title":"Assessment of Food and Drug Administration- and European Medicines Agency-Approved Systemic Oncology Therapies and Clinically Meaningful Improvements in Quality of Life: A Systematic Review","volume":"4","author":"Arciero","year":"2021","journal-title":"JAMA Netw. Open"},{"key":"ref_7","first-page":"456","article-title":"Efficacy and safety of long-term complementary treatment with standardized European mistletoe extract (Viscum album L.) in addition to the conventional adjuvant oncologic therapy in patients with primary non-metastasized mammary carcinoma. Results of a multi-center, comparative, epidemiological cohort study in Germany and Switzerland","volume":"54","author":"Bock","year":"2004","journal-title":"Arzneimittelforschung"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1016\/j.ejca.2012.11.007","article-title":"Mistletoe as complementary treatment in patients with advanced non-small-cell lung cancer treated with carboplatin-based combinations: A randomised phase II study","volume":"49","author":"Wollner","year":"2013","journal-title":"Eur. J. Cancer"},{"key":"ref_9","first-page":"508","article-title":"Immune Modulation Using Mistletoe (Viscum album L.) Extracts Iscador","volume":"56","year":"2006","journal-title":"Arzneimittelforschung"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1177\/1534735416681641","article-title":"Safety of Combined Treatment With Monoclonal Antibodies and Viscum album L Preparations","volume":"17","author":"Schad","year":"2016","journal-title":"Integr. Cancer Ther."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Thronicke, A., Steele, M.L., Grah, C., Matthes, B., and Schad, F. (2017). Clinical safety of combined therapy of immune checkpoint inhibitors and Viscum album L. therapy in patients with advanced or metastatic cancer. BMC Complement. Altern. Med., 17.","DOI":"10.1186\/s12906-017-2045-0"},{"key":"ref_12","unstructured":"Thronicke, A., Oei, S.L., Grah, C., Matthes, B., and Schad, F. (2018, January 21\u201324). Nivolumab-induced toxicity profile in patients with advanced or metastasized lung cancer treated with Viscum album L. extracts. Abstract. Proceedings of the German Cancer Congress, Berlin, Germany."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Thronicke, A., Oei, S.L., Merkle, A., Matthes, H., and Schad, F. (2018). Clinical Safety of Combined Targeted and Viscum album L. Therapy in Oncological Patients. Medicines, 5.","DOI":"10.3390\/medicines5030100"},{"key":"ref_14","first-page":"353","article-title":"Network Oncology (NO)--a clinical cancer register for health services research and the evaluation of integrative therapeutic interventions in anthroposophic medicine","volume":"20","author":"Schad","year":"2013","journal-title":"Forsch Komplementmed"},{"key":"ref_15","unstructured":"ICH (2023, January 19). Ich Harmonised Tripartite Guideline. Clinical Safety Data Management: Definitions and Standards for Expedited Reporting e2a. Available online: https:\/\/database.ich.org\/sites\/default\/files\/E2A_Guideline.pdf."},{"key":"ref_16","unstructured":"University of Virginia Library (2023, January 19). A Brief on Brier Score. Available online: https:\/\/data.library.virginia.edu\/a-brief-on-brier-scores\/."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1016\/S0140-6736(05)67887-7","article-title":"Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials","volume":"366","author":"Clarke","year":"2005","journal-title":"Lancet"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Early Breast Cancer Trialists\u2019 Collaborative Group (2011). Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: Meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet, 378, 1707\u20131716.","DOI":"10.1016\/S0140-6736(11)61629-2"},{"key":"ref_19","unstructured":"EMA (2022, November 11). Herceptin, Annex I, Summary of Product Characteristics, Available online: http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/EPAR_-_Product_Information\/human\/000278\/WC500074922.pdf."},{"key":"ref_20","unstructured":"EMA (2022, November 11). European Public Assessment Report. Ibrance, Available online: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/ibrance."},{"key":"ref_21","unstructured":"EMA (2022, November 11). European Public Assessment Report. Tecentriq, Available online: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/tecentriq."},{"key":"ref_22","unstructured":"EMA (2022, November 11). European Public Assessment Report. Tyverb, Available online: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/tyverb."},{"key":"ref_23","first-page":"303","article-title":"Impact of complementary mistletoe extract treatment on quality of life in breast, ovarian and non-small cell lung cancer patients. A prospective randomized controlled clinical trial","volume":"24","author":"Piao","year":"2004","journal-title":"Anticancer. Res."},{"key":"ref_24","first-page":"9","article-title":"Additional therapy with a mistletoe product during adjuvant chemotherapy of breast cancer patients improves quality of life: An open randomized clinical pilot trial","volume":"2014","author":"Zdrale","year":"2014","journal-title":"ECAM"},{"key":"ref_25","unstructured":"EMA (2022, November 11). Perjeta. Summary of Product Characteristics, Available online: https:\/\/www.ema.europa.eu\/en\/documents\/product-information\/perjeta-epar-product-information_en.pdf."},{"key":"ref_26","unstructured":"EMA (2022, November 11). Zejula. Summary of Product Characteristics, Available online: https:\/\/www.ema.europa.eu\/en\/documents\/product-information\/zejula-epar-product-information_en.pdf."},{"key":"ref_27","unstructured":"EMA (2022, November 11). Herceptin. Summary of Product Characteristics, Available online: https:\/\/www.ema.europa.eu\/en\/documents\/product-information\/herceptin-epar-product-information_en.pdf."},{"key":"ref_28","unstructured":"EMA (2022, November 11). Votrient. Summary of product characteristics, Available online: https:\/\/www.ema.europa.eu\/en\/documents\/product-information\/votrient-epar-product-information_en.pdf."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"385","DOI":"10.2165\/00002018-200629050-00003","article-title":"Under-reporting of adverse drug reactions: A systematic review","volume":"29","author":"Hazell","year":"2006","journal-title":"Drug Saf."}],"container-title":["International Journal of Environmental Research and Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-4601\/20\/3\/2565\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:19:56Z","timestamp":1760120396000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-4601\/20\/3\/2565"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,31]]},"references-count":29,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijerph20032565"],"URL":"https:\/\/doi.org\/10.3390\/ijerph20032565","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints202212.0542.v1","asserted-by":"object"},{"id-type":"doi","id":"10.20944\/preprints202212.0542.v2","asserted-by":"object"}]},"ISSN":["1660-4601"],"issn-type":[{"value":"1660-4601","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,31]]}}}