The current case report details the ongoing, long-time survival (49 months) of a patient with an initially inoperable metastatic pancreatic cancer, which, following treatment, underwent complete regression of liver metastases. Successful R0-resection was performed. Therapeutic measures included 1 cycle of FOLFOX/Mitomycin, 3 cycles of FOLFIRINOX/Mitomycin, 4 cycles of FOLFIRINOX/Mitomycin after relapse, surgical treatment, and integrative medical interventions such as local and systemic VAE administration, resulting in strong immunological reactions (high fever, erythema, swelling, induration and itching at the injection site).
In the setting of PC, neoadjuvant treatment with FOLFIRINOX is typically only considered in patients with borderline tumors, but is not usually considered in patients with metastatic disease.
Complete response following treatment with FOLFIRINOX is rare. For example, in the PRODIGE 4 ACCORD 11 trial, of the 171 metastatic PC patients who received a median of 10 cycles of FOLFIRINOX, there was only one complete remission. Furthermore, in a study by Hackert et al, of the 125 patients diagnosed with locally advanced, unresectable PC, and who were treated with neoadjuvant FOLFIRINIOX, and—where possible—underwent surgery, only 2 patients reached an UICC stage 0. Two other complete remissions of metastatic PC, and another case of remission of borderline resectable PC, were described as occurring after 8 and 13 cycles of FOLFIRINOX.[18,19] The rare event of spontaneous regression in PC is often associated with fever. In a metastatic PC patient undergoing complete remission of liver metastases after FOLFIRINOX treatment a strong inflammatory event (pneumonia) during chemotherapy was reported. Furthermore, inflammatory events (e.g., peritonitis, cholangitis) were also observed in patients with advanced inoperable PC, who then demonstrated unexpectedly long survival.
Remarkable in our case report is the long tumor-free survival period of 49 months to date. Hackert et al reported 29 patients with metastatic PC, which, after neo-adjuvant treatment with FOLFIRINOX, became resectable. However, median survival in this group of patients was only 13 months (tumor-free survival was not reported). In a recent case report a long-time survival period of 30 and 36 months were reported for 2 patients receiving FOLFIRINOX in an integrative medicine setting including hyperthermia and VAE.
High-dose fever-inducing VAE treatment has been described in small trials on hepatic and breast cancer,[23,24] as well as in case reports. All reports describe relevant, long-lasting tumor regressions. Historically, similar courses of tumor regressions were seen following treatment with fever-inducing bacterial vaccines prepared from Streptococcus pyogenes, and Serratia marcescens (“Coley's toxins”), and spontaneous regressions have been reported in the course of Erysipelas. Therefore, we presume that VAE treatment with high fever responses—despite the relatively short treatment period—may have contributed to the favorable outcome in this case.
Strong immunological reactions to VAE are explainable based on its immunological properties. These include induction of pro-inflammatory cytokines (interleukin-6, tumor necrosis factor alpha, interleukin-1), the stimulation of both proliferation and antigen presentation of dendritic cells and CD4 + T cells, the increase of natural killer cell-mediated cytotoxicity, and various other pathways. Besides the immunological effects however, direct cytotoxic and synergistic effects of VAE (as adjunct to chemotherapy) may have contributed to the positive outcome in this case. Similar cytotoxic effects have also been documented in PC cell lines and animal studies (PA-TU-8902, PAXF 736, PAXF 546).[27–29] Furthermore, a pilot study of intratumoral VAE treatment of inoperable advanced pancreatic cancer patients showed a response in 57% of patients, and progression to stable disease in 36%. Synergistic antineoplastic effects of VAE administered along with gemcitabine were also seen in PC cell lines.
Overall survival in patients with PC stage IV is poor, and further treatment options are therefore needed and being sought. As VAE shows positive effects on PC, further research should be carried out regarding its efficacy, as well as specifications for application forms and dosages.
3.1 Informed consent
Informed consent was received from the patient for the publication of the report and accompanying images. The patient read the submission version of the report and confirmed its content.
We are thankful to the Klinik St. Georg, Bad Aibling for providing detailed data about the patient's course of disease, to Dr Helmut Kiene (IFAEMM), Dr Arnoud Templeton (Department of Onkology, St. Claraspital Basel, Switzerland) and Dr Reiner Penter (Department of Onkology, Klinik Arlesheim, Arlesheim, Switzerland) for revision of the manuscript, to Prof. Dale O’Brien, MD, MPH, Executive Director of Cancer Patients Alliance, for his help in the literature search and to the “Stiftung Integrative Medizin” for financial support.
PGW, PI and GSK contributed to the case report design. PI was the physician in charge who provided the patient's information. PGW and PI collected and provided the data. TW and RG were involved in the perioperative and operative treatment of the patient, provided the respective data, and helped to draft the manuscript. RG provided the surgical pictures. AKS provided the histologic pictures and revised the diagnosis. MD and MGS have special experience with intratumoral Viscum album extract therapy, carried out the intratumoral treatment of the patient and provided the respective data. PGW was the principle author of the paper, had full access to all data and is the guarantor. GSK supervised the report and the publication process.
Conceptualization: Paul Georg Werthmann, Gunver Sophia Kienle.
Data curation: Paul Georg Werthmann, Pia Inter, Thilo Welsch, Anne-Kathrin Sturm.
Investigation: Paul Georg Werthmann, Thilo Welsch, Anne-Kathrin Sturm, Robert Grützmann, Markus Debus, Martin-Günther Sterner, Gunver Sophia Kienle.
Methodology: Paul Georg Werthmann, Gunver Sophia Kienle.
Supervision: Gunver Sophia Kienle.
Validation: Paul Georg Werthmann, Pia Inter, Anne-Kathrin Sturm, Gunver Sophia Kienle.
Visualization: Paul Georg Werthmann.
Writing – original draft: Paul Georg Werthmann.
Writing – review & editing: Paul Georg Werthmann, Pia Inter, Thilo Welsch, Anne-Kathrin Sturm, Robert Grützmann, Markus Debus, Martin-Günther Sterner, Gunver Sophia Kienle.
Paul Georg Werthmann orcid: 0000-0002-1808-7787.
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Keywords:Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
fever; integrative medicine; mistletoe; pancreatic cancer; Viscum album