NCCAM/NCI Phase 1 Study of Mistletoe Extract and Gemcitabine in Patients with Advanced Solid Tumors

Patrick J Mansky, Dawn B Wallerstedt, Timothy S Sannes, Jamie Stagl, Laura Lee Johnson, Marc R Blackman, Jean L Grem, Sandra M Swain, Brian P Monahan, Patrick J Mansky, Dawn B Wallerstedt, Timothy S Sannes, Jamie Stagl, Laura Lee Johnson, Marc R Blackman, Jean L Grem, Sandra M Swain, Brian P Monahan

Abstract

Purpose: European Mistletoe (Viscum album L.) extracts (mistletoe) are commonly used for cancer treatment in Europe. This phase I study of gemcitabine (GEM) and mistletoe in advanced solid cancers (ASC) evaluated: (1) safety, toxicity, and maximum tolerated dose (MTD), (2) absolute neutrophil count (ANC) recovery, (3) formation of mistletoe lectin antibodies (ML ab), (4) cytokine plasma concentrations, (5) clinical response, and (6) pharmacokinetics of GEM.

Design: increasing mistletoe and fixed GEM dose in stage I and increasing doses of GEM with a fixed dose of mistletoe in stage II. Dose limiting toxicities (DLT) were grade (G) 3 nonhematologic and G4 hematologic events related to platelets and granulocytes only [corrected]; MTD was reached with 2 DLTs in one dosage level. Response in stage IV ASC was assessed with descriptive statistics. Statistical analyses examined clinical response/survival and ANC recovery.

Results: DLTs were G4 neutropenia, G4 thrombocytopenia, G4 acute renal failure, and G3 cellulitis, attributed to mistletoe. GEM 1300 mg/m(2) [corrected] and mistletoe 250 mg combined were the MTD. Of 44 patients, 24 developed nonneutropenic fever and flu-like syndrome. GEM pharmacokinetics were unaffected by mistletoe. All patients developed ML3 IgG antibodies. ANC showed a trend to increase between baseline and cycle 2 in stage I dose escalation. 6% of patients showed partial response, 42% stable disease. Median survival was 200 days. Compliance with mistletoe injections was high.

Conclusion: GEM plus mistletoe is well tolerated. No botanical/drug interactions were observed. Clinical response is similar to GEM alone.

Figures

Figure 1
Figure 1
(a) Best clinical response and (b) best overall response by diagnosis.
Figure 2
Figure 2
Time from enrollment to death.

References

    1. Elluru S, van Huyen JD, Delignat S, et al. Molecular mechanisms underlying the immunomodulatory effects of mistletoe (Viscum album L.) extracts Iscador. Arzneimittel-Forschung. 2006;56(6):461–466.
    1. Steiner R. Geisteswissenschaft und Medizin. Dornach, Switzerland: Rudolf Steiner; 1985.
    1. Hostanska K, Hajto T, Spagnoli GC, Fischer J, Lentzen H, Herrman R. A plant lectin derived from Viscum album induces cytokine gene expression and protein production in cultures of human peripheral blood mononuclear cells. Natural Immunity. 1995;14(5-6):295–304.
    1. Stein G, Berg PA. Non-lectin component in a fermented extract from Viscum album L, grown on pines induces proliferation of lymphocytes from healthy and allergic individuals in vitro . European Journal of Clinical Pharmacology. 1994;47(1):33–38.
    1. Rentea R, Lyon E, Hunter R. Biologic properties of Iscador: a Viscum album preparation. I. Hyperplasia of the thymic cortex and accelerated regeneration of hematopoietic cells following X-irradiation. Laboratory Investigation. 1981;44(1):43–48.
    1. Beuth J, Ko HL, Tunggal L, et al. Thymocyte proliferation and maturation in response to galactoside-specific mistletoe lectin-1. In Vivo. 1993;7(5):407–410.
    1. Kuttan G. Tumoricidal activity of mouse peritoneal macrophages treated with Viscum album extract. Immunological Investigations. 1993;22(6-7):431–440.
    1. Hamprecht K, Handgretinger R, Voetsch W, Anderer FA. Mediation of human NK-activity by components in extracts of Viscum album . International Journal of Immunopharmacology. 1987;9(2):199–209.
    1. Hajto T, Lanzrein C. Natural killer and antibody-dependent cell-mediated cytotoxicity activities and large granular lymphocyte frequencies in Viscum album-treated breast cancer patients. Oncology. 1986;43(2):93–97.
    1. Bussing A. Mistletoe therapy and immunological research. Anti-Cancer Drugs. 1997;8(1):p. S65.
    1. Stein GM, Berg PA. Mistletoe extract-induced effects on immunocompetent cells: in vitro studies. Anti-Cancer Drugs. 1997;8(1):S39–S42.
    1. Gabius HJ, André S, Kaltner H, Siebert HC, von der Lieth CW, Gabius S. The mistletoe myth: claims, reality and provable perspectives. Zeitschrift fur Arztliche Fortbildung. 1996;90(2):103–110.
    1. Franz H. Mistletoe lectins and their A and B chains. Oncology. 1986;43(1):23–34.
    1. Elsasser-Beile U, Voss M, Schuhle R, Wetterauer U. Biological effects of natural and recombinant mistletoe lectin and an aqueous mistletoe extract on human monocytes and lymphocytes in vitro . Journal of Clinical Laboratory Analysis. 2000;14(6):255–259.
    1. Elsässer-Beile U, Lusebrink S, Grussenmeyer T, Wetterauer U, Schultze-Seemann W. Comparison of the effects of various clinically applied mistletoe preparations on peripheral blood leukocytes. Arzneimittel-Forschung. 1998;48(12):1185–1189.
    1. Hajto T, Berki T, Palinkas L, Boldizsar F, Nemeth P. Investigation of the effect of mistletoe (Viscum album L.) extract Iscador on the proliferation and apoptosis of murine thymocytes. Arzneimittelforschung. 2006;56(6):441–446.
    1. Samtleben R, Hajto T, Hostanska K. Mistletoe lectins as immunostimulants (chemistry, pharmacology and clinic) In: Wagner H, editor. Immunomodulatory Agents from Plants. Basel, Switzerland: Birkhäauser; 1999. pp. 223–241.
    1. Lee RT, Gabius HJ, Lee YC. Ligand binding characteristics of the major mistletoe lectin. The Journal of Biological Chemistry. 1992;267(33):23722–23727.
    1. Ribéreau-Gayon G, Dumont S, Muller C, Jung ML, Poindron P, Anton R. Mistletoe lectins I, II and III induce the production of cytokines by cultured human monocytes. Cancer Letters. 1996;109(1-2):33–38.
    1. Hajto T, Hostanska K, Weber K, et al. Effect of a recombinant lectin, Viscum album agglutinin on the secretion of interleukin-12 in cultured human peripheral blood mononuclear cells and on NK-cell-mediated cytotoxicity of rat splenocytes in vitro and in vivo . Natural Immunity. 1998;16(1):34–46.
    1. Hajto T, Hostanska K, Frei K, Rordorf C, Gabius HJ. Increased secretion of tumor necrosis factor α, interleukin 1, and interleukin 6 by human mononuclear cells exposed to β-galactoside-specific lectin from clinically applied mistletoe extract. Cancer Research. 1990;50(11):3322–3326.
    1. Pae HO, Seo WG, Oh GS, et al. Potentiation of tumor necrosis factor-α-induced apoptosis by mistletoe lectin. Immunopharmacology and Immunotoxicology. 2000;22(4):697–709.
    1. Büssing A, Stein GM, Pfüller U, Schietzel M. Induction of Fas ligand (CD95L) by the toxic mistletoe lectins in human lymphocytes. Anticancer Research. 1999;19(3):1785–1790.
    1. Eggenschwiler J, Patrignani A, Wagner U, et al. Gene expression profiles of different breast cancer cells compared with their responsiveness to fermented mistletoe (Viscum album L.) extracts Iscador from oak (Quercus), pine (Pinus), white fir (Abies) and apple tree (Malus) in vitro . Arzneimittel-Forschung. 2006;56(6):483–496.
    1. Weber K, Mengs U, Schwarz T, Becker H, Lentzen H. Stimulation of neutropoiesis by a special standardized mistletoe preparation after cyclophosphamide chemotherapy in mice. Arzneimittel-Forschung. 1996;46(12):1174–1178.
    1. Savoie A, Lavastre V, Pelletier M, Hajto T, Hostanska K, Girard D. Activation of human neutrophils by the plant lectin Viscum album agglutinin-I: modulation of de novo protein synthesis and evidence that caspases are involved in induction of apoptosis. Journal of Leukocyte Biology. 2000;68(6):845–853.
    1. Stettin A, Schultze JL, Stechemesser E, Berg PA. Anti-mistletoe lectin antibodies are produced in patients during therapy with an aqueous mistletoe extract derived from Viscum album L. and neutralize lectin-induced cytotoxicity in vitro . Klinische Wochenschrift. 1990;68(18):896–900.
    1. Stein GM, Berg PA. Characterisation of immunological reactivity of patients with adverse effects during therapy with an aqueous mistletoe extract. European Journal of Medical Research. 1999;4(5):169–177.
    1. Stein GM, Pfüller U, Berg PA. Recognition of different antigens of mistletoe extracts by anti-mistletoe lectin antibodies. Cancer Letters. 1999;135(2):165–170.
    1. Gorter RW, van Wely M, Reif M, Stoss M. Tolerability of an extract of European mistletoe among immunocompromised and healthy individuals. Alternative Therapies in Health and Medicine. 1999;5(6):37–48.
    1. Huber R, Eisenbraun J, Miletzki B, et al. Pharmacokinetics of natural mistletoe lectins after subcutaneous injection. European Journal of Clinical Pharmacology. 2010;66(9):889–897.
    1. Bock PR, Friedel WE, Hanisch J, Karasmann M, Schneider B. 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 multicenter, comparative, epidemiological cohort study in Germany and Switzerland. Arzneimittel-Forschung. 2004;54(8):456–466.
    1. Matthes H, Friedel WE, Bock PR, Zanker KS. Molecular mistletoe therapy: friend or foe in established anti-tumor protocols? A multicenter, controlled, retrospective pharmaco-epidemiological study in pancreas cancer. Current Molecular Medicine. 2010;10(4):430–439.
    1. Ostermann T, Bussing A. Retrolective studies on the survival of cancer patients treated with mistletoe extracts: a meta-analysis. Explore. 2012;8(5):277–281.
    1. Kienle GS, Glockmann A, Schink M, Kiene H. Viscum album L. extracts in breast and gynaecological cancers: a systematic review of clinical and preclinical research. Journal of Experimental and Clinical Cancer Research. 2009;28(article 79)
    1. Ostermann T, Raak C, Bussing A. Survival of cancer patients treated with mistletoe extract (Iscador): a systematic literature review. BMC Cancer. 2009;9(article 451)
    1. Horneber MA, Bueschel G, Huber R, Linde K, Rostock M. Mistletoe therapy in oncology. Cochrane Database of Systematic Reviews. 2008;(2)CD003297
    1. Kienle GS, Kiene H. Complementary cancer therapy: a systematic review of prospective clinical trials on anthroposophic mistletoe extracts. European Journal of Medical Research. 2007;12(3):103–119.
    1. Grossarth-Maticek R, Kiene H, Baumgartner SM, Ziegler R. Use of iscador, an extract of European mistletoe (Viscum album), in cancer treatment: prospective nonrandomized and randomized matched-pair studies nested within a cohort study. Alternative Therapies in Health and Medicine. 2001;7(3):57–76.
    1. Lenartz D, Dott U, Menzel J, Schierholz JM, Beuth J. Survival of glioma patients after complementary treatment with galactoside-specific lectin from mistletoe. Anticancer Research. 2000;20(3):2073–2076.
    1. Steuer-Vogt MK, Bonkowsky V, Ambrosch P, et al. The effect of an adjuvant mistletoe treatment programme in resected head and neck cancer patients: a randomised controlled clinical trial. European Journal of Cancer. 2001;37(1):23–31.
    1. Bar-Sela G, Wollner M, Hammer L, Agbarya A, Dudnik E, Haim N. Mistletoe as complementary treatment in patients with advanced non-small-cell lung cancer treated with carboplatin-based combinations: a randomised phase II study. European Journal of Cancer. 2013;49(5):1058–1064.
    1. Mansky PJ, Grem J, Wallerstedt DB, Monahan BP, Blackman MR. Mistletoe and gemcitabine in patients with advanced cancer: a model for the phase I study of botanicals and botanical-drug interactions in cancer therapy. Integrative Cancer Therapies. 2003;2(4):345–352.
    1. .
    1. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. Journal of the American Statistical Association. 1958;53(282):457–481.
    1. Jonckheere AR. A distribution-free k-sample test against ordered alternatives. Biometrika. 1954;41(1-2):133–145.

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