A Randomized Study on Postrelapse Disease-Free Survival with Adjuvant Mistletoe versus Oral Etoposide in Osteosarcoma Patients

Alessandra Longhi, Marcus Reif, Erminia Mariani, Stefano Ferrari, Alessandra Longhi, Marcus Reif, Erminia Mariani, Stefano Ferrari

Abstract

Background. Osteosarcoma is a highly malignant bone tumour. After the second relapse, the 12-month postrelapse disease-free survival (PRDFS) rate decreases below 20%. Oral Etoposide is often used in clinical practice after surgery as an "adjuvant" outside any protocol and with only limited evidence of improved survival. Viscum album fermentatum Pini (Viscum) is an extract of mistletoe plants grown on pine trees for subcutaneous (sc) injection with immunomodulatory activity. Methods. Encouraged by preliminary findings, we conducted a study where osteosarcoma patients free from disease after second metastatic relapse were randomly assigned to Viscum sc or Oral Etoposide. Our goal was to compare 12-month PRDFS rates with an equivalent historical control group. Results. Twenty patients have been enrolled, with a median age of 34 years (range 11-65) and a median follow-up time of 38.5 months (3-73). The median PRDSF is currently 4 months (1-47) in the Etoposide and 39 months (2-73) in the Viscum group. Patients getting Viscum reported a higher quality of life due to lower toxicity. Conclusion. Viscum shows promise as adjuvant treatment in prolonging PRDFS after second relapse in osteosarcoma patients. A larger study is required to conclusively determine efficacy and immunomodulatory mechanisms of Viscum therapy in osteosarcoma patients.

Figures

Figure 1
Figure 1
PRDFS rates and exact 95% confidence intervals after 12 months of treatment with Viscum or Etoposide, respectively. The horizontal line represents the 12% PRDFS rate derived from historical controls. By crossing the 12% line, the Etoposide confidence interval indicates that this treatment cannot statistically be distinguished from the historical rate, whereas for Viscum a significant difference can be deduced.
Figure 2
Figure 2
Kaplan-Meier graph of the course of PRDFS for Viscum and Etoposide patients, respectively, over the period of the trial and during follow-up. The vertical line indicates the end of the trial period. Last dates are from July 2013 and are updated on an ongoing basis.

References

    1. Briccoli A, Rocca M, Salone M, et al. Resection of recurrent pulmonary metastases in patients with osteosarcoma. Cancer. 2005;104(8):1721–1725.
    1. Fagioli F, Aglietta M, Tienghi A, et al. High-dose chemotherapy in the treatment of relapsed osteosarcoma: an Italian Sarcoma Group study. Journal of Clinical Oncology. 2002;20(8):2150–2156.
    1. Bacci G, Briccoli A, Longhi A, et al. Treatment and outcome of recurrent osteosarcoma: experience at Rizzoli in 235 patients initially treated with neoadjuvant chemotherapy. Acta Oncologica. 2005;44(7):748–755.
    1. Ritter J, Bielack SS. Osteosarcoma. Annals of Oncology. 2010;21(supplement 7):vii320–vii325.
    1. Leary SE, Wozniak AW, Billups CA, et al. Survival of pediatric patients after relapsed osteosarcoma: the St. Jude Children's Research Hospital experience. Cancer. 2013;119(14):2645–2653.
    1. EURAMOS-1. A randomized trial of the European and American Osteosarcoma Study Group to optimize treatment strategies for resectable osteosarcoma based on histological response to pre-operative chemotherapy. ISRCTN67613327, 2009, .
    1. Kebudi R, Görgün Ö, Ayan I. Oral etoposide for recurrent/progressive sarcomas of childhood. Pediatric Blood and Cancer. 2004;42(4):320–324.
    1. Sandri A, Massimino M, Mastrodicasa L, et al. Treatment with oral etoposide for childhood recurrent ependymomas. Journal of Pediatric Hematology/Oncology. 2005;27(9):486–490.
    1. Hugo F, Dittmar T, Treutler EK, Zänker KS, Kuehn JJ. The Viscum album extract Iscador P does not cause an autocrine interleukin-6 loop in B-Non-Hodgkin’s lymphoma cell lines. Onkologie. 2005;28(8-9):415–420.
    1. Mueller EA, Anderer FA. A Viscum album oligosaccharide activating human natural cytotoxicity is an interferon γ inducer. Cancer Immunology Immunotherapy. 1990;32(4):221–227.
    1. Braun JM, Ko HL, Schierholz JM, Beuth J. Standardized mistletoe extract augments immune response and down-regulates local and metastatic tumor growth in murine models. Anticancer Research. 2002;22(6):4187–4190.
    1. Schaffrath B, Mengs U, Schwarz T, et al. Anticancer activity of rViscumin (recombinant mistletoe lectin) in tumor colonization models with immunocompetent mice. Anticancer Research. 2001;21(6):3981–3987.
    1. Kuttan G, Menon LG, Antony S, Kuttan R. Anticarcinogenic and antimetastatic activity of Iscador. Anti-Cancer Drugs. 1997;8(1):S15–S16.
    1. Hajto T, Hostanska K, Frei K, Rordorf C, Gabius H-J. 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. Chernyshov VP, Heusser P, Omelchenko LI, et al. Immunomodulatory and clinical effects of Viscum album (Iscador M and Iscador P) in children with recurrent respiratory infections as a result of the chernobyl nuclear accident. American Journal of Therapeutics. 2000;7(3):195–203.
    1. Kienle GS, Berrino F, Büssing A, Portalupi E, Rosenzweig S, Kiene H. Mistletoe in cancer—a systematic review on controlled clinical trials. European Journal of Medical Research. 2003;8(3):109–119.
    1. Möckel B, Schwarz T, Zinke H, Eck J, Langer M, Lentzen H. Effects of mistletoe lectin I on human blood cell lines and peripheral blood cells—cytotoxicity, apoptosis and induction of cytokines. Arzneimittel-Forschung/Drug Research. 1997;47(10):1145–1151.
    1. van Huyen J-PD, Bayry J, Delignat S, et al. Induction of apoptosis of endothelial cells by Viscum album: a role for anti-tumoral properties of mistletoe lectins. Molecular Medicine. 2002;8(10):600–606.
    1. Harmsma M, Ummelen M, Dignef W, Tusenius KJ, Ramaekers FCS. Effects of mistletoe (Viscum album L.) extracts Iscador on cell cycle and survival of tumor cells. Arzneimittel-Forschung/Drug Research. 2006;56(6):474–482.
    1. Hajtò T, Berki T, Pàlinkàs L, Boldizsàr F, Németh P. Investigation of the effect of mistletoe (Viscum album L.) extract Iscador on the proliferation and apoptosis of murine thymocytes. Arzneimittel-Forschung/Drug Research. 2006;56(6):441–446.
    1. Schöffski P, Riggert S, Fumoleau P, et al. Phase I trial of intravenous aviscumine (rViscumin) in patients with solid tumors: a study of the European Organization for research and treatment of cancer new drug development group. Annals of Oncology. 2004;15(12):1816–1824.
    1. Longhi A, Mariani E, Kuehn JJ. A randomized study with adjuvant mistletoe versus oral Etoposide on post relapse disease-free survival in osteosarcoma patients. European Journal of Integrative Medicine. 2009;1(1):31–39.
    1. Stein GM, Meink H, Durst J, Berg PA. Release of cytokines by a fermented lectin-1 (ML-1) free mistletoe extract reflects differences in the reactivity of PBMC in healthy and allergic individuals and tumour patients. European Journal of Clinical Pharmacology. 1996;51(3-4):247–252.
    1. Mueller EA, Hamprecht K, Anderer FA. Biochemical characterization of a component in extracts of Viscum album enhancing human NK cytotoxicity. Immunopharmacology. 1989;17(1):11–18.
    1. Stein GM, Berg PA. Flow cytometric analyses of the specific activation of peripheral blood mononuclear cells from healthy donors after in vitro stimulation with a fermented mistletoe extract and mistletoe lectins. European Journal of Cancer. 1998;34(7):1105–1110.
    1. Stein GM, Büssing A, Schietzel M. Stimulation of the maturation of dendritic cells in vitro by a fermented mistletoe extract. Anticancer Research. 2002;22(6):4215–4219.
    1. Mossalayi MD, Alkharrat A, Malvy D. Nitric oxide involvement in the anti-tumor effect of mistletoe (Viscum album L.) extracts iscador on human macrophages: short communication. Arzneimittel-Forschung/Drug Research. 2006;56(6):457–460.
    1. Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika. 1934;26(4):404–413.
    1. Blair GE, Cook GP. Cancer and the immune system: an overview. Oncogene. 2008;27(45, article 5868)
    1. Jeys LM, Grimer RJ, Carter SR, Tillman RM, Abudu A. Post operative infection and increased survival in osteosarcoma patients: are they associated? Annals of Surgical Oncology. 2007;14(10):2887–2895.
    1. Müller CR, Smeland S, Bauer HCF, Sæter G, Strander H. Interferon-α as the only adjuvant treatment in high-grade osteosarcoma: long term results of the Karolinska Hospital series. Acta Oncologica. 2005;44(5):475–480.
    1. Meyers PA, Schwartz CL, Krailo MD, et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival—a report from the children’s oncology group. Journal of Clinical Oncology. 2008;26(4):633–638.
    1. Weleda AG. Iscador in Cancer Therapy. Recommendations for Treatment. 3rd edition. Arlesheim, Switzerland: Weleda AG Medical Affairs, Schwäbisch-Gmünd, Germany, Society for Cancer Research; 2013.
    1. Janssen O, Scheffler A, Kabelitz D. In vitro effects of mistletoe extracts and mistletoe lectins. Cytotoxicity towards tumor cells due to the induction of programmed cell death (apoptosis) Arzneimittel-Forschung/Drug Research. 1993;43(11):1221–1227.
    1. Büssing A, Suzart K, Bergmann J, Pfüller U, Schietzel M, Schweizer K. Induction of apoptosis in human lymphocytes treated with Viscum album L. is mediated by the mistletoe lectins. Cancer Letters. 1996;99(1):59–72.
    1. Büssing A, Vervecken W, Wagner M, Wagner B, Pfüller U, Schietzel M. Expression of mitochondrial Apo2.7 molecules and Caspase-3 activation in human lymphocytes treated with the ribosome-inhibiting mistletoe lectins and the cell membrane permeabilizing viscotoxins. Cytometry. 1999;37(2):133–139.
    1. Stein GM, Berg PA. Immunmodulation durch Mistelextrakte: ergebnisse von in vitro und ex vivo Studien (abstract) Der Merkurstab. 1997;50(2):p. 35.
    1. Büssing A, Schaller G, Pfüller U. Generation of reactive oxygen intermediates (ROI) by the thionins from Viscum album L. Anticancer Research. 1998;18(6):4291–4296.
    1. Tabiasco J, Pont F, Fournié J-J, Vercellone A. Mistletoe viscotoxins increase natural killer cell-mediated cytotoxicity. European Journal of Biochemistry. 2002;269(10):2591–2600.
    1. Kuttan G, Vasudevan DM, Kuttan R. Isolation and identification of a tumour reducing component from mistletoe extract (Iscador) Cancer Letters. 1988;41(3):307–314.
    1. Becker H, Exner J. Vergleichende Untersuchungen von Misteln verschiedener Wirtsbäume an Hand der Flavonoide and Phenolcarbonsäuren. Zeitschrift für Pflanzenphysiologie. 1980;97(5):417–428.
    1. Sekeroğlu ZA, Sekeroğlu V. Effects of Viscum album L. extract and quercetin on methotrexate-induced cyto-genotoxicity in mouse bone-marrow cells. Mutation Research. 2012;746(1):56–59.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj