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Efficacy of intracerebral delivery of cisplatin in combination with photon irradiation for treatment of brain tumors

  • Laboratory Investigation - Human/Animal Tissue
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Abstract

We have evaluated the efficacy of intracerebral (i.c.) convection-enhanced delivery (CED) of cisplatin in combination with photon irradiation for the treatment of F98 glioma-bearing rats. One thousand glioma cells were stereotactically implanted into the brains of Fischer rats and 13 days later cisplatin (6 μg/20 μl) was administered i.c. by CED at a flow rate of 0.5 μl/min. On the following day the animals were irradiated with a single 15 Gy dose of X-rays, administered by a linear accelerator (LINAC) or 78.8 keV synchrotron X-rays at the European Synchrotron Radiation Facility (ESRF). Untreated controls had a mean survival time (MST) ± standard error of 24 ± 1 days compared to >59 ± 13 days for rats that received cisplatin alone with 13% of the latter surviving >200 days. Rats that received cisplatin in combination with either 6 MV (LINAC) or 78.8 keV (synchrotron) X-rays had almost identical MSTs of >75 ± 18 and >74 ± 19 days, respectively with 17 and 18% long-term survivors. Microscopic examination of the brains of long-term surviving rats revealed an absence of viable tumor cells and cystic areas at the presumptive site of the tumor. Our data demonstrate that i.c. CED of cisplatin in combination with external X-irradiation significantly enhanced the survival of F98 glioma-bearing rats. This was independent of the X-ray beam energy and probably was not due to the production of Auger electrons as we previously had postulated. Our data provide strong support for the approach of concomitantly administering platinum-based chemotherapy in combination with radiotherapy for the treatment of brain tumors. Since a conventional LINAC can be used as the radiation source, this should significantly broaden the clinical applicability of this approach compared to synchrotron radiotherapy, which could only be carried out at a very small number of specialized facilities.

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References

  1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996

    Article  CAS  PubMed  Google Scholar 

  2. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol

  3. Adam JF, Elleaume H, Joubert A, Biston MC, Charvet AM, Balosso J, Le Bas JF, Esteve F (2003) Synchrotron radiation therapy of malignant brain glioma loaded with an iodinated contrast agent: first trial on rats bearing F98 gliomas. Int J Radiat Oncol Biol Phys 57:1413–1426

    CAS  PubMed  Google Scholar 

  4. Adam JF, Joubert A, Biston MC, Charvet AM, Peoc’h M, Le Bas JF, Balosso J, Esteve F, Elleaume H (2006) Prolonged survival of Fischer rats bearing F98 glioma after iodine-enhanced synchrotron stereotactic radiotherapy. Int J Radiat Oncol Biol Phys 64:603–611

    CAS  PubMed  Google Scholar 

  5. Barth RF, Coderre JA, Vicente MG, Blue TE (2005) Boron neutron capture therapy of cancer: current status and future prospects. Clin Cancer Res 11:3987–4002

    Article  CAS  PubMed  Google Scholar 

  6. Boudou C, Balosso J, Esteve F, Elleaume H (2005) Monte Carlo dosimetry for synchrotron stereotactic radiotherapy of brain tumours. Phys Med Biol 50:4841–4851

    Article  PubMed  Google Scholar 

  7. Boudou C, Biston MC, Corde S, Adam JF, Ferrero C, Esteve F, Elleaume H (2004) Synchrotron stereotactic radiotherapy: dosimetry by Fricke gel and Monte Carlo simulations. Phys Med Biol 49:5135–5144

    Article  PubMed  Google Scholar 

  8. Biston MC, Joubert A, Adam JF, Elleaume H, Bohic S, Charvet AM, Esteve F, Foray N, Balosso J (2004) Cure of Fisher rats bearing radioresistant F98 glioma treated with cis-platinum and irradiated with monochromatic synchrotron X-rays. Cancer Res 64:2317–2323

    Article  CAS  PubMed  Google Scholar 

  9. Rousseau J, Barth RF, Moeschberger ML, Elleaume H (2009) Efficacy of intracerebral delivery of carboplatin in combination with photon irradiation for treatment of F98 glioma-bearing rats. Int J Radiat Oncol Biol Phys 73:530–536

    CAS  PubMed  Google Scholar 

  10. Rousseau J, Boudou C, Barth RF, Balosso J, Esteve F, Elleaume H (2007) Enhanced survival and cure of F98 glioma-bearing rats following intracerebral delivery of carboplatin in combination with photon irradiation. Clin Cancer Res 13:5195–5201

    Article  CAS  PubMed  Google Scholar 

  11. Karnas SJ, Yu E, McGarry RC, Battista JJ (1999) Optimal photon energies for IUdR K edge radiosensitization with filtered x-ray and radioisotope sources. Phys Med Biol 44:2537–2549

    Article  CAS  PubMed  Google Scholar 

  12. Robar JL, Riccio SA, Martin MA (2002) Tumour dose enhancement using modified megavoltage photon beams and contrast media. Phys Med Biol 47:2433–2449

    Article  PubMed  Google Scholar 

  13. Corde S, Balosso J, Elleaume H, Renier M, Joubert A, Biston MC, Adam JF, Charvet AM, Brochard T, Le Bas JF, Esteve F, Foray N (2003) Synchrotron photoactivation of cisplatin elicits an extra number of DNA breaks that stimulate RAD51-mediated repair pathways. Cancer Res 63:3221–3227

    CAS  PubMed  Google Scholar 

  14. Corde S, Biston MC, Elleaume H, Esteve F, Charvet AM, Joubert A, Ducros V, Bohic S, Simionovici A, Brochard T, Nemoz C, Renier M, Tropres I, Fiedler S, Bravin A, Thomlinson W, Le Bas JF, Balosso J (2002) Lack of cell death enhancement after irradiation with monochromatic synchrotron X rays at the K-shell edge of platinum incorporated in living SQ20B human cells as cis-diaminedichloroplatinum (II). Radiat Res 158:763–770

    Article  CAS  PubMed  Google Scholar 

  15. Hainfeld JF, Dilmanian FA, Slatkin DN, Smilowitz HM (2008) Radiotherapy enhancement with gold nanoparticles. J Pharm Pharmacol 60:977–985

    Article  CAS  PubMed  Google Scholar 

  16. Hainfeld JF, Slatkin DN, Smilowitz HM (2004) The use of gold nanoparticles to enhance radiotherapy in mice. Phys Med Biol 49:N309–N315

    Article  CAS  PubMed  Google Scholar 

  17. De Stasio G, Rajesh D, Ford JM, Daniels MJ, Erhardt RJ, Frazer BH, Tyliszczak T, Gilles MK, Conhaim RL, Howard SP, Fowler JF, Esteve F, Mehta MP (2006) Motexafin-gadolinium taken up in vitro by at least 90% of glioblastoma cell nuclei. Clin Cancer Res 12:206–213

    Article  PubMed  Google Scholar 

  18. Kelland L (2007) The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer 7:573–584

    Article  CAS  PubMed  Google Scholar 

  19. Jung Y, Lippard SJ (2007) Direct cellular responses to platinum-induced DNA damage. Chem Rev 107:1387–1407

    Article  CAS  PubMed  Google Scholar 

  20. Muldoon LL, Soussain C, Jahnke K, Johanson C, Siegal T, Smith QR, Hall WA, Hynynen K, Senter PD, Peereboom DM, Neuwelt EA (2007) Chemotherapy delivery issues in central nervous system malignancy: a reality check. J Clin Oncol 25:2295–2305

    Article  CAS  PubMed  Google Scholar 

  21. Kroin JS, Penn RD (1982) Intracerebral chemotherapy: chronic microinfusion of cisplatin. Neurosurgery 10:349–354

    Article  CAS  PubMed  Google Scholar 

  22. Boudou C, Tropres I, Rousseau J, Lamalle L, Adam JF, Esteve F, Elleaume H (2007) Polymer gel dosimetry for synchrotron stereotactic radiotherapy and iodine dose-enhancement measurements. Phys Med Biol 52:4881–4892

    Article  CAS  PubMed  Google Scholar 

  23. Barth RF, Kaur B (2009) Rat brain tumor models in experimental neuro-oncology: the C6, 9L, T9, RG2, F98, BT4C, RT-2 and CNS-1 gliomas. J Neurooncol 94:299–312

    Article  PubMed  Google Scholar 

  24. Nias AH (1985) Radiation and platinum drug interaction. Int J Radiat Biol Relat Stud Phys, Chem Med 48:297–314

    Article  CAS  Google Scholar 

  25. Elleaume H, Charvet AM, Berkvens P, Berruyer G, Brochard T, Dabin Y, Dominguez MC, Draperi A, Fiedler S, Goujon G, Le Duc G, Mattenet M, Nemoz C, Perez M, Renier M, Schulze C, Spanne P, Suortti P, Thomlinson W, Esteve F, Bertrand B, Le Bas JF (1999) Instrumentation of the ESRF medical imaging facility. Nucl Instrum Methods A 428:513–527

    Article  CAS  Google Scholar 

  26. Rousseau J, Adam JF, Deman P, Wu TD, Guerquin-Kern JL, Gouget B, Barth RF, Esteve F, Elleaume H (2009) Intracerebral delivery of 5-iodo-2′-deoxyuridine in combination with synchrotron stereotactic radiation for the therapy of the F98 glioma. J Synchrotron Radiat 16:573–581

    Article  CAS  PubMed  Google Scholar 

  27. Yang WL, Barth RF, Wu G, Ciesielski LJ, Fenstermaker RA, Moffat BA, Ross BD, Wikstrand CJ (2005) Development of a syngeneic rat brain tumor model expressing EGFRvIII and its use for molecular targeting studies with monoclonal antibody L8A4. Clin Cancer Res 11:341–350

    CAS  PubMed  Google Scholar 

  28. Moeschberger ML, Klein JP (1985) A comparison of several methods of estimating the survival function when there is extreme right censoring. Biometrics 41:253–259

    Article  CAS  PubMed  Google Scholar 

  29. Penn RD, Kroin JS, Harris JE, Chiu KM, Braun DP (1983) Chronic intratumoral chemotherapy of a rat tumor with cisplatin and fluorouracil. Appl Neurophysiol 46:240–244

    CAS  PubMed  Google Scholar 

  30. Kimler BF, Liu C, Evans RG, Morantz RA (1993) Combination of aziridinylbenzoquinone and cis-platinum with radiation therapy in the 9L rat brain tumor model. Int J Radiat Oncol Biol Phys 26:445–450

    CAS  PubMed  Google Scholar 

  31. Degen JW, Walbridge S, Vortmeyer AO, Oldfield EH, Lonser RR (2003) Safety and efficacy of convection-enhanced delivery of gemcitabine or carboplatin in a malignant glioma model in rats. J Neurosurg 99:893–898

    Article  CAS  PubMed  Google Scholar 

  32. Bouvier G, Penn RD, Kroin JS, Beique R, Guerard MJ (1987) Direct delivery of medication into a brain tumor through multiple chronically implanted catheters. Neurosurgery 20:286–291

    Article  CAS  PubMed  Google Scholar 

  33. Sheleg SV, Korotkevich EA, Zhavrid EA, Muravskaya GV, Smeyanovich AF, Shanko YG, Yurkshtovich TL, Bychkovsky PB, Belyaev SA (2002) Local chemotherapy with cisplatin-depot for glioblastoma multiforme. J Neurooncol 60:53–59

    Article  PubMed  Google Scholar 

  34. Bernhardt P, Friedland W, Paretzke HG (2004) The role of atomic inner shell relaxations for photon-induced DNA damage. Radiat Environ Biophys 43:77–84

    Article  CAS  PubMed  Google Scholar 

  35. Ortega R, Biston MC, Deves G, Bohic S, Carmona A (2005) Nuclear microprobe determination of platinum quantitative distribution in rat brain tumors after cisplatin or carboplatin injection for PAT treatment of glioma. Nucl Instrum Methods Phys Res Sect B-Beam Interact Mater At 231:321–325

    CAS  Google Scholar 

  36. Herold DM, Das IJ, Stobbe CC, Iyer RV, Chapman JD (2000) Gold microspheres: a selective technique for producing biologically effective dose enhancement. Int J Radiat Biol 76:1357–1364

    Article  CAS  PubMed  Google Scholar 

  37. Cho SH (2005) Estimation of tumour dose enhancement due to gold nanoparticles during typical radiation treatments: a preliminary Monte Carlo study. Phys Med Biol 50:N163–N173

    Article  PubMed  Google Scholar 

  38. Usami N, Furusawa Y, Kobayashi K, Lacombe S, Reynaud-Angelin A, Sage E, Wu TD, Croisy A, Guerquin-Kern JL, Le Sech C (2008) Mammalian cells loaded with platinum-containing molecules are sensitized to fast atomic ions. Int J Radiat Biol 84:603–611

    Article  CAS  PubMed  Google Scholar 

  39. Boulikas T, Vougiouka M (2003) Cisplatin and platinum drugs at the molecular level (review). Oncol Rep 10:1663–1682

    CAS  PubMed  Google Scholar 

  40. Huynh GH, Deen DF, Szoka FC Jr (2006) Barriers to carrier mediated drug and gene delivery to brain tumors. J Control Release 110:236–259

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank the European Synchrotron Radiation Facility for providing beam time; Mrs. C. Massart, Ms. E. Kerboul, Mr. T. Brochard, Dr. C. Nemoz for help during the experiments; Mr. D. Dallery and Mrs. A. Honkimaki for animal care; Dr. S. Corde for CHU dosimetry; Ms. M. Van Fossen for secretarial assistance. R.F.B. acknowledges the support of the Grey Ribbon Crusade, the Musella Foundation and The Ohio State University Department of Pathology.

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Authors and Affiliations

  1. INSERM U836, Equipe 6, ESRF, Medical Beamline, BP 220, 38043, Grenoble Cedex 9, France

    Julia Rousseau, Manuel Fernandez, Jean-François Adam, Jacques Balosso, François Estève & Hélène Elleaume

  2. Université Joseph Fourier, Grenoble, France

    Julia Rousseau, Manuel Fernandez, Jean-François Adam, Jacques Balosso, François Estève & Hélène Elleaume

  3. European Synchrotron Radiation Facility, Grenoble, France

    Julia Rousseau, Manuel Fernandez, Jean-François Adam, Jacques Balosso, François Estève & Hélène Elleaume

  4. Department of Pathology, The Ohio State University, Columbus, OH, 43210, USA

    Rolf F. Barth

  5. Centre Hospitalier Universitaire, Grenoble, France

    Jacques Balosso, François Estève & Hélène Elleaume

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  1. Julia Rousseau
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  2. Rolf F. Barth
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Correspondence to Hélène Elleaume.

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Rousseau, J., Barth, R.F., Fernandez, M. et al. Efficacy of intracerebral delivery of cisplatin in combination with photon irradiation for treatment of brain tumors. J Neurooncol 98, 287–295 (2010). https://doi.org/10.1007/s11060-009-0074-3

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  • DOI: https://doi.org/10.1007/s11060-009-0074-3

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