Journal of Neuro-Oncology

, Volume 72, Issue 2, pp 125–131 | Cite as

Intratumoral delivery of mitoxantrone in association with 90-Y radioimmunotherapy (RIT) in recurrent glioblastoma

  • Amerigo BoiardiEmail author
  • Mirco Bartolomei
  • Antonio Silvani
  • Marica Eoli
  • Andrea Salmaggi
  • Elena Lamperti
  • Ida Milanesi
  • Andrea Botturi
  • Paola Rocca
  • Lisa Bodei
  • Giovanni Broggi
  • Giovanni Paganelli
Clinical Study


Twenty-six recurrent Glioblastoma (rGBM) patients sequentially treated at the National Neurological Institute ‘C Besta’ were enrolled for a second surgery in order to remove recurrent tumor and to place an Ommaya reservoire to allow local delivery of chemotherapy and local pre-targeted radio-immunotherapy (RIT). All patients had partial tumor resection and 75% of them had a residual tumor mass after exeresis larger than 2 cm. After surgery all patients were managed with a second line systemic chemotherapy (PCV). Moreover the protocol scheduled two cycles of local RIT (90 Yttrium 5– 25 mCi per cycle) with a 10 week interval. Locoregional mitoxantrone chemotherapy was locally delivered as a single dose of 4 mg every 20 days. Responses to treatment were assessed by monthly neurological examination and by MRI or contrast-enhanced CT scan performed every 2 months.

For the whole group of patients the PFS after second surgery at 6 and 12 months was 61% and 22%, respectively and survival after recurrence at 6, 12 and 18 months was 80%, 53% and 42%, respectively. Neither major side effects occurred systemically nor related on the place of local injections. The percentage of long-term survivors was very high: 42% of patients were still alive at 18 months. We stress the concept that the combined treatments could be more effective if delivered into a smaller residual tumor mass and probably in an adjuvant setting, before tumour recurrence.


locoregional chemotherapy locoregional radioimmunotherapy mitoxantrone recurrent glioblastoma 


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  1. 1.
    Walker, MD, Green, SB, Byar, DP, Alexander, Ejr, Batzdorf, U, Brooks, WH, Hunt, WE, McCarty, CS, Mahavley, MS,Jr, Mealey, J, Owens, G, Ransohoff, J, Robertson, JT, Shapiro, WR, Smith, KR,Jr, Wilson, CB, Strike, TA 1980Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgeryN Engl J Med30313231327PubMedGoogle Scholar
  2. 2.
    Fine, HA, Dear, KBG, Loeffler, YS, Black, PML, Canellos, GP 1993Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adultsCancer7125852597PubMedGoogle Scholar
  3. 3.
    EORTC Brain Tumor Group1978Effect of CCNU on survival rate, objective remission and duration of free interval in patients with malignant brain glioma.Final evaluation.Eur J Cancer14851856Google Scholar
  4. 4.
    Kornblith, PL, Walker, M 1998Chemotherapy for malignant gliomasJ Neurosurg68117Google Scholar
  5. 5.
    Tomita, T 1991Interstitial chemotherapy for brain tumors: reviewJ Neuro-oncol105774CrossRefGoogle Scholar
  6. 6.
    Boiardi, A, Salmaggi, A, Pozzi, A, Broggi, G, Silvani, A 1996Interstitial chemotherapy with mitoxantrone in recurrent malignant glioma: preliminary dataJ Neuro-oncol27157162CrossRefGoogle Scholar
  7. 7.
    Boiardi, A, Silvani, A, Pozzi, AL, Fariselli, L, Broggi, G, Salmaggi, G 1999Interstitial chemotherapy plus systemic chemotherapy for glioblastoma patients: improved survival in sequential studiesJ Neuro-oncol41151157CrossRefGoogle Scholar
  8. 8.
    Brem, H, Piantadossi, S, Burger, P, Walker, M, Selker, RW, Vick, NA, Black, K, Sisti, M, Brem, S, Mohr, G, Muller, P, Morawetz, R, Schold, SC 1995controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas.The Polymer-brain Tumor Treatment Group.Lancet34510081012CrossRefPubMedGoogle Scholar
  9. 9.
    Valtonen, S, Timonen, U, Toivanen, P, Kalimo, H, Kivipelto, L, Heiskanen, O, Usgaard, G, Kuurne, T 1997Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind studyNeurosurg414449CrossRefGoogle Scholar
  10. 10.
    Sipos, EP, Tyler, B, Piantadosi, S, Burger, PC, Brem, H 1997Optimizing interstitial delivery of BCNU from controlled release polymers for the treatment of brain tumorsCancer Chemother Pharmacol39383389CrossRefPubMedGoogle Scholar
  11. 11.
    Fung, LK, Ewend, MG, Sills, A, Sipos, EP, Thompson, R, Watts, M, Colvin, OM, Brem, H, Salzman, WM 1998Pharmacokinetics of interstitial delivery of carmustine 4-hydroperoxycyclophosphamide and paclitaxel from a biodegradable polymer implant in the monkey brainCancer Res58672684PubMedGoogle Scholar
  12. 12.
    Riva, P, Arista, A, Tison, V, Sturiale, C, Franceschi, G, Spinelli, A, Riva, N, Casi, M, Moscatelli, G, Frattarelli, M 1994Intralesional radioimmunotherapy of malignant gliomas.An effective treatment in recurrent tumors.Cancer7310761082PubMedGoogle Scholar
  13. 13.
    Paganelli, G, Bartolomei, M, Ferrari, M, Cremonesi, M, Broggi, G, Maira, G, Sturiale, C, Grana, C, Prisco, G, Gatti, M, Caliceti, P, Chinol, M 2001Pre-targeted locoregional radioimmunotherapy with 90Y-biotin in glioma patients: phase I study and preliminary therapeutic resultsCancer Biother Radiopharm16227235CrossRefPubMedGoogle Scholar
  14. 14.
    Akabani, G, Reist, CJ, Cokgor, I, Friedman, AH, Friedman, HS, Coleman, RE, Zhao, XG, Bigner, DD, Zalutsky, MR 1999Dosimetry of 131I-labeled 81C6 monoclonal antibody administered into surgically created resection cavities in patients with malignant brain tumorsJ Nucl Med40631638PubMedGoogle Scholar
  15. 15.
    Perego, P, Boiardi, A, Carenini, N, De Cesare, M, Dolfini, E, Giardino, R, Magnani, I, Silvani, A, Soranzo, C 1994Characterisation of an established human malignat glioblastoma cell line and its response to conventional grugsJ Cancer Res Clin Oncol120585592CrossRefPubMedGoogle Scholar
  16. 16.
    Jordan, JP, Hand, CM, Markowitz, RS, Black, P 1992Test for chemotherapeutic sensitivity of cerebral gliomas: use of colorimetric MTT assayJ Neuro-oncol141935CrossRefGoogle Scholar
  17. 17.
    Senkal, M, Tonn, JC, Schonmayr, R, Schachenmayr, W, Eickhoff, U, Kemen, M, Kollig, E 1987Mitoxantrone-induced DNA strand breaks in cell-cultures of malignant human astrocytoma and glioblastoma tumorsJ Neuro-oncol32203208CrossRefGoogle Scholar
  18. 18.
    MacDonald, DR, Cascino, TL, Clifford, S 1990Response criteria for phase II studies of supratentorial malignant gliomaJ Clin Oncol812771280PubMedGoogle Scholar
  19. 19.
    Oken, MM, Creech, RH, Tormey, DC, Horton, J, Davis, TE, McFadden, ET, Carbone, PP 1982Toxicity and response criteria of the Eastern Cooperative Oncology GroupAm J Clin Oncol5649655PubMedGoogle Scholar
  20. 20.
    Kaplan, EL, Meier, P 1958Nonparametric estimation from incomplete observationsJ Am Stat Assoc53457481Google Scholar
  21. 21.
    Huncharek, M, Muscat, J 1998Treatment of recurrent high grade astrocytoma; results of a systematic review of 1415 patientsAnticancer Res1813031312PubMedGoogle Scholar
  22. 22.
    Boiardi, A, Eoli, M, Salmaggi, A, Zappacosta, B, Fariselli, L, Milanesi, I, Broggi, G, Silvani, A 2001Efficacy of intratumoral delivery of mitoxantrone in recurrent malignant glial tumorsJ Neuro-oncol543947CrossRefGoogle Scholar
  23. 23.
    Nieder, C, Grosu, AL, Molls, M 2000A comparison of treatment results for recurrent malignant gliomasCancer Treat Rev26397409CrossRefPubMedGoogle Scholar
  24. 24.
    Brada, M, Hoang-Xuan, K, Rampling, R, Dietrich, PY, Dirix, LY, Macdonald, D, Heimans, JJ, Zonnenberg, BA, Bravo-Marques, JM, Henriksson, R, Stupp, R, Yue, N, Bruner, J, Dugan, M, Rao, S, Zaknoen, S 2001phase II trial of temozolomide in patients with glioblastoma multiforme at first relapseAnn Oncol12149150CrossRefPubMedGoogle Scholar
  25. 25.
    Brandes, AA, Ermani, M, Basso, U, Amista, P, Berti, F, Scienza, R, Rotilio, A, Pinna, G, Gardiman, M, Monfardini, S 2001Temozolomide as a second-line systemic regimen in recurrent high-grade glioma: a phase II studyAnn Oncol12149150CrossRefPubMedGoogle Scholar
  26. 26.
    Dinnes, J, Cave, C, Huang, S, Milne, R 2002A rapid and systematic review of the effectiveness of temozolomide for the treatment of recurrent malignant gliomaBr J Cancer12499500Google Scholar
  27. 27.
    Sipos, L, Vitanovics, D, Afra, D 2002Treatment of recidive malignant gliomas with temozolomideOrv Hetil14312011204PubMedGoogle Scholar
  28. 28.
    Lieberman, DM, Laske, DW, Morrison, PF, Bankiewicz, KS, Oldfield, EH 1995Convection-enhanced distribution of large molecules in gray matter during interstitial drug infusionJ Neurosurg8210211029PubMedGoogle Scholar
  29. 29.
    White, RJ, Durr, FE 1985Development of mitoxantroneInvest New Drugs38593CrossRefPubMedGoogle Scholar
  30. 30.
    Green RM, Stewart DJ, Hugenholtz H, Richard MT, Thibault M, Montpetit V: Human central nervous system and plasma pharmacology of mitoxantrone. J Neuro-oncol: 75– 83,1988Google Scholar
  31. 31.
    Stewart, DJ, Green, RM, Mikhael, NZ, Montpetit, V, Thibault, M, Maroun, JA 1986Human autopsy tissue concentration of mitoxantroneCancer Treat Rep7012551261PubMedGoogle Scholar
  32. 32.
    Broggi, G, Ferroli, P, Franzini, A, Silvani, A, Salmaggi, A, Eoli, M, Boiardi, A 2003Local delivery of mitoxantrone for the treatment of malignant brain tumors in ratsJ Neurosurg98935936PubMedGoogle Scholar
  33. 33.
    Riva, P, Arista, A, Franceschi, G, Frattarelli, M, Sturiale, C, Riva, N, Casi, M, Rossitti, R 1995Local treatment of malignant gliomas by direct infusion of specific monoclonal antibodies labeled with 131I: comparison of the results obtained in recurrent and newly diagnosed tumorsCancer Res5559525956Google Scholar
  34. 34.
    Riva, P, Franceschi, G, Riva, N, Casi, M, Santimaria, M, Adamo, M 2000Role of nuclear medicine in the treatment of malignant gliomas: the locoregional radioimmunotherapy approachEur J Nucl Med27601609CrossRefPubMedGoogle Scholar
  35. 35.
    Proske, H, Schachtschabel, DO, Paul, N, Pfab, R 1992Electron microscopic studies on the effects of irradiation and mitoxantrone alone or in combination on cells of Harding Passey melanoma in monolayer cultureStrahler Onkol168361368Google Scholar
  36. 36.
    Linassier, C, Barin, C, Calais, G, Letortorec, S, Bremond, JL, Delain, M, Petit, A, Georget, MT, Cartron, G, Raban, N, Benboubker, L, Leloup, R, Binet, C, Lamagnere, JP, Colombat, P 2000Early secondary acute myelogenous leukemia in breast cancer patients after treatment with mitoxantrone, cyclophosphamide, fluorouracil and radiation therapyAnn Oncol1112891294CrossRefPubMedGoogle Scholar
  37. 37.
    Grana, C, Chinol, M, Robertson, C, Mazzetta, C, Bartolomei, M, De Cicco, C, Fiorenza, M, Gatti, M, Caliceti, P, Paganelli, G 2002Pretargeted adjuvant radioimmunotherapy with yttrium-90-biotin in malignant glioma patients: a pilot studyBr J Cancer21207212CrossRefGoogle Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  • Amerigo Boiardi
    • 1
    Email author
  • Mirco Bartolomei
    • 4
  • Antonio Silvani
    • 1
  • Marica Eoli
    • 1
  • Andrea Salmaggi
    • 1
  • Elena Lamperti
    • 1
  • Ida Milanesi
    • 3
  • Andrea Botturi
    • 1
  • Paola Rocca
    • 4
  • Lisa Bodei
    • 4
  • Giovanni Broggi
    • 2
  • Giovanni Paganelli
    • 4
  1. 1.Department of Neuro-oncologyIstituto Nazionale Neurologico, “C. Besta”MilanItaly
  2. 2.Department of NeurosurgeryIstituto Nazionale Neurologico, “C. Besta”MilanItaly
  3. 3.Radiotherapy UnitIstituto Nazionale Neurologico, “C. Besta”MilanItaly
  4. 4.Nuclear Medicine UnitIstituto Oncologico EuropeoMilanItaly

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