Journal of Neuro-Oncology

, Volume 118, Issue 2, pp 305–312 | Cite as

Results of nimotuzumab and vinorelbine, radiation and re-irradiation for diffuse pontine glioma in childhood

  • Maura Massimino
  • Veronica Biassoni
  • Rosalba Miceli
  • Elisabetta Schiavello
  • Monika Warmuth-Metz
  • Piergiorgio Modena
  • Michela Casanova
  • Emilia Pecori
  • Felice Giangaspero
  • Manila Antonelli
  • Francesca Romana Buttarelli
  • Paolo Potepan
  • Bianca Pollo
  • Raffaele Nunziata
  • Filippo Spreafico
  • Marta Podda
  • Andrea Anichini
  • Carlo Alfredo Clerici
  • Iacopo Sardi
  • Loris De Cecco
  • Udo Bode
  • Ferdinand Bach
  • Lorenza Gandola
Clinical Study

Abstract

Radiotherapy is the only treatment definitely indicated for diffuse pontine gliomas (DIPG). Findings on the role of EGFR signaling in the onset of childhood DIPG prompted the use of nimotuzumab, an anti-EGFR monoclonal antibody. Assuming a potential synergy with both radiotherapy and vinorelbine, a pilot phase 2 protocol was launched that combined nimotuzumab with concomitant radiation and vinorelbine. An amendment in July 2011 introduced re-irradiation at relapse. The primary endpoint for first-line treatment was objective response rate (CR + PR + SD) according to the RECIST. This report concerns the outcome of this strategy as a whole. Vinorelbine 20 mg/m2 was administered weekly, with nimotuzumab 150 mg/m2 in the first 12 weeks of treatment; radiotherapy was delivered from weeks 3 to 9, for a total dose of 54 Gy. Vinorelbine 25 mg/m2 and nimotuzumab were given every other week thereafter until the tumor progressed or for up to 2 years. Re-irradiation consisted of 19.8 Gy, fractionated over 11 days. Baseline and latest MRIs were assessed blindly by an outside neuroradiologist. Twenty five children (mean age 7.4 years) were enrolled as of August 2009 (median follow-up 29 months). A response was observed in 24/25 patients (96 %). The nimotuzumab/vinorelbine combination was very well tolerated, with no acute side-effects. Eleven of 16 locally-relapsing patients were re-irradiated. One-year PFS and OS rates were 30 ± 10 % and 76 ± 9 %, respectively; 2-year OS was 27 ± 9 %; the median PFS and OS were 8.5 and 15 months, respectively. This strategy generated interesting results and warrants further investigation.

Keywords

DIPG Nimotuzumab Target therapy Anti-EGFR Re-irradiation 

Notes

Acknowledgments

This work was supported by the Associazione Bianca Garavaglia Onlus (Busto Arsizio Italy), the Fondo di Giò Onlus (Trieste, Italy), and the Associazione Italiana per la Ricerca Sul Cancro (AIRC); nimotuzumab was given on compassionate grounds by Oncoscience AG.

Conflict of interest

There are no other conflicts of interest to disclose.

References

  1. 1.
    Fischbein NJ, Prados MD, Wara W, Russo C, Edwards MS, Barkovich AJ (1996) Radiologic classification of brain stem tumors: correlation of magnetic resonance imaging appearance with clinical outcome. Pediatr Neurosurg 24:9–23PubMedCrossRefGoogle Scholar
  2. 2.
    Donaldson SS, Laningham F, Fisher PG (2006) Advances toward an understanding of brainstem gliomas. J Clin Oncol 24:1266–1272PubMedCrossRefGoogle Scholar
  3. 3.
    Massimino M, Spreafico F, Biassoni V et al (2008) Diffuse pontine gliomas in children: changing strategies, changing results? A mono-institutional 20-year experience. J Neurooncol 87:355–361PubMedCrossRefGoogle Scholar
  4. 4.
    Hargrave D, Bartels U, Bouffet E (2006) Diffuse brainstem glioma in children: critical review of clinical trials. Lancet Oncol 7:241–248PubMedCrossRefGoogle Scholar
  5. 5.
    Jansen MH, van Vuurden DG, Vandertop WP, Kaspers GJ (2012) Diffuse intrinsic pontine gliomas: a systematic update on clinical trials and biology. Cancer Treat Rev 38:27–35PubMedCrossRefGoogle Scholar
  6. 6.
    Bode U, Massimino M, Bach F et al (2012) Nimotuzumab treatment of malignant gliomas. Expert Opin Biol Ther. 12:1649–1659PubMedCrossRefGoogle Scholar
  7. 7.
    Poussaint TY, Kocak M, Vajapeyam S et al (2011) MRI as a central component of clinical trials analysis in brainstem glioma: a report from the Pediatric Brain Tumor Consortium (PBTC). Neuro Oncol 13:417–427PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Gilbertson RJ, Hill DA, Hernan R et al (2003) ERBB1 is amplified and overexpressed in high-grade diffusely infiltrative pediatric brain stem glioma. Clin Cancer Res 9:3620–3624PubMedGoogle Scholar
  9. 9.
    Zarghooni M, Bartels U, Lee E et al (2010) Whole-genome profiling of pediatric diffuse intrinsic pontine gliomas highlights platelet-derived growth factor receptor alpha and poly (ADP-ribose) polymerase as potential therapeutic targets. J Clin Oncol 28:1337–1344PubMedCrossRefGoogle Scholar
  10. 10.
    Warren KE, Killian K, Suuriniemi M, Wang Y, Quezado M, Meltzer PS (2012) Genomic aberrations in pediatric diffuse intrinsic pontine gliomas. Neuro Oncol 14:326–332PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Wu G, Broniscer A, McEachron TA et al (2012) Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 44:251–253PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Schwartzentruber J, Korshunov A, Liu XY et al (2012) Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482:226–231PubMedCrossRefGoogle Scholar
  13. 13.
    Sturm D, Witt H, Hovestadt V et al (2012) Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22:425–437PubMedCrossRefGoogle Scholar
  14. 14.
    Ballester LY, Wang Z, Shandilya S et al (2013) Morphologic characteristics and immunohistochemical profile of diffuse intrinsic pontine gliomas. Am J Surg Pathol 37:1357–1364PubMedCrossRefGoogle Scholar
  15. 15.
    Massimino M, Bode U, Biassoni V, Fleischhack G (2011) Nimotuzumab for pediatric diffuse intrinsic pontine gliomas. Expert Opin Biol Ther 11:247–256PubMedCrossRefGoogle Scholar
  16. 16.
    Dietil M. Scientifically based report on the blood–brain-barrier in malignant tumors. Expert Opinion—BBB—malignant brain tumors. BBB-09-11-16:1–9, Institute for Pathology, Charite´-University Medicine BerlinGoogle Scholar
  17. 17.
    Fichtner I, Nowak CH. Report: biodistribution of nimotuzumab in xenografetd mice. Experimental Pharmacology & Oncology, Berlin-Buch gmbh, 22 April 2010Google Scholar
  18. 18.
    Crombet Ramos T, Figueredo J, Catala S et al (2006) Treatment of high-grade glioma patients with the humanized anti-epidermal growth factor receptor (EGFR) antibody h-R3. Cancer Biol Ther 5:375–379CrossRefGoogle Scholar
  19. 19.
    Hanley ML, Elion GB, Colvin OM et al (1998) Therapeutic efficacy of vinorelbine against pediatric and adult central nervous system tumors. Cancer Chemother Pharmacol 42:479–482PubMedCrossRefGoogle Scholar
  20. 20.
    Mouchard-Delmas C, Gourdier B, Vistelle R, Wiczewski M (1995) Modification of the blood-brain barrier permeability following intracarotid infusion of vinorelbine. Anticancer Res 15:2593–2596PubMedGoogle Scholar
  21. 21.
    Binet S, Fellous A, Lataste H, Krikorian A, Couzinier JP, Meininger V (1989) In situ analysis of the action of Navelbine on various types of microtubules using immunofluorescence. Semin Oncol 16(Suppl 4):5–8PubMedGoogle Scholar
  22. 22.
    Crinò L, Cappuzzo F, Zatloukal P et al (2008) Gefitinib versus vinorelbine in chemotherapy-naive elderly patients with advanced non-small-cell lung cancer (INVITE): a randomized, phase II study. J Clin Oncol 26:4253–4260PubMedCrossRefGoogle Scholar
  23. 23.
    Depenbrock H, Shirvani A, Rastetter J, Hanauske AR (1995) Effects of vinorelbine on epidermal growth factor-receptor binding of human breast cancer cell lines in vitro. Invest New Drugs 13:187–193PubMedCrossRefGoogle Scholar
  24. 24.
    Tsai CM, Chiu CH, Chang KT et al (2012) Gefitinib enahances cytotoxicities of antimicrotubile agents in non-small cell lung cancer cells exhibiting no sensitizing epidermal growth factor mutation. J Thorac Oncol 7:1218–1227PubMedCrossRefGoogle Scholar
  25. 25.
    Fontanilla HP, Pinnix CC, Ketonen LM et al (2012) Palliative reirradiation for progressive diffuse intrinsic pontine glioma. Am J Clin Oncol 35:51–57PubMedCrossRefGoogle Scholar
  26. 26.
    Fleischhack G, Siegler N, Zimmermann M, et al (2010) Concomitant therapy of nimotuzumab and standard radiotherapy for the treatment of newly diagnosed diffuse intrinsic pontine gliomas in children and adolescents. 14th international symposium of pediatric neuro-oncology, Vienna, Austria 20–23 June 2010 [abstract]. Neurooncology 12:ii8Google Scholar
  27. 27.
    Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216PubMedCrossRefGoogle Scholar
  28. 28.
    Casanova M, Ferrari A, Spreafico F et al (2002) Vinorelbine in previously treated advanced childhood sarcomas: evidence of activity in rhabdomyosarcoma. Cancer 94:3263–3268PubMedCrossRefGoogle Scholar
  29. 29.
    Geoerger B, Hargrave D, Thomas F et al (2011) Innovative Therapies for Children with Cancer pediatric phase I study of erlotinib in brainstem glioma and relapsing/refractory brain tumors. Neuro Oncol 13:109–118PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Pollack IF, Stewart CF, Kocak M et al (2011) A phase II study of gefitinib and irradiation in children with newly diagnosed brainstem gliomas: a report from the Pediatric Brain Tumor Consortium. Neuro Oncol 13:290–297PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Broniscer A, Baker JN, Tagen M et al (2010) Phase I study of vandetanib during and after radiotherapy in children with diffuse intrinsic pontine glioma. J Clin Oncol 28:4762–4768PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Broniscer A, Baker SD, Wetmore C et al (2013) Phase I trial, pharmacokinetics, and pharmacodynamics of vandetanib and dasatinib in children with newly diagnosed diffuse intrinsic pontine glioma. Clin Cancer Res 19:3050–3058PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Lewis J, Lucraft H, Gholkar A (1997) UKCCSG study of accelerated radiotherapy for paediatric brain stem gliomas. United Kingdom Childhood Cancer Study Group. Int J Radiat Oncol Biol Phys 38:925–929PubMedCrossRefGoogle Scholar
  34. 34.
    Janssens GO, Jansen MH, Lauwers SJ et al (2009) The role of hypofractionation radiotherapy for diffuse intrinsic brainstem glioma in children: a pilot study. Int J Radiat Oncol Biol Phys 73:722–726PubMedCrossRefGoogle Scholar
  35. 35.
    Negretti L, Bouchireb K, Levy-Piedbois C et al (2011) Hypofractionated radiotherapy in the treatment of diffuse intrinsic pontine glioma in children: a single institution’s experience. J Neurooncol 104:773–777PubMedCrossRefGoogle Scholar
  36. 36.
    Sedlacik J, Winchell A, Kocak M, Loeffler RB, Broniscer A, Hillenbrand CM (2013) MR Imaging assessment of tumor perfusion and 3D segmented volume at baseline, during treatment, and at tumor progression in children with newly diagnosed diffuse intrinsic pontine glioma. Am J Neuroradiol 34:1450–1455PubMedCrossRefGoogle Scholar
  37. 37.
    Broniscer A, Laningham FH, Sanders RP, Kun LE, Ellison DW, Gajjar A (2008) Young age may predict a better outcome for children with diffuse pontine glioma. Cancer 113:566–572PubMedCrossRefGoogle Scholar
  38. 38.
    Wolff JE, Rytting ME, Vats TS, Zage PE, Ater JL, Woo S et al (2012) Treatment of recurrent diffuse intrinsic pontine glioma: the MD Anderson Cancer Center experience. J Neurooncol 106:391–397PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Maura Massimino
    • 1
  • Veronica Biassoni
    • 1
  • Rosalba Miceli
    • 2
  • Elisabetta Schiavello
    • 1
  • Monika Warmuth-Metz
    • 8
  • Piergiorgio Modena
    • 9
  • Michela Casanova
    • 1
  • Emilia Pecori
    • 3
  • Felice Giangaspero
    • 10
  • Manila Antonelli
    • 10
  • Francesca Romana Buttarelli
    • 11
  • Paolo Potepan
    • 4
  • Bianca Pollo
    • 12
  • Raffaele Nunziata
    • 12
  • Filippo Spreafico
    • 1
  • Marta Podda
    • 1
  • Andrea Anichini
    • 5
  • Carlo Alfredo Clerici
    • 1
    • 7
  • Iacopo Sardi
    • 13
  • Loris De Cecco
    • 6
  • Udo Bode
    • 14
  • Ferdinand Bach
    • 15
  • Lorenza Gandola
    • 3
  1. 1.Pediatric UnitFondazione IRCCS Istituto Nazionale dei Tumori (INT)MilanoItaly
  2. 2.Medical Statistics, Biometry and Bioinformatics UnitFondazione IRCCS Istituto Nazionale dei Tumori (INT)MilanoItaly
  3. 3.Radiotherapy UnitFondazione IRCCS Istituto Nazionale dei Tumori (INT)MilanoItaly
  4. 4.Radiology UnitFondazione IRCCS Istituto Nazionale dei Tumori (INT)MilanoItaly
  5. 5.Human Tumor Immunobiology UnitFondazione IRCCS Istituto Nazionale dei Tumori (INT)MilanoItaly
  6. 6.Molecular Therapies UnitFondazione IRCCS Istituto Nazionale dei Tumori (INT)MilanoItaly
  7. 7.Physiopathology DepartmentState Medical SchoolMilanoItaly
  8. 8.Department of NeuroradiologyUniversity of WürzburgWurzburgGermany
  9. 9.Genetics Unit, Pathology DepartmentOspedale S. AnnaComoItaly
  10. 10.Radiological and Oncological Sciences DepartmentUniversita` SapienzaRomaItaly
  11. 11.Pathology DepartmentUniversita` SapienzaRomaItaly
  12. 12.Neuropathology UnitIRCCS Istituto Neurologico Carlo BestaMilanoItaly
  13. 13.Neuro-Oncology UnitOspedale MeyerFirenzeItaly
  14. 14.Department of Pediatric Hematology/OncologyUniversity of Bonn Medical SchoolBonnGermany
  15. 15.Oncoscience AGWedelGermany

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