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Response to bevacizumab, irinotecan, and temozolomide in children with relapsed medulloblastoma: a multi-institutional experience

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Abstract

Purpose

Chemotherapy for relapsed medulloblastoma has been inadequate, and most patients succumb to disease.

Methods

We retrospectively reviewed nine cases of relapsed medulloblastoma treated with bevacizumab, irinotecan, ± temozolomide. Patients received one to three prior therapeutic regimens. Five patients received 10 mg/kg bevacizumab and 125–150 mg/m2 irinotecan IV every 2 weeks, with temozolomide, starting at a median dose of 150 mg/m2 orally for 5 days monthly. Two patients received bevacizumab and irinotecan, but not temozolomide, due to provider preference. Two of nine patients received 15 mg/kg bevacizumab IV, 90 mg/m2 irinotecan orally for five consecutive days, 100 mg/m2/day temozolomide IV for 5 days, and 1.5 mg/m2 vincristine IV, each administered every 21 days.

Results

Median time to progression was 11 months. Median overall survival was 13 months. Objective tumor response at 3 months was 67 %, including six patients with partial response (PR) and three patients with stable disease (SD). At 6 months, objective response was 55 %, with two patients with PR and three with complete response. Additionally, one patient had SD and three had PD. Two patients remain alive and progression free at 15 and 55 months; another is alive with disease at 20 months. Toxicities included two patients with grade III neutropenia, two with grade III thrombocytopenia, one with grade III elevation of liver function tests, and one patient with grade III diarrhea.

Conclusions

The combination of bevacizumab and irinotecan, with or without temozolomide, produces objective responses with minimal toxicity in children with recurrent medulloblastoma. Prospective clinical trials are needed to evaluate the efficacy of this strategy.

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References

  1. Packer RJ, Gajjar A, Vezina G, Rorke-Adams L, Burger PC, Robertson PL, Bayer L, LaFond D, Donahue BR, Marymont MH, Muraszko K, Langston J, Sposto R (2006) Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol 24:4202–4208

    Article  PubMed  CAS  Google Scholar 

  2. Torres CF, Rebsamen S, Silber JH, Sutton LN, Bilaniuk LT, Zimmerman RA, Goldwein JW, Phillips PC, Lange BJ (1994) Surveillance scanning of children with medulloblastoma. N Engl J Med 330:892–895

    Article  PubMed  CAS  Google Scholar 

  3. Chang CH, Housepian EM, Herbert C Jr (1969) An operative staging system and a megavoltage radiotherapeutic technic for cerebellar medulloblastomas. Radiology 93:1351–1359

    PubMed  CAS  Google Scholar 

  4. Evans AE, Jenkin RD, Sposto R, Ortega JA, Wilson CB, Wara W, Ertel IJ, Kramer S, Chang CH, Leikin SL et al (1990) The treatment of medulloblastoma. Results of a prospective randomized trial of radiation therapy with and without CCNU, vincristine, and prednisone. J Neurosurg 72:572–582

    Article  PubMed  CAS  Google Scholar 

  5. Zeltzer PM, Boyett JM, Finlay JL, Albright AL, Rorke LB, Milstein JM, Allen JC, Stevens KR, Stanley P, Li H, Wisoff JH, Geyer JR, McGuire-Cullen P, Stehbens JA, Shurin SB, Packer RJ (1999) Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children’s Cancer Group 921 randomized phase III study. J Clin Oncol 17:832–845

    PubMed  CAS  Google Scholar 

  6. Eberhart CG, Kepner JL, Goldthwaite PT, Kun LE, Duffner PK, Friedman HS, Strother DR, Burger PC (2002) Histopathologic grading of medulloblastomas: a pediatric oncology group study. Cancer 94:552–560

    Article  PubMed  Google Scholar 

  7. Pan E, Pellarin M, Holmes E, Smirnov I, Misra A, Eberhart CG, Burger PC, Biegel JA, Feuerstein BG (2005) Isochromosome 17q is a negative prognostic factor in poor-risk childhood medulloblastoma patients. Clin Cancer Res 11:4733–4740

    Article  PubMed  CAS  Google Scholar 

  8. Rossi MR, Conroy J, McQuaid D, Nowak NJ, Rutka JT, Cowell JK (2006) Array CGH analysis of pediatric medulloblastomas. Genes Chromosome Cancer 45:290–303

    Article  CAS  Google Scholar 

  9. Yao MS, Mehta MP, Boyett JM, Li H, Donahue B, Rorke LB, Zeltzer PM (1997) The effect of M-stage on patterns of failure in posterior fossa primitive neuroectodermal tumors treated on CCG-921: a phase III study in a high-risk patient population. Int J Radiat Oncol Biol Phys 38:469–476

    Article  PubMed  CAS  Google Scholar 

  10. Bowers DC, Gargan L, Weprin BE, Mulne AF, Elterman RD, Munoz L, Giller CA, Winick NJ (2007) Impact of site of tumor recurrence upon survival for children with recurrent or progressive medulloblastoma. J Neurosurg 107:5–10

    PubMed  Google Scholar 

  11. Bakst RL, Dunkel IJ, Gilheeney S, Khakoo Y, Becher O, Souweidane MM, Wolden SL (2011) Reirradiation for recurrent medulloblastoma. Cancer 117(21):4977–4982

    Article  PubMed  Google Scholar 

  12. Dunkel IJ, Gardner SL, Garvin JH Jr, Goldman S, Shi W, Finlay JL (2010) High-dose carboplatin, thiotepa, and etoposide with autologous stem cell rescue for patients with previously irradiated recurrent medulloblastoma. Neuro Oncol 12:297–303

    Article  PubMed  CAS  Google Scholar 

  13. Aguilera DG, Goldman S, Fangusaro J (2011) Bevacizumab and irinotecan in the treatment of children with recurrent/refractory medulloblastoma. Pediatr Blood Cancer 56:491–494

    Article  PubMed  Google Scholar 

  14. Milker-Zabel S, Zabel A, Thilmann C, Zuna I, Hoess A, Wannenmacher M, Debus J (2002) Results of three-dimensional stereotactically-guided radiotherapy in recurrent medulloblastoma. J Neurooncol 60:227–233

    Article  PubMed  Google Scholar 

  15. Bauman GS, Sneed PK, Wara WM, Stalpers LJ, Chang SM, McDermott MW, Gutin PH, Larson DA (1996) Reirradiation of primary CNS tumors. Int J Radiat Oncol Biol Phys 36:433–441

    Article  PubMed  CAS  Google Scholar 

  16. Ashley DM, Meier L, Kerby T, Zalduondo FM, Friedman HS, Gajjar A, Kun L, Duffner PK, Smith S, Longee D (1996) Response of recurrent medulloblastoma to low-dose oral etoposide. J Clin Oncol 14:1922–1927

    PubMed  CAS  Google Scholar 

  17. Chamberlain MC, Kormanik PA (1997) Chronic oral VP-16 for recurrent medulloblastoma. Pediatr Neurol 17:230–234

    Article  PubMed  CAS  Google Scholar 

  18. Gajjar A, Pizer B (2010) Role of high-dose chemotherapy for recurrent medulloblastoma and other CNS primitive neuroectodermal tumors. Pediatr Blood Cancer 54:649–651

    Article  PubMed  Google Scholar 

  19. Finlay JL, Goldman S, Wong MC, Cairo M, Garvin J, August C, Cohen BH, Stanley P, Zimmerman RA, Bostrom B, Geyer JR, Harris RE, Sanders J, Yates AJ, Boyett JM, Packer RJ (1996) Pilot study of high-dose thiotepa and etoposide with autologous bone marrow rescue in children and young adults with recurrent CNS tumors. The Children’s Cancer Group. J Clin Oncol 14:2495–2503

    PubMed  CAS  Google Scholar 

  20. Dunkel IJ, Boyett JM, Yates A, Rosenblum M, Garvin JH Jr, Bostrom BC, Goldman S, Sender LS, Gardner SL, Li H, Allen JC, Finlay JL (1998) High-dose carboplatin, thiotepa, and etoposide with autologous stem-cell rescue for patients with recurrent medulloblastoma. Children’s Cancer Group. J Clin Oncol 16:222–228

    PubMed  CAS  Google Scholar 

  21. Nicholson HS, Kretschmar CS, Krailo M, Bernstein M, Kadota R, Fort D, Friedman H, Harris MB, Tedeschi-Blok N, Mazewski C, Sato J, Reaman GH (2007) Phase 2 study of temozolomide in children and adolescents with recurrent central nervous system tumors: a report from the Children’s Oncology Group. Cancer 110:1542–1550

    Article  PubMed  CAS  Google Scholar 

  22. Wang CH, Hsu TR, Wong TT, Chang KP (2009) Efficacy of temozolomide for recurrent embryonal brain tumors in children. Childs Nerv Syst 25:535–541

    Article  PubMed  Google Scholar 

  23. Ruggiero A, Rizzo D, Attina G, Lazzareschi I, Mastrangelo S, Maurizi P, Migliorati R, Bertolini P, Pastore M, Colosimo C, Riccardi R (2010) Phase I study of temozolomide combined with oral etoposide in children with recurrent or progressive medulloblastoma. Eur J Cancer 46:2943–2949

    Article  PubMed  CAS  Google Scholar 

  24. Vassal G, Boland I, Santos A, Bissery MC, Terrier-Lacombe MJ, Morizet J, Sainte-Rose C, Lellouch-Tubiana A, Kalifa C, Gouyette A (1997) Potent therapeutic activity of irinotecan (CPT-11) and its schedule dependency in medulloblastoma xenografts in nude mice. Int J Cancer 73:156–163

    Article  PubMed  CAS  Google Scholar 

  25. Turner CD, Gururangan S, Eastwood J, Bottom K, Watral M, Beason R, McLendon RE, Friedman AH, Tourt-Uhlig S, Miller LL, Friedman HS (2002) Phase II study of irinotecan (CPT-11) in children with high-risk malignant brain tumors: the duke experience. Neuro Oncol 4:102–108

    PubMed  CAS  Google Scholar 

  26. Bomgaars LR, Bernstein M, Krailo M, Kadota R, Das S, Chen Z, Adamson PC, Blaney SM (2007) Phase II trial of irinotecan in children with refractory solid tumors: a Children’s Oncology Group Study. J Clin Oncol 25:4622–4627

    Article  PubMed  CAS  Google Scholar 

  27. Gajjar AJ, Stewart CF, Ellison DW, Curran T, Phillips P, Goldman S, Packer R, Kun LE, Boyett JM, Gilbertson RJ (2010 (suppl; abstr CRA9501)) A phase I pharmacokinetic trial of sonic hedgehog (SHH) antagonist GDC-0449 in pediatric patients with recurrent of refractory medulloblastoma: A Pediatric Brain Tumor Consortium study (PBTC 25). J Clin Oncol 28

  28. Li VW, Folkerth RD, Watanabe H, Yu C, Rupnick M, Barnes P, Scott RM, Black PM, Sallan SE, Folkman J (1994) Microvessel count and cerebrospinal fluid basic fibroblast growth factor in children with brain tumours. Lancet 344:82–86

    Article  PubMed  CAS  Google Scholar 

  29. Grotzer MA, Wiewrodt R, Janss AJ, Zhao H, Cnaan A, Sutton LN, Rorke LB, Phillips PC (2001) High microvessel density in primitive neuroectodermal brain tumors of childhood. Neuropediatrics 32:75–79

    Article  PubMed  CAS  Google Scholar 

  30. Huber H, Eggert A, Janss AJ, Wiewrodt R, Zhao H, Sutton LN, Rorke LB, Phillips PC, Grotzer MA (2001) Angiogenic profile of childhood primitive neuroectodermal brain tumours/medulloblastomas. Eur J Cancer 37:2064–2072

    Article  PubMed  CAS  Google Scholar 

  31. Castellino RC, Barwick BG, Schniederjan M, Buss MC, Becher O, Hambardzumyan D, Macdonald TJ, Brat DJ, Durden DL (2010) Heterozygosity for pten promotes tumorigenesis in a mouse model of medulloblastoma. PLoS One 5:e10849

    Article  PubMed  Google Scholar 

  32. Cohen MH, Shen YL, Keegan P, Pazdur R (2009) FDA drug approval summary: bevacizumab (avastin) as treatment of recurrent glioblastoma multiforme. Oncologist 14:1131–1138

    Article  PubMed  CAS  Google Scholar 

  33. Privitera G, Acquaviva G, Ettorre GC, Spatola C (2009) Antiangiogenic therapy in the treatment of recurrent medulloblastoma in the adult: case report and review of the literature. J Oncol 2009:247873

    Article  PubMed  Google Scholar 

  34. Kieran MW, Turner CD, Rubin JB, Chi SN, Zimmerman MA, Chordas C, Klement G, Laforme A, Gordon A, Thomas A, Neuberg D, Browder T, Folkman J (2005) A feasibility trial of antiangiogenic (metronomic) chemotherapy in pediatric patients with recurrent or progressive cancer. J Pediatr Hematol Oncol 27:573–581

    Article  PubMed  Google Scholar 

  35. Choi LM, Rood B, Kamani N, La Fond D, Packer RJ, Santi MR, Macdonald TJ (2008) Feasibility of metronomic maintenance chemotherapy following high-dose chemotherapy for malignant central nervous system tumors. Pediatr Blood Cancer 50:970–975

    Article  PubMed  Google Scholar 

  36. Peyrl A, Chocholous M, Kieran MW, Azizi AA, Prucker C, Czech T, Dieckmann K, Schmook MT, Haberler C, Leiss U, Slavc I (2012) Antiangiogenic metronomic therapy for children with recurrent embryonal brain tumors. Pediatr Blood Cancer 59:511–517

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from St. Baldrick’s Foundation (R.C.C.), CURE Childhood Cancer Foundation (R.C.C.), Southeastern Brain Tumor Foundation (R.C.C.), and the Emory Egleston Children’s Research Center (R.C.C.)

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Authors and Affiliations

  1. Aflac Cancer & Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University School of Medicine, 5455 Meridian Mark Rd., N.E., Suite 400, Atlanta, GA, 30342, USA

    Dolly Aguilera & Claire Mazewski

  2. Department of Hematology/Oncology/Stem Cell Transplantation, Ann and Robert H. Lurie Children’s Hospital of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60614, USA

    Jason Fangusaro

  3. Aflac Cancer & Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University School of Medicine, 2015 Uppergate Drive, N.E., Room 442, Atlanta, GA, 30322, USA

    Tobey J. MacDonald

  4. Pediatric Hematology/Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA

    Rene Y. McNall-Knapp

  5. Department of Radiology, Children’s Healthcare of Atlanta, Atlanta, GA, 30342, USA

    Laura L. Hayes

  6. Biostatistics & Bioinformatics Shared Resource, Winship Cancer Institute, Emory University, Atlanta, GA, 30322, USA

    Sungjin Kim

  7. Aflac Cancer & Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University School of Medicine, 2015 Uppergate Drive, N.E., Room 426H, Atlanta, GA, 30322, USA

    Robert C. Castellino

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  1. Dolly Aguilera
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Correspondence to Robert C. Castellino.

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Aguilera, D., Mazewski, C., Fangusaro, J. et al. Response to bevacizumab, irinotecan, and temozolomide in children with relapsed medulloblastoma: a multi-institutional experience. Childs Nerv Syst 29, 589–596 (2013). https://doi.org/10.1007/s00381-012-2013-4

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  • DOI: https://doi.org/10.1007/s00381-012-2013-4

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