Pediatric Drugs

, Volume 13, Issue 4, pp 245–255

Pharmacologic Management of High-Risk Neuroblastoma in Children

Review Article

Abstract

Neuroblastoma is the most common extracranial solid tumor of childhood. It accounts for 15% of pediatric cancer deaths. Children with high-risk disease have a 3-year event-free survival rate of only 20%. Chemotherapy is the mainstay of treatment in children with advanced neuroblastoma.

The aim of this article was to review and critically evaluate the pharmacotherapy of neuroblastoma, using peer reviewed and review literature from 2000–11. All peer reviewed, published human subject studies of therapy for neuroblastoma in children were included. Animal model and in vitro studies were included only if they added to the understanding of the mechanism of a proposed or existing human neuroblastoma therapy.

Current therapeutic options for neuroblastoma involve insufficient differentiation of normal from neoplastic tissue. Critically needed new approaches will increasingly exploit targeting of therapy for unique characteristics of the neuroblastoma cell. Pharmacotherapy for neuroblastoma still suffers from an inadequate therapeutic window. Enhancement of toxicity for tumor and safety for normal tissues will entail innovation in targeting neuroblastoma cells and rescuing or protecting normal tissue elements.

References

  1. 1.
    van Noesel MM, Versteeg R. Pediatric neuroblastomas: genetic and epigenetic ‘danse macabre’. Gene 2004 Jan 21; 325: 1–15PubMedCrossRefGoogle Scholar
  2. 2.
    Bowen KA, Chung DH. Recent advances in neuroblastoma. Curr Opin Pediatr 2009 Jun; 21(3): 350–6PubMedCrossRefGoogle Scholar
  3. 3.
    Wagner LM, Danks MK. New therapeutic targets for the treatment of highrisk neuroblastoma. J Cell Biochem 2009 May 1; 107(1): 46–57PubMedCrossRefGoogle Scholar
  4. 4.
    Janoueix-Lerosey I, Schleiermacher G, Delattre O. Molecular pathogenesis of peripheral neuroblastic tumors. Oncogene 2010 Mar 18; 29(11): 1566–79PubMedCrossRefGoogle Scholar
  5. 5.
    Park JR, Eggert A, Caron H. Neuroblastoma: biology, prognosis, and treatment. Pediatr Clin North Am 2008 Feb; 55(1): 97–120PubMedCrossRefGoogle Scholar
  6. 6.
    Maris JM, Hogarty MD, Bagatell R, et al. Neuroblastoma. Lancet 2007 Jun 23; 369(9579): 2106–20PubMedCrossRefGoogle Scholar
  7. 7.
    Mazur KA. Neuroblastoma: what the nurse practitioner should know. J Am Acad Nurse Pract 2010 May; 22(5): 236–45PubMedCrossRefGoogle Scholar
  8. 8.
    Bown N, Cotterill S, Lastowska M, et al. Gain of chromosome arm 17q and adverse outcome in patients with neuroblastoma. N Engl J Med 1999 Jun 24; 340(25): 1954–61PubMedCrossRefGoogle Scholar
  9. 9.
    Yalçin B, Kremer LC, Caron HN, et al. High-dose chemotherapy and autologous haematopoietic stem cell rescue for children with high-risk neuroblastoma. Cochrane Database Syst Rev 2010 May 12; (5): CD006301Google Scholar
  10. 10.
    Vermeulen J, De Preter K, Mestdagh P, et al. Predicting outcomes for children with neuroblastoma. Discov Med 2010 Jul; 10(50): 29–36PubMedGoogle Scholar
  11. 11.
    Kurt BA, Armstrong GT, Cash DK, et al. Primary care management of the childhood cancer survivor. J Pediatr 2008 Apr; 152(4): 458–66PubMedCrossRefGoogle Scholar
  12. 12.
    De Bernardi B, Pianca C, Pistamiglio P, et al. Neuroblastoma with symptomatic spinal cord compression at diagnosis: treatment and results with 76 cases. J Clin Oncol 2001 Jan; 19(1): 183–90PubMedGoogle Scholar
  13. 13.
    Burke MJ, Cohn SL. Rituximab for treatment of opsoclonus-myoclonus syndrome in neuroblastoma. Pediatr Blood Cancer 2008 Mar; 50(3): 679–80PubMedCrossRefGoogle Scholar
  14. 14.
    Gorman MP. Update on diagnosis, treatment, and prognosis in opsoclonus-myoclonus-ataxia syndrome. Curr Opin Pediatr. Epub 2010 Sep 30Google Scholar
  15. 15.
    Modak S, Cheung NK. Neuroblastoma: Therapeutic strategies for a clinical enigma. Cancer Treat Rev 2010 Jun; 36(4): 307–17PubMedCrossRefGoogle Scholar
  16. 16.
    Mullassery D, Dominici C, Jesudason EC, et al. Neuroblastoma: contemporary management. Arch Dis Child Educ Pract Ed 2009 Dec; 94(6): 177–85PubMedCrossRefGoogle Scholar
  17. 17.
    Schor NF. Neuroblastoma as a neurobiological disease. J Neuro Oncol 1999; 41: 159–66CrossRefGoogle Scholar
  18. 18.
    Dole M, Nunez G, Merchant AK, et al. Bcl-2 inhibits chemotherapy-induced apoptosis in neuroblastoma. Cancer Res 1994 Jun 15; 54(12): 3253–9PubMedGoogle Scholar
  19. 19.
    National Cancer Institute. Cixutumumab in treating patients with relapsed or refractory solid tumors [ClinicalTrials.gov identifier NCT00831844]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov/ct2/show/NCT00831844 [Accessed 2011 May 12]
  20. 20.
    Ishola TA, Chung DH. Neuroblastoma. Surg Oncol 2007 Nov; 16(3): 149–56PubMedCrossRefGoogle Scholar
  21. 21.
    Barrett JA, Joyal JL, Hillier SM, et al. Comparison of high-specific-activity ultratrace 123/131I-MIBG and carrier-added 123/131I-MIBG on efficacy, pharmacokinetics, and tissue distribution. Cancer Biother Radiopharm 2010 Jun; 25(3): 299–308PubMedCrossRefGoogle Scholar
  22. 22.
    Matthay KK, Villablanca JG, Seeger RC, et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children’s Cancer Group. N Engl J Med 1999 Oct 14; 341(16): 1165–73PubMedCrossRefGoogle Scholar
  23. 23.
    Matthay KK, Tan JC, Villablanca JG, et al. Phase I dose escalation of iodine-131-metaiodobenzylguanidine with myeloablative chemotherapy and autologous stem-cell transplantation in refractory neuroblastoma: a new approaches to Neuroblastoma Therapy Consortium Study. J Clin Oncol 2006 Jan 20; 24(3): 500–6PubMedCrossRefGoogle Scholar
  24. 24.
    Matthay KK, O’Leary MC, Ramsay NK, et al. Role of myeloablative therapy in improved outcome for high risk neuroblastoma: review of recent Children’s Cancer Group results. Eur J Cancer 1995; 31A(4): 572–5PubMedCrossRefGoogle Scholar
  25. 25.
    Matthay KK, Reynolds CP, Seeger RC, et al. Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a Children’s Oncology Group study. J Clin Oncol 2009 Mar 1; 27(7): 1007–13PubMedCrossRefGoogle Scholar
  26. 26.
    Hakomori S. Tumor-associated carbohydrate antigens defining tumor malignancy: basis for development of anti-cancer vaccines. Adv Exp Med Biol 2001; 491: 369–402PubMedCrossRefGoogle Scholar
  27. 27.
    Cheung NK, Modak S. Oral (1–>3),(1–>4)-beta-D-glucan synergizes with antiganglioside GD2 monoclonal antibody 3F8 in the therapy of neuroblastoma. Clin Cancer Res 2002 May; 8(5): 1217–23PubMedGoogle Scholar
  28. 28.
    Freemantle SJ, Spinella MJ, Dmitrovsky E. Retinoids in cancer therapy and chemoprevention: promise meets resistance. Oncogene 2003 Oct 20; 22(47): 7305–15PubMedCrossRefGoogle Scholar
  29. 29.
    Linney E. Retinoic acid receptors: transcription factors modulating gene regulation, development, and differentiation. Curr Top Dev Biol 1992; 27: 309–50PubMedCrossRefGoogle Scholar
  30. 30.
    Garaventa A, Luksch R, Lo Piccolo MS, et al. Phase I trial and pharmacokinetics of fenretinide in children with neuroblastoma. Clin Cancer Res 2003 Jun; 9(6): 2032–9PubMedGoogle Scholar
  31. 31.
    Di Francesco AM, Meco D, Torella AR, et al. The novel atypical retinoid ST1926 is active in ATRA resistant neuroblastoma cells acting by a different mechanism. Biochem Pharmacol 2007 Mar 1; 73(5): 643–55PubMedCrossRefGoogle Scholar
  32. 32.
    Fouladi M, Park JR, Stewart CF, et al. Pediatric phase I trial and pharmacokinetic study of vorinostat: a Children’s Oncology Group phase I consortium report. J Clin Oncol 2010 Aug 1; 28(22): 3623–9PubMedCrossRefGoogle Scholar
  33. 33.
    Natale RB. Dual targeting of the vascular endothelial growth factor receptor and epidermal growth factor receptor pathways with vandetinib (ZD6474) in patients with advanced or metastatic non-small cell lung cancer. J Thorac Oncol 2008 Jun; 3 (6 Suppl. 2): S128–30PubMedCrossRefGoogle Scholar
  34. 34.
    Ganeshan VR, Schor NF. Role of p75NTR and its signaling pathways in fenretinide-induced apoptosis in neuroblastoma cells. Neurology 2011 Mar 1; 76Suppl. 4: A295Google Scholar
  35. 35.
    Cuperus R, Leen R, Tytgat GA, et al. Fenretinide induces mitochondrial ROS and inhibits the mitochondrial respiratory chain in neuroblastoma. Cell Mol Life Sci 2010 Mar; 67(5): 807–16PubMedCrossRefGoogle Scholar
  36. 36.
    Lovat PE, Corazzari M, Goranov B, et al. Molecular mechanisms of fenretinide-induced apoptosis of neuroblastoma cells. Ann N Y Acad Sci 2004 Dec; 1028: 81–9PubMedCrossRefGoogle Scholar
  37. 37.
    Wagner LM, Villablanca JG, Stewart CF, et al. Phase I trial of oral irinotecan and temozolomide for children with relapsed high-risk neuroblastoma: a new approach to neuroblastoma therapy consortium study. J Clin Oncol 2009 Mar 10; 27(8): 1290–6PubMedCrossRefGoogle Scholar
  38. 38.
    Meany HJ, Sackett DL, Maris JM, et al. Clinical outcome in children with recurrent neuroblastoma treated with ABT-751 and effect of ABT-751 on proliferation of neuroblastoma cell lines and on tubulin polymerization in vitro. Pediatr Blood Cancer 2010; 54: 47–54PubMedCrossRefGoogle Scholar
  39. 39.
    Gautschi O, Heighway J, Mack PC, et al. Aurora kinases as anticancer drug targets. Clin Cancer Res 2008 Mar 15; 14(6): 1639–48PubMedCrossRefGoogle Scholar
  40. 40.
    Maris JM, Morton CL, Gorlick R, et al. Initial testing of the aurora kinase A inhibitor MLN8237 by the Pediatric Preclinical Testing Program (PPTP). Pediatr Blood Cancer 2010 Jul 15; 55(1): 26–34PubMedGoogle Scholar
  41. 41.
    Hamner JB, Dickson PV, Sims TL, et al. Bortezomib inhibits angiogenesis and reduces tumor burden in a murine model of neuroblastoma. Surgery 2007 Aug; 142(2): 185–91PubMedCrossRefGoogle Scholar
  42. 42.
    Combaret V, Boyault S, Iacono I, et al. Effect of bortezomib on human neuroblastoma: analysis of molecular mechanisms involved in cytotoxicity. Mol Cancer 2008 Jun 5; 7: 50PubMedCrossRefGoogle Scholar
  43. 43.
    Brignole C, Marimpietri D, Pastorino F, et al. Effect of bortezomib on human neuroblastoma cell growth, apoptosis, and angiogenesis. J Natl Cancer Inst 2006 Aug 16; 98(16): 1142–57PubMedCrossRefGoogle Scholar
  44. 44.
    Schramm A, Schulte JH, Astrahantseff K, et al. Biological effects of TrkA and TrkB receptor signaling in neuroblastoma. Cancer Lett 2005 Oct 18; 228(1–2): 143–53PubMedCrossRefGoogle Scholar
  45. 45.
    Evans AE, Kisselbach KD, Liu X, et al. Effect of CEP-751 (KT-6587) on neuroblastoma xenografts expressing TrkB. Med Pediatr Oncol 2001 Jan; 36(1): 181–4PubMedCrossRefGoogle Scholar
  46. 46.
    Evans AE, Kisselbach KD, Yamashiro DJ, et al. Antitumor activity of CEP-751 (KT-6587) on human neuroblastoma and medulloblastoma xenografts. Clin Cancer Res 1999 Nov; 5(11): 3594–602PubMedGoogle Scholar
  47. 47.
    Iyer R, Evans AE, Qi X, et al. Lestaurtinib enhances the antitumor efficacy of chemotherapy in murine xenograft models of neuroblastoma. Clin Cancer Res 2010 Mar 1; 16(5): 1478–85PubMedCrossRefGoogle Scholar
  48. 48.
    Norris RE, Minturn JE, Brodeur GM, et al. Preclinical evaluation of lestaurtinib (CEP-701) in combination with retinoids for neuroblastoma. Cancer Chemother Pharmacol. Epub 2011 Apr 12Google Scholar
  49. 49.
    Minturn JE, Evans AE, Villablanca JG, et al. Phase I trial of lestaurtinib for children with refractory neuroblastoma: a New Approaches to Neuroblastoma Therapy Consortium study. Cancer Chemother Pharmacol. Epub 2011 Feb 22Google Scholar
  50. 50.
    Ho R, Minturn JE, Hishiki T, et al. Proliferation of human neuroblastomas mediated by the epidermal growth factor receptor. Cancer Res 2005 Nov 1; 65(21): 9868–75PubMedCrossRefGoogle Scholar
  51. 51.
    Beppu K, Jaboine J, Merchant MS, et al. Effect of imatinib mesylate on neuroblastoma tumorigenesis and vascular endothelial growth factor expression. J Natl Cancer Inst 2004 Jan 7; 96(1): 46–55PubMedCrossRefGoogle Scholar
  52. 52.
    Vitali R, Cesi V, Nicotra MR, et al. c-Kit is preferentially expressed in MYCN-amplified neuroblastoma and its effect on cell proliferation is inhibited in vitro by STI-571. Int J Cancer 2003 Aug 20; 106(2): 147–52PubMedCrossRefGoogle Scholar
  53. 53.
    Bassili M, Birman E, Schor NF, et al. Differential roles of Trk and p75 neurotrophin receptors in tumorigenesis and chemoresistance ex vivo and in vivo. Cancer Chemother Pharmacol 2010 May; 65(6): 1047–56PubMedCrossRefGoogle Scholar
  54. 54.
    Fritz MD, Mirnics ZK, Nylander KD, et al. p75NTR enhances PC12 cell tumor growth by a non-receptor mechanism involving downregulation of cyclin D2. Exp Cell Res 2006 Oct 15; 312(17): 3287–97PubMedCrossRefGoogle Scholar
  55. 55.
    Mi Z, Rogers DA, Mirnics ZK, et al. p75NTR-dependent modulation of cellular handling of reactive oxygen species. J Neurochem 2009 Jul; 110(1): 295–306PubMedCrossRefGoogle Scholar
  56. 56.
    Tyurina YY, Nylander KD, Mirnics ZK, et al. The intracellular domain of p75NTR as a determinant of cellular reducing potential and response to oxidant stress. Aging Cell 2005 Aug; 4(4): 187–96PubMedCrossRefGoogle Scholar
  57. 57.
    Yan C, Liang Y, Nylander KD, et al. TrkA as a life and death receptor: receptor dose as a mediator of function. Cancer Res 2002 Sep 1; 62(17): 4867–75PubMedGoogle Scholar
  58. 58.
    Yan C, Liang Y, Nylander KD, et al. p75-nerve growth factor as an antiapoptotic complex: independence versus cooperativity in protection from enediyne chemotherapeutic agents. Mol Pharmacol 2002 Apr; 61(4): 710–9PubMedCrossRefGoogle Scholar
  59. 59.
    Cortazzo M, Schor NF. Potentiation of enediyne-induced apoptosis and differentiation by Bcl-2. Cancer Res 1996 Mar 15; 56(6): 1199–203PubMedGoogle Scholar
  60. 60.
    Liang Y, Nylander KD, Yan C, et al. Role of caspase 3-dependent Bcl-2 cleavage in potentiation of apoptosis by Bcl-2. Mol Pharmacol 2002 Jan; 61(1): 142–9PubMedCrossRefGoogle Scholar
  61. 61.
    Mi Z, Hong B, Mirnics ZK, et al. Bcl-2-mediated potentiation of neocarzinostatininduced apoptosis: requirement for caspase-3, sulfhydryl groups, and cleavable Bcl-2. Cancer Chemother Pharmacol 2006 Feb; 57(3): 357–67PubMedCrossRefGoogle Scholar
  62. 62.
    Rogers D, Nylander KD, Mi Z, et al. Molecular predictors of human nervous system cancer responsiveness to enediyne chemotherapy. Cancer Chemother Pharmacol 2008 Sep; 62(4): 699–706PubMedCrossRefGoogle Scholar
  63. 63.
    Schor NF. Neuroblastoma: a neurochemical approach. J Child Neurol 1991 Jul; 6(3): 220–8PubMedCrossRefGoogle Scholar
  64. 64.
    Schor NF, Rudin CM, Hartman AR, et al. Cell line dependence of Bcl-2-induced alteration of glutathione handling. Oncogene 2000 Jan 20; 19(3): 472–6PubMedCrossRefGoogle Scholar
  65. 65.
    Gustafson WC, De Berry BB, Evers BM, et al. Role of gastrointestinal hormones in neuroblastoma. World J Surg 2005 Mar; 29(3): 281–6PubMedCrossRefGoogle Scholar
  66. 66.
    Kitlinska J. Neuropeptide Y (NPY) in neuroblastoma: effect on growth and vascularization. Peptides 2007 Feb; 28(2): 405–12PubMedCrossRefGoogle Scholar
  67. 67.
    Segerstrom L, Fuchs D, Backman U, et al. The anti-VEGF antibody bevacizumab potently reduces the growth rate of high-risk neuroblastoma xenografts. Pediatr Res 2006 Nov; 60(5): 576–81PubMedCrossRefGoogle Scholar
  68. 68.
    Dickson PV, Hamner JB, Sims TL, et al. Bevacizumab-induced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy. Clin Cancer Res 2007 Jul 1; 13(13): 3942–50PubMedCrossRefGoogle Scholar
  69. 69.
    Kitlinska J, Abe K, Kuo L, et al. Differential effects of neuropeptide Y on the growth and vascularization of neural crest-derived tumors. Cancer Res 2005 Mar 1; 65(5): 1719–28PubMedCrossRefGoogle Scholar
  70. 70.
    Fukuzawa M, Sugiura H, Koshinaga T, et al. Expression of vascular endothelial growth factor and its receptor Flk-1 in human neuroblastoma using in situ hybridization. J Pediatr Surg 2002 Dec; 37(12): 1747–50PubMedCrossRefGoogle Scholar
  71. 71.
    Langer I, Vertongen P, Perret J, et al. Expression of vascular endothelial growth factor (VEGF) and VEGF receptors in human neuroblastomas. Med Pediatr Oncol 2000 Jun; 34(6): 386–93PubMedCrossRefGoogle Scholar
  72. 72.
    Meitar D, Crawford SE, Rademaker AW, et al. Tumor angiogenesis correlates with metastatic disease, N-myc amplification, and poor outcome in human neuroblastoma. J Clin Oncol 1996 Feb; 14(2): 405–14PubMedGoogle Scholar
  73. 73.
    Ribatti D, Ponzoni M. Antiangiogenic strategies in neuroblastoma. Cancer Treat Rev 2005 Feb; 31(1): 27–34PubMedCrossRefGoogle Scholar
  74. 74.
    Saulnier Sholler GL, Bergendahl GM, Brard L, et al. A phase 1 study of nifurtimox in patients with relapsed/refractory neuroblastoma. J Pediatr Hematol Oncol 2011 Jan; 33(1): 25–30PubMedCrossRefGoogle Scholar
  75. 75.
    Morton CL, Houghton PJ, Kolb EA, et al. Initial testing of the replication competent Seneca Valley virus (NTX-010) by the pediatric preclinical testing program. Pediatr Blood Cancer 2010 Aug; 55(2): 295–303PubMedCrossRefGoogle Scholar
  76. 76.
    Mahller YY, Vaikunth SS, Ripberger MC, et al. Tissue inhibitor of metalloproteinase-3 via oncolytic herpesvirus inhibits tumor growth and vascular progenitors. Cancer Res 2008; 68(4): 1170–9PubMedCrossRefGoogle Scholar
  77. 77.
    Parikh NS, Currier MA, Mahller YY, et al. Oncolytic herpes simplex virus mutants are more efficacious than wild-type adenovirus type 5 for the treatment of high-risk neuroblastomas in preclinical models. Pediatr Blood Cancer 2005; 44: 469–78PubMedCrossRefGoogle Scholar
  78. 78.
    Keshelava N, Seeger RC, Groshen S, et al. Drug resistance patterns of human neuroblastoma cell lines derived from patients at different phases of therapy. Cancer Res 1998; 58: 5396–405PubMedGoogle Scholar
  79. 79.
    Deyell RJ, Attiyeh EF. Advances in the understanding of constitutional and somatic genomic alterations in neuroblastoma. Cancer Genet 2011 Mar; 204(3): 113–21PubMedCrossRefGoogle Scholar
  80. 80.
    De Brouwer S, De Preter K, Kumps C, et al. Meta-analysis of neuroblastomas reveals a skewed ALK mutation spectrum in tumors with MYCN amplification. Clin Cancer Res 2010 Sep 1; 16(17): 4353–62PubMedCrossRefGoogle Scholar
  81. 81.
    Subramaniam MM, Piqueras M, Navarro S, et al. Aberrant copy numbers of ALK gene is a frequent genetic alteration in neuroblastomas. Hum Pathol 2009 Nov; 40(11): 1638–42PubMedCrossRefGoogle Scholar
  82. 82.
    Milkiewicz KL, Ott GR. Inhibitors of anaplastic lymphoma kinase: a patent review. Expert Opin Ther Pat 2010 Dec; 20(12): 1653–81PubMedCrossRefGoogle Scholar
  83. 83.
    Di Paolo D, Brignole C, Pastorino F, et al. Neuroblastoma-targeted nanoparticles entrapping siRNA specifically knockdown ALK. Mol Ther. Epub 2011 Apr 12Google Scholar
  84. 84.

Copyright information

© Adis Data Information BV 2011

Authors and Affiliations

  1. 1.Center for Neural Development and Disease, and Department of PediatricsUniversity of Rochester School of Medicine and DentistryRochesterUSA
  2. 2.Department of PediatricsUniversity of Rochester Medical CenterRochesterUSA

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