Pediatric Neuroblastoma Medication

Updated: Oct 09, 2017
  • Author: Norman J Lacayo, MD; Chief Editor: Max J Coppes, MD, PhD, MBA  more...
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Medication

Medication Summary

All chemotherapy orders are written by pediatric oncologists and countersigned, usually by another physician. With recurrent disease, various salvage protocols may be used; with refractory disease, a limited number of phase I/II studies are available through the Children's Oncology Group (COG) and New Approaches to Neuroblastoma Therapy (NANT) consortia.

Resources presented in this section should serve as a guide to indication, usual dosages, and adverse effects of specific agents. Antineoplastic drugs have a narrow therapeutic index and effective doses usually cause severe toxicities, some of which can be life threatening.

Individual chemotherapy drugs are discussed below. These agents are almost invariably given in combination. Commonly used combinations include the following:

  • Vincristine, cyclophosphamide, and doxorubicin
  • Carboplatin and etoposide
  • Cisplatin and etoposide
  • Ifosfamide and etoposide
  • Cyclophosphamide and topotecan

Consolidation regimens used in neuroblastoma include the following:

  • Carboplatin and etoposide with melphalan or cyclophosphamide
  • Thiotepa and cyclophosphamide
  • Melphalan and total body irradiation

In Europe, several studies have used busulfan with melphalan or cyclophosphamide. One commonly used salvage or relapse therapy regimen is the combination of topotecan and cyclophosphamide. The use or retinoids have been incorporated in maintenance regimens in the posttransplant setting. Irinotecan is also under investigation.

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Antineoplastic Agents

Class Summary

Cancer chemotherapy is based on an understanding of tumor cell growth and how drugs affect this growth. After cells divide, they enter a period of growth (ie, phase G1), followed by DNA synthesis (ie, phase S). The next phase is a premitotic phase (ie, G2), which is followed by a mitotic cell division (ie, phase M).

Cell division rate varies for different tumors. Most common cancers increase very slowly in size compared with normal tissues, and the rate may decrease further in large tumors. This difference allows normal cells to recover more quickly from chemotherapy than malignant cells; it is the rationale behind current cyclic dosage schedules.

Antineoplastic agents interfere with cell reproduction. Some agents are cell cycle specific, whereas others (eg, alkylating agents, anthracyclines, cisplatin) are not phase specific. Cellular apoptosis (ie, programmed cell death) is also a potential mechanism of many antineoplastic agents.

Carboplatin (Paraplatin)

Alkylating agent. Interferes with metabolism of DNA by covalent binding.

Cisplatin (Platinol)

Mechanism of action is similar to other alkylating agents. Binds and cross-links DNA strands.

Cyclophosphamide (Cytoxan)

Immunosuppressant antineoplastic agent. Metabolism of cyclophosphamide by hepatic microsomal enzymes produces active alkylating metabolites, which probably damage DNA.

Doxorubicin (Adriamycin)

Causes DNA strand breakage mediated by effects on topoisomerase II. Intercalates into DNA and inhibits DNA polymerase.

Etoposide (VP-16, VePesid)

Interacts with topoisomerase II and produces single strand breaks in DNA. Arrests cells in late S or G2 phase.

Ifosfamide (Ifex)

Alkylating agent. Metabolic activation by microsomal liver enzymes produces biologically active intermediates that attack nucleophilic sites, particularly on DNA.

Melphalan (Alkeran)

Inhibits mitosis by cross-linking DNA strands.

Isotretinoin (13-cis-retinoic acid, Accutane)

Vitamin A derivative. Interacts with retinoic acid responsive elements on DNA, which results in gene activation and differentiation of target cells.

Thiotepa (Thioplex)

Ethyleneimine derivative alkylating agent. Action involves transfer of the alkyl group to amino, carboxyl, hydroxyl, imidazole, phosphate, and sulfhydryl groups within the cell, altering structure and function of DNA, RNA, and proteins.

Vincristine (Oncovin)

Mitotic inhibitor. This vinca alkaloid binds tubulin leading to its depolymerization, resulting in mitotic inhibition and metaphase arrest.

Topotecan (Hycamtin)

Inhibits topoisomerase I, inhibiting DNA replication.

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Colony-stimulating Factors

Class Summary

These agents act as a hematopoietic growth factor that stimulates the development of granulocytes. They are used to treat or prevent neutropenia when receiving myelosuppressive cancer chemotherapy and to reduce the period of neutropenia associated with bone marrow transplantation. They are also used to mobilize autologous peripheral blood progenitor cells for bone marrow transplantation and in the management of chronic neutropenia.

A multicenter, randomized trial by Ladenstein et al observed pediatric patients (n=239) with neuroblastoma in 16 countries. [25] Patients who were given primary prophylactic G-CSF had significantly fewer febrile neutropenic episodes, days with fever, hospital days, and antibiotic days compared with those who received symptom-triggered G-CSF. Other toxicities were significantly reduced as well including infections, fever, severe leukopenia, neutropenia, mucositis, nausea/vomiting, constipation, and weight loss.

Filgrastim (G-CSF, Neupogen)

Promotes growth and differentiation of myeloid progenitor cells. May improve survival and function of granulocytes. In the posttransplant setting, administer until marrow recovery with absolute neutrophil count >10,000.

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Chemoprotective Agents

Class Summary

Mesna is a prophylactic detoxifying agent used to inhibit hemorrhagic cystitis caused by ifosfamide and cyclophosphamide. In the kidney, mesna disulfide is reduced to free mesna. Free mesna has thiol groups that react with acrolein, which is the ifosfamide and cyclophosphamide metabolite considered to be responsible for urotoxicity.

Mesna (Mesnex)

Interacts in the bladder with acrolein, a toxic metabolite of cyclophosphamide or ifosfamide to prevent hemorrhagic cystitis.

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Antineoplastics, Monoclonal Antibody

Class Summary

Monoclonal antibodies that bind to the glycolipid disialoganglioside (GD2), expressed on neuroblastoma cells and on normal cells of neuroectodermal origin, have been shown to produce superior outcomes as part of a multimodality regimen.

Dinutuximab (Unituxin)

Dinutuximab is a chimetic monoclonal antibody that binds to the glycolipid disialoganglioside (GD2). GD2 is a glycolipid expressed on neuroblastoma cells and on normal cells of neuroectodermal origin, including central nervous system and peripheral nerves. Dinutuximab binds to cell surface GD2 and induces lysis of GD2-expressing cells through antibody-dependent cell-mediated cycotoxicity and complement-dependent cytotoxicity.

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