title: A phase I dose escalation of combination chemotherapy with granulocyte-macrophage-colony stimulating factor in patients with neuroblastoma.
abstract: BACKGROUND
  Dose intensity is important in the response to chemotherapy in patients with advanced neuroblastoma. The aim of the current study was to determine the maximum tolerated dose of a combination chemotherapy regimen in the treatment of patients with recurrent neuroblastoma and peripheral neuroepithelioma (primitive neuroectodermal tumor [PNET]) and whether the use of growth factor would allow increased dose intensity.
  
  
  METHODS
  Twenty-nine patients diagnosed with recurrent neuroblastoma or PNET were treated with a combination chemotherapy regimen of cisplatin, 160 mg/m(2)/96 hours; doxorubicin, 40 mg/m(2)/96 hours; and escalated doses of etoposide and ifosfamide. Granulocyte-macrophage-colony stimulating factor (GM-CSF) was administered beginning 24 hours after the completion of the chemotherapy. Courses were repeated at 28-day intervals. Once the maximum tolerated dose (MTD) was defined the interval between courses was shortened by administering the next course as soon as the patient's neutrophil and platelet counts had recovered to > 1500/microL and > 75,000/microL, respectively.
  
  
  RESULTS
  Sixteen patients were treated at 3 dose levels. The MTD was defined as 10 g/m(2)/96 hours of ifosfamide and 800 mg/m(2)/96 hours of etoposide. Thirteen additional patients then were treated at 1 level below the MTD to try and decrease the interval between courses. A total of 12 of 29 patients developed a dose-limiting toxicity (DLT) after the first course of therapy. The most common DLT was gastrointestinal toxicity followed by hematologic toxicity. Twenty-seven patients developed standard National Cancer Institute criteria Grade 3 or 4 toxicity after the first course of treatment and 7 patients achieved a complete or partial response to the first course. The use of GM-CSF did not allow further dose intensification.
  
  
  CONCLUSIONS
  This chemotherapy combination achieved a 31% overall response rate. A further increase in the dose intensity of this regimen may require supportive measures other than GM-CSF to decrease toxicity.
authors.affiliation: Department of Pediatrics, University of California San Francisco School of Medicine, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Fernandez
authors.forename: M D
authors.initials: MD
authors.lastname: Krailo
authors.forename: R R
authors.initials: RR
authors.lastname: Gerbing
authors.forename: K K
authors.initials: KK
authors.lastname: Matthay
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D009503:Neutropenia / Q000139:chemically induced / Q000517:prevention & control; D013921:Thrombocytopenia / Q000139:chemically induced / Q000517:prevention & control; D016896:Treatment Outcome
chemical_list: D005047:Etoposide; D004317:Doxorubicin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D002945:Cisplatin; D007069:Ifosfamide