title: Gefitinib in combination with oral topotecan and cyclophosphamide in relapsed neuroblastoma: pharmacological rationale and clinical response.
abstract: OBJECTIVE
  Activity and toxiciy of gefitinib in combination with topotecan and cyclophosphamide (CPA) were evaluated in a case-series of relapsed neuroblastoma (NB) patients. The in vitro activity of the combination was also assessed.
  
  
  METHODS
  Gefitinib (250 mg/day), topotecan (0.8 mg/m(2)/day), and CPA (50 mg/m(2)/day) (GTC) were administered orally for 14 consecutive days out of 28 days. Antitumor activity of gefitinib as single agent and in combination with either topotecan or CPA was assessed in a panel of NB cell lines.
  
  
  RESULTS
  Ninety-two courses were given in 10 patients. Grade 4 neutropenia was observed in 7/92 courses (8%) and grade 4 thrombocytopenia in 8/92 (9%). Two patients had a grade 2 liver toxicity, four a grade 1/2 skin toxicity, and two a grade 1/2 diarrhea. Dose reduction of topotecan and/or CPA was required in eight patients. After four courses, three patients were in partial response (PR) and four with a stable disease (SD), while three experienced a progressive disease (PD). Time to progression (TTP) was 9 months (range, 1-27). After a median follow-up of 16 months (range 5-54), seven patients are died of disease (DOD) and three alive with disease (AWD). All but one patient discontinued oral chemotherapy because of a PD, whilst one patient stopped chemotherapy after 27 months with a SD. In vitro, gefitinib was synergistic with topotecan and additive with CPA.
  
  
  CONCLUSIONS
  The GTC combination was well tolerated and the TTP was encouraging. These promising results, also supported by in vitro evidence, should be further confirmed in a phase II study.
authors.affiliation: Division of Oncology, Ospedale Pediatrico Bambino Gesù (IRCCS), Rome, Italy. donfrancesco@opbg.net
authors.forename: Alberto
authors.initials: A
authors.lastname: Donfrancesco
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: De Ioris
authors.forename: Heather Prudence
authors.initials: HP
authors.lastname: McDowell
authors.forename: Maria Debora
authors.initials: MD
authors.lastname: De Pasquale
authors.forename: Ilaria
authors.initials: I
authors.lastname: Ilari
authors.forename: Alessandro
authors.initials: A
authors.lastname: Jenkner
authors.forename: Aurora
authors.initials: A
authors.lastname: Castellano
authors.forename: Samantha
authors.initials: S
authors.lastname: Cialfi
authors.forename: Clementina
authors.initials: C
authors.lastname: De Laurentis
authors.forename: Carlo
authors.initials: C
authors.lastname: Dominici
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010865:Pilot Projects; D011379:Prognosis; D011799:Quinazolines / Q000008:administration & dosage; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016879:Salvage Therapy; D015996:Survival Rate; D019772:Topotecan / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D011799:Quinazolines; D012333:RNA, Messenger; D019772:Topotecan; D003520:Cyclophosphamide; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib