title: Imatinib plus low-dose doxorubicin in patients with advanced gastrointestinal stromal tumors refractory to high-dose imatinib: a phase I-II study by the Spanish Group for Research on Sarcomas.
abstract: BACKGROUND
  In KIT-expressing Ewing sarcoma cell lines, the addition of doxorubicin to imatinib increases apoptosis, compared with imatinib or doxorubicin alone. On the basis of these in vitro data, the authors conducted a phase 1-2 trial of doxorubicin with imatinib in patients with gastrointestinal sarcoma tumors refractory to high-dose imatinib therapy.
  
  
  METHODS
  Patients with metastatic gastrointestinal sarcoma tumor resistant to imatinib at 400 mg by mouth (p.o.) twice a day were eligible for this multicenter study, and received imatinib (400 mg p.o. every day [q.d.]) concomitantly with doxorubicin 15-20 mg/m2/weekly for 4 cycles (monthly cycles), followed by imatinib (400 mg p.o. q.d.) maintenance in nonprogressive patients. Spiral computed tomography and positron emission tomography with F18-fluorodeoxyglucose were done basally and after 2 months of therapy to evaluate response. An in vitro study assessed the effect of combining imatinib and doxorubicin.
  
  
  RESULTS
  Twenty-six patients with progressive gastrointestinal sarcoma tumor were entered in the study. Treatment was well tolerated. Three (14%) of 22 evaluable patients had partial responses per Response Evaluation Criteria in Solid Tumors, and 8 (36%) had clinical benefit (partial response or stable disease for >or=6 months). Median progression-free survival (PFS) was 100 days (95% confidence interval [CI], 62-138), and median survival was 390 days (95% CI, 264-516). Interestingly, PFS was 211 days (95% CI, 52-370) in patients with wild type (WT) KIT and 82 days (95% CI, 53-111) in non-WT patients (10 mutant, 6 not assessed). A synergistic effect on cell line proliferation and apoptosis was found with imatinib and doxorubicin combination.
  
  
  CONCLUSIONS
  Low-dose chemobiotherapy combination showed promising activity in heavily pretreated gastrointestinal sarcoma tumor patients, especially in those with WT-KIT genotype.
authors.affiliation: Department of Medical Oncology, Barcelona Hospital Clinic, August Pi i Sunyer Biomedical Investigations Institute, CIBEREHD, Barcelona, Spain. jmaurel@clinic.ub.es
authors.forename: Joan
authors.initials: J
authors.lastname: Maurel
authors.forename: Ana Sofia
authors.initials: AS
authors.lastname: Martins
authors.forename: Andrés
authors.initials: A
authors.lastname: Poveda
authors.forename: José Antonio
authors.initials: JA
authors.lastname: López-Guerrero
authors.forename: Ricardo
authors.initials: R
authors.lastname: Cubedo
authors.forename: Antonio
authors.initials: A
authors.lastname: Casado
authors.forename: Javier
authors.initials: J
authors.lastname: Martínez-Trufero
authors.forename: Juan
authors.initials: J
authors.lastname: Ramón Ayuso
authors.forename: Antonio
authors.initials: A
authors.lastname: Lopez-Pousa
authors.forename: Xabier
authors.initials: X
authors.lastname: Garcia-Albeniz
authors.forename: Xavier
authors.initials: X
authors.lastname: Garcia del Muro
authors.forename: Enrique
authors.initials: E
authors.lastname: de Alava
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage*; D049268:Positron-Emission Tomography; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D011743:Pyrimidines / Q000008:administration & dosage*
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D004317:Doxorubicin; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit