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.
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.
Maurel
Joan
J
Department of Medical Oncology, Barcelona Hospital Clinic, August Pi i Sunyer Biomedical Investigations Institute, CIBEREHD, Barcelona, Spain. jmaurel@clinic.ub.es
Martins
Ana Sofia
AS
Poveda
Andrés
A
López-Guerrero
José Antonio
JA
Cubedo
Ricardo
R
Casado
Antonio
A
Martínez-Trufero
Javier
J
Ramón Ayuso
Juan
J
Lopez-Pousa
Antonio
A
Garcia-Albeniz
Xabier
X
Garcia del Muro
Xavier
X
de Alava
Enrique
E
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*
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D004317:Doxorubicin; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit