Fast track — ArticlesProgression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial*
Introduction
Gastrointestinal stromal tumours (GIST) are a subgroup of soft-tissue sarcomas with an estimated prevalence of 15–20 per 1 000 000.1, 2 These tumours are thought to arise from Cajal cells in intestinal walls, which are important for intestinal motor function.3, 4 GIST were previously classified as leiomyoma, leioblastoma, or leiomyosarcoma. They are insensitive to conventional chemotherapy5 and are generally characterised by a gain-of-function mutation of the KIT receptor6 and, occasionally, of the platelet-derived growth factor receptor α.
The clinical activity of imatinib—a small-molecule tyrosine-kinase inhibitor active against BCR-ABL, KIT, and platelet-derived growth factor—has been confirmed in GIST, both in an EORTC (European Organisation for Research and Treatment of Cancer) phase I study,7 in which the highest feasible dose of imatinib was identified as 400 mg twice a day, and in phase II studies with doses of 400–800 mg daily.8, 9 Imatinib is approved worldwide for use in GIST, with a usual recommended dose of 400 mg daily. However, we still do not know whether the highest feasible daily dose yields a higher initial response rate or a better progression-free survival than the recommended dose. For this reason, we did a randomised trial to compare imatinib 400 mg once a day with 400 mg twice daily.
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Patients
Between February, 2001, and February, 2002, we recruited patients from 56 hospitals in 13 countries from Europe, Australia, New Zealand, and Singapore into our study. Eligibility criteria included histologically proven advanced or metastatic GIST characterised by c-KIT expression (assessed by DAKO immunohistochemical assay). Patients were not required to have measurable disease, and we did not need histological re-confirmation of malignant disease. Previous chemotherapy was accepted but should
Results
A total of 946 patients were randomly allocated treatment; 473 were assigned imatinib 400 mg once daily and 473 the twice daily regimen (figure 1). 18 patients (2%) were ineligible for the study: six had another type of cancer, four had concomitant diseases excluded by protocol, and eight were ineligible for miscellaneous reasons. According to the intention-to-treat policy, these patients were included in the analysis. At the time of analysis (May, 2004) per-protocol treatment had been
Discussion
Our study has shown similar response induction rates for imatinib 400 mg given once or twice a day but significantly better progression-free survival for the twice daily regimen.
Previously, GIST—if not resectable or if metastatic—were judged to be untreatable. Clinical trials of imatinib for treatment of GIST led to early registration in 2002, with a recommended initial dose of 400 mg daily.7, 8, 9 However, the formal phase I study in solid tumours7 identified a highest feasible dose of 400 mg
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Study investigators listed at end of report