Elsevier

The Lancet

Volume 364, Issue 9440, 25 September–1 October 2004, Pages 1127-1134
The Lancet

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Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial*

https://doi.org/10.1016/S0140-6736(04)17098-0Get rights and content

Summary

Background

Imatinib is approved worldwide for use in gastrointestinal stromal tumours (GIST). We aimed to assess dose dependency of response and progression-free survival with imatinib for metastatic GIST.

Methods

946 patients were randomly allocated imatinib 400 mg either once or twice a day. Those assigned the once a day regimen who had progression were offered the option of crossover. The primary endpoint was progression-free survival. Analysis was by intention to treat.

Findings

At median follow-up of 760 days (IQR 644–859), 263 (56%) of 473 patients allocated imatinib once a day had progressed compared with 235 (50%) of 473 who were assigned treatment twice a day (estimated hazard ratio 0·82 [95% CI 0·69–0·98]; p=0·026). Side-effects arose in 465/470 (99%) patients allocated the once daily regimen compared with 468/472 (99%) assigned treatment twice a day. By comparison with the group treated once a day, more dose reductions (77 [16%] vs 282 [60%]) and treatment interruptions (189 [40%] vs 302 [64%]) were recorded in patients allocated the twice daily regimen, but treatment in both arms was fairly well tolerated. 52 (5%) patients achieved a complete response, 442 (47%) a partial response, and 300 (32%) stable disease, with no difference between groups. Median time to best response was 107 days (IQR 58–172).

Interpretation

If response induction is the only aim of treatment, a daily dose of 400 mg of imatinib is sufficient; however, a dose of 400 mg twice a day achieves significantly longer progression-free survival.

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.

Section snippets

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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