TY - JOUR
T1 - Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour
T2 - a randomised, double-blind, placebo-controlled trial
AU - DeMatteo, Ronald P.
AU - Ballman, Karla V.
AU - Antonescu, Cristina R.
AU - Maki, Robert G.
AU - Pisters, Peter WT
AU - Demetri, George D.
AU - Blackstein, Martin E.
AU - Blanke, Charles D.
AU - von Mehren, Margaret
AU - Brennan, Murray F.
AU - Patel, Shreyaskumar
AU - McCarter, Martin D.
AU - Polikoff, Jonathan A.
AU - Tan, Benjamin R.
AU - Owzar, Kouros
N1 - Funding Information:
The ACOSOG Z9001 trial was undertaken through a collaboration between the American College of Surgeons Oncology Group (ACOSOG) and the National Cancer Institute (NCI) and through a contract between Novartis and NCI under CRADA 1111.1. This work was supported by Public Health Service Grants U10 CA076001 (ACOSOG) and CA94503 and CA102613 (RPD) from the National Cancer Institute, National Institutes of Health, and by Novartis, who provided imatinib and the placebo. The views expressed are those of the authors and do not necessarily represent the official views of the National Cancer Institute. We are indebted to members of CTEP who made this trial possible. The trial was endorsed by the Southwest Oncology Group (SWOG), Cancer and Leukemia Group B (CALGB), Eastern Cooperative Oncology Group (ECOG), and the National Cancer Institute of Canada (NCI-C), all of which participated through the Cancer Trials Support Unit (CTSU). We thank Samuel A Wells Jr and Vijaya Chadaram who were instrumental in the development and early conduct of this trial, and Sue Budinger who coordinated the study; Chris Corless for providing assistance with pathological review; and Linda McCall for doing the analyses and creating the tables and graphs.
Funding Information:
Employees of the study sponsor provided input regarding the study design, but did not participate in the collection, analysis, or interpretation of the data. Data were collected at the local institution and transferred electronically to the ACOSOG central database. The database was audited and updated by members of the Duke Clinical Research Institute, which received funding from the study sponsor. The results were analysed by the principal academic investigators. KVB and KO had full access to all the data in the study. This article was written by the lead author and reviewed by all authors, and was submitted to the sponsor for comments. RPD, KVB, and KO had final responsibility for the decision to submit for publication.
PY - 2009
Y1 - 2009
N2 - Background: Gastrointestinal stromal tumour is the most common sarcoma of the intestinal tract. Imatinib mesylate is a small molecule that inhibits activation of the KIT and platelet-derived growth factor receptor α proteins, and is effective in first-line treatment of metastatic gastrointestinal stromal tumour. We postulated that adjuvant treatment with imatinib would improve recurrence-free survival compared with placebo after resection of localised, primary gastrointestinal stromal tumour. Methods: We undertook a randomised phase III, double-blind, placebo-controlled, multicentre trial. Eligible patients had complete gross resection of a primary gastrointestinal stromal tumour at least 3 cm in size and positive for the KIT protein by immunohistochemistry. Patients were randomly assigned, by a stratified biased coin design, to imatinib 400 mg (n=359) or to placebo (n=354) daily for 1 year after surgical resection. Patients and investigators were blinded to the treatment group. Patients assigned to placebo were eligible to crossover to imatinib treatment in the event of tumour recurrence. The primary endpoint was recurrence-free survival, and analysis was by intention to treat. Accrual was stopped early because the trial results crossed the interim analysis efficacy boundary for recurrence-free survival. This study is registered with ClinicalTrials.gov, number NCT00041197. Findings: All randomised patients were included in the analysis. At median follow-up of 19·7 months (minimum-maximum 0-56·4), 30 (8%) patients in the imatinib group and 70 (20%) in the placebo group had had tumour recurrence or had died. Imatinib significantly improved recurrence-free survival compared with placebo (98% [95% CI 96-100] vs 83% [78-88] at 1 year; hazard ratio [HR] 0·35 [0·22-0·53]; one-sided p<0·0001). Adjuvant imatinib was well tolerated, with the most common serious events being dermatitis (11 [3%] vs 0), abdominal pain (12 [3%] vs six [1%]), and diarrhoea (ten [2%] vs five [1%]) in the imatinib group and hyperglycaemia (two [<1%] vs seven [2%]) in the placebo group. Interpretation: Adjuvant imatinib therapy is safe and seems to improve recurrence-free survival compared with placebo after the resection of primary gastrointestinal stromal tumour. Funding: US National Institutes of Health and Novartis Pharmaceuticals.
AB - Background: Gastrointestinal stromal tumour is the most common sarcoma of the intestinal tract. Imatinib mesylate is a small molecule that inhibits activation of the KIT and platelet-derived growth factor receptor α proteins, and is effective in first-line treatment of metastatic gastrointestinal stromal tumour. We postulated that adjuvant treatment with imatinib would improve recurrence-free survival compared with placebo after resection of localised, primary gastrointestinal stromal tumour. Methods: We undertook a randomised phase III, double-blind, placebo-controlled, multicentre trial. Eligible patients had complete gross resection of a primary gastrointestinal stromal tumour at least 3 cm in size and positive for the KIT protein by immunohistochemistry. Patients were randomly assigned, by a stratified biased coin design, to imatinib 400 mg (n=359) or to placebo (n=354) daily for 1 year after surgical resection. Patients and investigators were blinded to the treatment group. Patients assigned to placebo were eligible to crossover to imatinib treatment in the event of tumour recurrence. The primary endpoint was recurrence-free survival, and analysis was by intention to treat. Accrual was stopped early because the trial results crossed the interim analysis efficacy boundary for recurrence-free survival. This study is registered with ClinicalTrials.gov, number NCT00041197. Findings: All randomised patients were included in the analysis. At median follow-up of 19·7 months (minimum-maximum 0-56·4), 30 (8%) patients in the imatinib group and 70 (20%) in the placebo group had had tumour recurrence or had died. Imatinib significantly improved recurrence-free survival compared with placebo (98% [95% CI 96-100] vs 83% [78-88] at 1 year; hazard ratio [HR] 0·35 [0·22-0·53]; one-sided p<0·0001). Adjuvant imatinib was well tolerated, with the most common serious events being dermatitis (11 [3%] vs 0), abdominal pain (12 [3%] vs six [1%]), and diarrhoea (ten [2%] vs five [1%]) in the imatinib group and hyperglycaemia (two [<1%] vs seven [2%]) in the placebo group. Interpretation: Adjuvant imatinib therapy is safe and seems to improve recurrence-free survival compared with placebo after the resection of primary gastrointestinal stromal tumour. Funding: US National Institutes of Health and Novartis Pharmaceuticals.
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U2 - 10.1016/S0140-6736(09)60500-6
DO - 10.1016/S0140-6736(09)60500-6
M3 - Article
C2 - 19303137
AN - SCOPUS:62849096370
SN - 0140-6736
VL - 373
SP - 1097
EP - 1104
JO - The Lancet
JF - The Lancet
IS - 9669
ER -