Article

Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial

Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
The Lancet (Impact Factor: 45.22). 03/2009; 373(9669):1097-104. DOI: 10.1016/S0140-6736(09)60500-6
Source: PubMed

ABSTRACT 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 alpha 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.
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.
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.
Adjuvant imatinib therapy is safe and seems to improve recurrence-free survival compared with placebo after the resection of primary gastrointestinal stromal tumour.
US National Institutes of Health and Novartis Pharmaceuticals.

Download full-text

Full-text

Available from: Margaret von Mehren, Jul 30, 2015
0 Followers
 · 
653 Views
  • Source
    • "Treatment of GIST patients harboring c-kit or PDGFRA mutations, with tyrosine kinase inhibitors such as imatinib and sunitinib, has been proven to be effective in cases of inoperable or metastatic tumors. As adjuvant imatinib treatment significantly improves recurrence-free survival [77] "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sarcomas are rare and clinically diverse malignancies, and treatment optimization requires the development of suitable biomarkers. In earlier research employing proteomics analysis, we identified peroxiredoxin 2 as a biomarker of osteosarcoma (OS) that can predict response to neoadjuvant chemotherapy and verified its functional significance in the resistance of OS cells to chemotherapeutic drugs. In addition, in gastrointestinal stromal tumor (GIST), we identified pfetin as a prognostic biomarker and validated its prognostic utility in multi-institutional studies by immunohistochemistry. Here, we present an overview of our progress in sarcoma proteomics and discuss future perspectives.
    09/2014; 4. DOI:10.1016/j.euprot.2014.06.004
  • Source
    • "In our institutions, administration of adjuvant or neoadjuvant imatinib has been considered for patients with a high-risk tumor, a tumor with a Ki-67 labeling index of 10% or greater, or a marginally resectable tumor since this therapy was approved in July 2009. Patients who received adjuvant/neoadjuvant imatinib were excluded from this analysis because adjuvant imatinib influences the natural course of the disease [8] and morphologic changes such as extensive hyalinization and hypocellularity and even the loss of KIT expression occur in tumor cells after imatinib treatment [15]. "
  • Source
    • "In our institutions, administration of adjuvant or neoadjuvant imatinib has been considered for patients with a high-risk tumor, a tumor with a Ki-67 labeling index of 10% or greater, or a marginally resectable tumor since this therapy was approved in July 2009. Patients who received adjuvant/neoadjuvant imatinib were excluded from this analysis because adjuvant imatinib influences the natural course of the disease [8] and morphologic changes such as extensive hyalinization and hypocellularity and even the loss of KIT expression occur in tumor cells after imatinib treatment [15]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Previously, we showed that the expression of potassium channel tetramerization domain-containing 12 (KCTD12), which was discovered by a proteomics approach, is associated with high-risk behavior of gastrointestinal stromal tumors (GISTs). Here, we examined the distribution and expression of this protein by immunostaining with a commercially available polyclonal KCTD12 antibody in GISTs (n = 64) and other types of malignancy (n = 168) to clarify its diagnostic and clinical significance. Diffuse KCTD12 immunoreactivity was found in most GISTs (52 cases; 81%). KCTD12 expression was observed primarily in vascular endothelial cells, Purkinje cells of the cerebellum, and some neurons scattered throughout the cerebral cortex. KCTD12 was absent from not only the interstitial cells of Cajal but also interstitial cells of Cajal hyperplasia that was encountered incidentally in colon diverticulitis. KCTD12 immunostaining was also seen in malignant peripheral nerve sheath tumors (2/10 cases; 20%), synovial sarcomas (2/10; 20%), solitary fibrous tumor (1/8; 13%), angiosarcoma (1/7; 14%), and colon adenocarcinoma (1/24; 4%). In survival analyses, the 5-year recurrence-free survival rate of patients without KCTD12 expression was only 16.7% compared with 95.6% in those with KCTD12 expression (P < .0001). Ki-67 and KCTD12 were significant predictors of recurrence-free survival, and KCTD12 expression provided additional information about recurrence-free survival after accounting for Ki-67 status. Overall, KCTD12 expression was specific for GISTs from neoplastic and nonneoplastic adult tissues other than brain and served as a predictor of GIST recurrence. These findings suggest that KCTD12 is a useful and reliable biomarker for both the diagnosis and prognosis of GIST.
    Human pathology 01/2013; 44(7). DOI:10.1016/j.humpath.2012.10.013 · 2.81 Impact Factor
Show more