Outcome of 1000 Patients With Gastrointestinal Stromal Tumor (GIST) Treated by Surgery in the Pre- and Post-imatinib Eras

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Abstract

To characterize the results of surgery for GIST in the pre- and post-imatinib eras at a single-institution and identify current prognostic clinicopathologic factors. Imatinib has radically changed the management of GIST, yet the magnitude of impact on outcome across the spectrum of GIST presentation and relevance of historical prognostic factors are not well defined. We retrospectively analyzed 1,000 patients who underwent surgery for GIST at our institution from 1982–2016. Patients were stratified by presentation status as primary tumor only (PRIM), primary with synchronous metastasis (PRIM+MET), or metachronous recurrence/metastases (MET), as well as imatinib era (before and after it became available). Cox proportional hazard models and Kaplan Meier methods were used to model and estimate overall and recurrence-free survival (OS, RFS). OS was longer in the imatinib era compared to the pre-imatinib era in each presentation group, including in Miettinen high risk primary tumors. Among PRIM patients from the pre-imatinib era, tumor site, size, and mitotic rate were independently associated with OS and RFS on multivariate analysis. PRIM patients in the imatinib era who received imatinib (neoadjuvant and/or adjuvant) had higher risk tumors, but after adjusting for treatment, only size >10cm remained independently prognostic of RFS (HR 3.85, 95% CI 2.00–7.40, p<0.0001) and OS (HR 3.37, 95% CI 1.60–7.13, p=0.001). Patients treated in the imatinib era had prolonged overall survival across all presentations. In the imatinib era, among site, size, and mitotic rate, high risk features were associated with treatment with the drug, but only size >10cm correlated with outcome. Imatinib should still be prescribed for patients with high risk features. In the pre-imatinib era, primary tumor site, size, and mitotic rate predicted outcome as expected. In the modern era, survival was dramatically longer. While primary tumor high risk features were associated with imatinib treatment, only tumor size >10cm remained associated with outcome. Imatinib should be prescribed for high risk features.

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

Ronald DeMatteo, Karla V. Ballman, Cristina R Antonescu … (2009)

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.