A randomized, phase II study of preoperative plus postoperative imatinib in GIST: evidence of rapid radiographic response and temporal induction of tumor cell apoptosis - PubMed (original) (raw)

Clinical Trial

A randomized, phase II study of preoperative plus postoperative imatinib in GIST: evidence of rapid radiographic response and temporal induction of tumor cell apoptosis

John C McAuliffe et al. Ann Surg Oncol. 2009 Apr.

Abstract

Gastrointestinal stromal tumor (GIST) is the most common sarcoma arising in the gastrointestinal (GI) tract. Imatinib mesylate (imatinib) is efficacious in treating advanced and metastatic GIST. Patients undergoing resection of GIST realize a highly variable median disease-free survival (DFS). In the absence of prospective data, we conducted a randomized, phase II study to assess the safety and efficacy of preoperative and postoperative imatinib for the treatment of GIST. Nineteen GIST patients undergoing surgical resection were randomized to receive 3, 5, or 7 days of preoperative imatinib (600 mg daily). Patients received postoperative imatinib for 2 years. Perioperative adverse events were compared with those in an imatinib-naïve historical control. The efficacy of imatinib was assessed by (18)fluorodeoxyglucose positron emission tomography ((18)FDG-PET), dynamic computed tomography (dCT), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and DFS. Imatinib did not affect surgical morbidity as compared with an imatinib-naïve cohort (p >/= 0.1). Most patients responded to preoperative imatinib by (18)FDG-PET and dCT (69% and 71%, respectively). Tumor cell apoptosis increased by an average of 12% (range 0-33%) and correlated with the duration of preoperative imatinib (p = 0.04). Median DFS of patients treated with surgery and imatinib was 46 months (range 10-46 months). Tumor size was a predictor of recurrence after postoperative imatinib (p = 0.02). Imatinib appears to be safe and may be considered for patients undergoing surgical resection of their GIST. Radiographic response and tumor cell apoptosis occur within the first week of imatinib therapy.

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Figures

Fig. 1

Fig. 1

Representative radiographic and functional imaging of GIST (arrows). (a) contrast-enhanced CT before and after preoperative imatinib. Some hypodensity within the tumor can be appreciated in presurgical scans compared with baseline scans. (b) 18FDG-PET before and after preoperative imatinib. Black indicates sites of 18FDG accumulation. Complete abrogation of avid disease can be appreciated in this representative patient in latter scans. (c) dCT blood flow reconstruction before and after preoperative imatinib. Red indicates blood flow similar to the abdominal aorta; other colors indicate blood flow less than the abdominal aorta, with blue and black representing the least blood flow. A decrease in the amount of red within the tumor in latter scans compared to pre-imatinib scans indicates a decrease in tumor blood flow in response to imatinib

Fig. 2

Fig. 2

Histologic evaluation of tumor tissue and TUNEL assay. Matched hematoxylin and eosin (H&E) and immunofluorescence of a representative frozen biopsy and surgical specimen from a single patient treated for 5 days with preoperative imatinib. Hypercellular, hyperchromic tissue can be appreciated in both the biopsy and surgical specimens. TUNEL assay indicates that tumor cells underwent apoptosis after 5 days of imatinib: blue, nuclei stained with DAPI; green, fluorescein isothiocyanate (FITC) tag of positive TUNEL reaction; merge, overlay of blue and green indicating nuclei undergoing apoptosis

Fig. 3

Fig. 3

Disease-free survival. Kaplan–Meier plot of DFS versus time (months) since recruitment to trial. Median DFS = 46 months. Tick marks = patients censored

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