ACRIN 6665/RTOG 0132 phase II trial of neoadjuvant imatinib mesylate for operable malignant gastrointestinal stromal tumor: monitoring with 18F-FDG PET and correlation with genotype and GLUT4 expression

Abstract

We investigated the correlation between metabolic response by (18)F-FDG PET and objective response, glucose transporter type 4 (GLUT4) expression, and KIT/PDGFRA mutation status in patients with gastrointestinal stromal tumor undergoing neoadjuvant imatinib mesylate therapy.

Methods: (18)F-FDG PET was performed at baseline, 1-7 d, and 4 or 8 wk after imatinib mesylate initiation. Best objective response was defined by version 1.0 of the Response Evaluation Criteria in Solid Tumors (RECIST). Mutational analysis and tumor GLUT4 expression by immunohistochemistry were done on tissue obtained at baseline or surgery.

Results: (18)F-FDG PET showed high baseline tumor glycolytic activity (mean SUV(max), 14.2; range, 1.3-53.2), decreasing after 1 wk of imatinib mesylate (mean, 5.5; range, -0.5-47.7, P < 0.001, n = 44), and again before surgery (mean, 3.0; range, -0.5-36.1, P < 0.001, n = 40). At week 1, there were 3 patients with complete metabolic response (CMR), 33 with partial metabolic response (PMR), 6 with stable metabolic disease (SMD), and 2 with progressive metabolic disease (PMD). Before surgery, there were 3 with CMR, 33 with PMR, 4 with SMD, and none with PMD. The best response according to RECIST was 2 with partial response, 36 with stable disease, and 1 with progressive disease (n = 39). Of the patients with a posttreatment decrease in GLUT4 expression, 1 had CMR, 15 had PMR, 2 had SMD, and 1 had PMD at week 1, whereas before surgery 1 patient had CMR, 16 had PMR, 2 had SMD, and none had PMD. Among 27 patients with KIT exon 11 mutations, 1 had CMR, 22 had PMR, 3 had SMD, and 1 had PMD at week 1, whereas 1 had CMR, 22 had PMR, 2 had SMD, and 2 were unknown before surgery; among 4 patients with a wild-type genotype, 2 had PMR and 2 SMD at week 1, whereas 1 had CMR, 2 had PMR, and 1 had SMD before surgery.

Conclusion: After imatinib mesylate initiation, metabolic response by (18)F-FDG PET was documented earlier (1-7 d) and was of much greater magnitude (36/44) than that documented by RECIST (2/39). Immunohistochemistry data suggest that GLUT4 may play a role in (18)F-FDG uptake in gastrointestinal stromal tumor, GLUT4 levels decrease after imatinib mesylate therapy in most patients with PMR, and the biologic action of imatinib mesylate interacts with glycolysis and GLUT4 expression. A greater than 85% metabolic response was observed as early as days 1-7 in patients with exon 11 mutations.

Figure 1

(A) ¹⁸F-FDG PET before therapy, 1 and 8 wk after imatinib mesylate initiation. Intense ¹⁸F-FDG uptake in seen at baseline within primary perigastric GIST, followed by complete resolution at 1 and 8 wk after therapy. Mild uptake seen in the left supraclavicular region is related to inflammatory changes around the site of the pacemaker. The remainder of ¹⁸F-FDG biodistribution is physiologic. (B) Axial CT, PET, and fused PET/CT slices through the right-upper-quadrant mass before and 1 and 8 wk after imatinib mesylate initiation. Intense ¹⁸F-FDG uptake is seen within the primary perigastric GIST at baseline, followed by marked decrease at 1 wk and complete resolution at 8 wk after therapy.

Figure 2

Percentage change in SUV_max from baseline to week 1 (A) and before surgery (B). CMR = complete metabolic response; PMR = partial metabolic response; SMD 5 stable metabolic disease; PMD = progressive metabolic disease. Percentage change in SUV_max from baseline to week 1 (C) and before surgery (D) by RECIST best response. PR = partial response; SD = stable disease; PD = progressive disease.

Figure 3

GLUT4 immunohistochemical (A) and ¹⁸F-FDG PET (B) studies of patient with primary gastric GIST before and 8 wk after imatinib mesylate therapy. GLUT4 intense brown staining at baseline is no longer apparent on week 8 surgical specimen. ¹⁸F-FDG PET images show intense ¹⁸F-FDG uptake in the gastric mass before treatment and resolution at week 8.