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 18F-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 18F-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 18F-FDG PET showed high baseline tumor glycolytic activity (mean SUVmax, 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 18F-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 18F-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.

Single-agent ibrutinib in relapsed or refractory follicular lymphoma: a phase 2 consortium trial

“…For example, day 8 PET correctly predicted all CT responses to imatinib in gastrointestinal stromal tumors but preceded them by 7 weeks and response on day 8 was associated with longer PFS. 38 In our study, SUV max at day 8 as a continuous measure was associated with both response and PFS with a significant difference in PFS for patients with day 8 SUV max ,13.78 vs $13.78. Unfortunately, more clinically useful parameters such as SUV max at baseline or ΔSUV max did not correlate with response, perhaps because of the small sample size.…”

State of the Art in the Treatment of Gastrointestinal Stromal Tumors

“…In rare cases where a locally advanced GIST is suspected on imaging but obtaining a histopathological diagnosis including mutational analysis is not feasible or associated with considerable risk, a possible alternative may be to start imatinib treatment using early assessment of treatment response by FDG-PET imaging. Metabolic response seen on FDG-PET as early as 1-2 weeks after initiation of treatment has been demonstrated to accurately predict CT morphological response occurring at 8-week follow-up [63,64,65]. Thus, patients with lesions that do not demonstrate major reduction in FDG uptake after 1-2 weeks of imatinib treatment should not continue to receive the drug and undergo definite histopathological assessment or upfront surgery.…”

Imaging of Platelet-Derived Growth Factor Receptor β Expression in Glioblastoma Xenografts Using Affibody Molecule111In-DOTA-Z09591

“…Currently, the response to many TKIs is monitored indirectly, for example, by measuring changes in 18 F-FDG uptake in gastrointestinal stromal tumors treated by imatinib (15). This method provides information mainly about metabolism in the lesion and its changes in response to therapy.…”