Abstract
Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality in the United States and pemetrexed-based therapies are regularly used to treat non-squamous NSCLC. Despite widespread use, pemetrexed has a modest effect on progression-free survival, with varying efficacy between individuals. Recent work has indicated that dexamethasone, given to prevent pemetrexed toxicity, is able to protect a subset of NSCLC cells from pemetrexed cytotoxicity by temporarily suppressing of the S-phase of the cell cycle. Therefore, dexamethasone may block treatment efficacy in a subpopulation of patients, and could be contributing to the variable response to pemetrexed. Methods: Differences in retention of the experimental positron emission tomography (PET) tracer 3’-deoxy-3’-fluorothymidine (FLT) were used to monitor S-phase suppression by dexamethasone in NSCLC cell models, animals with tumor xenografts, and patients with advanced cancer. Results: Significant reductions in tracer uptake were observed after 24h dexamethasone treatment in NSCLC cell lines and xenograft models expressing high levels of glucocorticoid receptor alpha, coincident with pemetrexed resistance visualized by attenuation of the ‘flare’ effect associated with pemetrexed activity. 2/4 patients imaged in a pilot study with 18F-FLT-PET following dexamethasone treatment demonstrated reductions in tracer uptake from baseline, with variable response between individual tumor lesions. Conclusion: 18F-FLT-PET presents a useful method for the non-invasive monitoring of dexamethasone-mediated S-phase suppression in NSCLC and could provide a method for the individualization of chemotherapy in patients receiving pemetrexed-based regimens.
- Copyright © 2018 by the Society of Nuclear Medicine and Molecular Imaging, Inc.