¹⁸F-FDG and ¹⁸F-FLT Uptake Early After Cyclophosphamide and mTOR Inhibition in an Experimental Lymphoma Model

Abstract

To be a reliable predictor of response, tracer uptake should reflect changes in the amount of active tumor cells. However, uptake of 18 F-FDG, the most commonly used PET tracer, is disturbed by the inflammatory cells that appear early after cytotoxic therapy. The first aim of this study was to investigate whether 39-18 F-fluoro-39-deoxy-L-thymidine ( 18 F-FLT), a marker of cellular proliferation, is a better tracer for response assessment early after cytotoxic therapy. A second objective of this study was to investigate whether 18 F-FDG and 18 F-FLT responses were comparable early after mammalian target of rapamycin (mTOR) inhibition, as an example of proliferation-targeting therapies. Methods: Severe combined immunodeficient mice were subcutaneously inoculated with Granta-519 cells, a human cell line derived from a leukemic mantle cell lymphoma. Half the mice were treated with cyclophosphamide and the other half with mTOR inhibition. 18 F-FDG and 18 F-FLT uptake was evaluated by small-animal PET on day 0 (D0; before treatment), D11, D12, D14, D17, D19, D111, and D114. At each time point, 2 mice of each treatment condition were sacrificed, and tumors were excised for histopathology. Results: After cyclophosphamide, 18 F-FDG and 18 F-FLT uptake decreased, with a maximum reduction of 229% for 18 F-FDG and 225% for 18 F-FLT uptake at D12, compared with baseline. Although 18 F-FDG uptake increased from D14 on, with a maximum on D17, 18 F-FLT uptake remained virtually stable. Histology showed an increase in apoptotic or necrotic tumor fraction, followed by an influx of inflammatory cells. In mTOR-inhibited mice, 18 F-FDG uptake dropped until D12 after therapy (243%) but increased at D14 (227%) to form a plateau on D17 and D19 (214% and 216%, respectively). Concurrently, 18 F-FLT uptake decreased to 231% on D12, followed by an increase with a peak value of 112% on D17, after which 18 F-FLT uptake decreased again. Cyclin D1 expression dropped from D11 until D14 and returned to baseline at D17. Conclusion: Because 18 F-FLT uptake is not significantly influenced by the temporary rise in inflammatory cells early after cyclophosphamide, it more accurately reflects tumor response. However, a formerly unknown temporary rise in 18 F-FLT uptake a few days after the administration of mTOR inhibition was defined, which makes it clear that drug-specific responses have to be considered when using PET for early treatment monitoring.

FLT-PET Is Superior to FDG-PET for Very Early Response Prediction in NPM-ALK-Positive Lymphoma Treated with Targeted Therapy

“…It is likely that an influx of inflammatory cells, which can be observed already 48 hours after mTOR inhibition (42), contributes to higher FDG-uptake in vivo. Because FDG-uptake of inflammatory cells is similar or may even exceed that of tumor cells, transient increase in stromal reaction may result in overestimation of viable tumor (43).…”

Monitoring Tumor Response to Therapy with 18F-FLT PET

“…However, some false-positive findings have been reported for 18 Because of these limitations of 18 F-FLT PET for tumor staging, monitoring tumor response to therapy is perhaps the most promising clinical application of 18 F-FLT PET. A series of animal studies has indicated that 18 F-FLT uptake decreases rapidly in response to radiotherapy (9,10), cytotoxic chemotherapy (11,12), and various protein kinase inhibitors (13)(14)(15)(16). In some (9,11,12,15) but not all of these studies (10,13,14), changes in 18 F-FLT uptake better reflected the effects of therapy than did changes in 18 F-FDG uptake.…”

A Personalized Preclinical Model to Evaluate the Metastatic Potential of Patient-Derived Colon Cancer Initiating Cells

“…The most frequently employed radiotracer was 18 (19,20). To our knowledge, there have been no other previously reported PET studies in mice inoculated orthotopically with patient-derived colon cancer cells.…”