Effects of capecitabine treatment on the uptake of thymidine analogs using exploratory PET imaging agents: 18F-FAU, 18F-FMAU, and 18F-FLT

Abstract

BackgroundA principal goal for the use of positron emission tomography (PET) in oncology is for real-time evaluation of tumor response to chemotherapy. Given that many contemporary anti-neoplastic agents function by impairing cellular proliferation, it is of interest to develop imaging modalities to monitor these pathways. Here we examined the effect of capecitabine on the uptake of thymidine analogs used with PET: 3’-deoxy-3’-[18F]fluorothymidine (18F-FLT), 1-(2’-deoxy-2’-[18F]fluoro-β-D-arabinofuranosyl) thymidine (18F-FMAU), and 1-(2’-deoxy-2’-[18F]fluoro-β-D-arabinofuranosyl) uracil (18F-FAU) in patients with advanced cancer.MethodsFifteen patients were imaged, five with each imaging agent. Patients had been previously diagnosed with breast, colorectal, gastric, and esophageal cancers and had not received therapy for at least 4 weeks prior to the first scan, and had not been treated with any prior fluoropyrimidines. Subjects were imaged within a week before the start of capecitabine and on the second day of treatment, after the third dose of capecitabine. Tracer uptake was quantified by mean standard uptake value (SUVmean) and using kinetic analysis.ResultsPatients imaged with 18F-FLT showed variable changes in retention and two patients exhibited an increase in SUVmean of 172.3 and 89.9 %, while the other patients had changes ranging from +19.4 to -25.4 %. The average change in 18F-FMAU retention was 0.2 % (range -24.4 to 23.1) and 18F-FAU was -10.2 % (range -40.3 to 19.2). Observed changes correlated strongly with SUVmax but not kinetic measurements.ConclusionsThis pilot study demonstrates that patients treated with capecitabine can produce a marked increase in 18F-FLT retention in some patients, which will require further study to determine if this flare is predictive of therapeutic response. 18F-FAU and 18F-FMAU showed little change, on average, after treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s40644-016-0092-2) contains supplementary material, which is available to authorized users.

Dexamethasone pretreatment impairs the thymidylate synthase inhibition mediated flare in thymidine salvage pathway activity in non-small cell lung cancer

“…Published work in our laboratory and others have demonstrated that successful TS inhibition can result in a compensatory “flare” in thymidine salvage pathway activity that occurs at approximately 2 hrs. following the start of therapy both in vitro[ 1 – 5 , 19 ] and in vivo[ 3 – 6 , 20 , 21 ] . This effect was also observed in vivo both in a mouse model of human NSCLC and in a human patient with NSCLC using FLT-PET ([18F]fluorothymidine-positron emission tomography) imaging[ 4 ].…”

“…Therapeutic inhibition of thymidylate synthase (TS) is a commonly used strategy in management of a number of malignancies including non-small cell lung cancer (NSCLC). The successful inhibition with commonly used therapeutics, 5-FU[ 1 – 3 ], pemetrexed[ 4 , 5 ] and capecitabine[ 6 ] have all been demonstrated to induce a transient burst of compensatory activity through the thymidine kinase pathway within hours of exposure to the chemotherapeutic. This transient burst in thymidine salvage pathway activity is measureable with FLT-PET ([18F]fluorothymidine -position emission tomography)[ 3 – 6 ].…”

“…The successful inhibition with commonly used therapeutics, 5-FU[ 1 – 3 ], pemetrexed[ 4 , 5 ] and capecitabine[ 6 ] have all been demonstrated to induce a transient burst of compensatory activity through the thymidine kinase pathway within hours of exposure to the chemotherapeutic. This transient burst in thymidine salvage pathway activity is measureable with FLT-PET ([18F]fluorothymidine -position emission tomography)[ 3 – 6 ]. FLT, first described by Shields et al[ 7 ] , is an analog of thymidine and highly specific surrogate marker of proliferation, including in lung cancer[ 8 – 11 ].…”

Early detection of thymidylate synthase resistance in non-small cell lung cancer with FLT-PET imaging

“…As a result, this drug-induced compensatory “flare” in thymidine salvage pathway activity is an indicator of successful TS inhibition. This drug-induced change in tumor metabolism can be made visible through 18 F-thymidine (FLT)-positron emission tomography (PET)[ 2 , 5 – 7 ], an analog of thymidine. FLT, first described by Shields in 1998 [ 8 ], is an investigational imaging biomarker of the thymidine salvage pathway currently in use for human clinical trials primarily as a validated surrogate marker of tumor proliferation [ 9 – 12 ].…”

Fluorothymidine Positron Emission Tomography (FLT-PET) Repeatability and Response Evaluation in Advanced Pancreatic Cancer Patients Treated with Gemcitabine-Based Chemotherapy

“…However, the absence of tumoural FLT flare with gemcitabine unlike fluoropyrimdines, in preclinical models has been attributed to the competition in tumoural uptake between FLT and gemcitabine, both of which use the same nucleoside transporter, hENT1. It is difficult to delineate if the decreased uptake in tumour and normal tissues in this subject is a true representation of decreased proliferative activity, or as a result of competition between gemcitabine and FLT for transport in to tissue [23,37]. No relationship between the imaging and pathologic parameters were identified.…”