Fluorothymidine PET Research Articles

Monitoring reversible and irreversible EGFR inhibition with erlotinib and afatinib in a patient with EGFR-mutated non-small cell lung cancer (NSCLC) using sequential [18F]fluorothymidine (FLT-)PET

Non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations benefit from treatment with EGFR-targeted therapy. While first-generation (“reversible”) EGFR tyrosine kinase inhibitors (TKIs) are well established in the treatment of these patients, the remarkably lower efficacy of second-generation (“irreversible”) EGFR-TKIs after failure of reversible EGFR inhibition is far less understood. Here we describe an EGFR-mutated patient treated sequentially with both reversible (erlotinib) and irreversible (afatinib) EGFR-TKIs monitored by sequential [18F]fluorothymidine (FLT-)PET. Our observations confirm the value of molecular imaging for assessment of pharmacodynamics and early prediction of response and relapse in these patients.

Comparison of 3′-deoxy-3′-[18F]fluorothymidine PET and O-(2-[18F]fluoroethyl)-L-tyrosine PET in patients with newly diagnosed glioma

The purpose of this prospective study was to clarify the value of FLT PET and FET PET for the noninvasive grading and prognosis of newly diagnosed gliomas. Twenty patients with newly diagnosed gliomas were investigated with FLT and FET PET before surgery. FLT and FET uptakes were assessed by the maximum standardized uptake (SUVmax) of tumor, and the ratio to uptake in the normal brain parenchyma (TNR). All tumors were graded by WHO system. FLT PET detected all 17 high-grade gliomas (HGG) and did not detect all 3 low-grade gliomas (LGG). FET PET detected all 20 HGG and LGG regardless of grading. The average FLT SUVmax in HGG and LGG was 1.51 ± 0.72 and 0.30 ± 0.07, and the average FLT TNR in HGG and LGG was 5.52 ± 3.09 and 1.12 ± 0.14, respectively. The differences of FLT SUVmax and TNR between HGG and LGG were statistically significant (p=0.0069, p=0.0070). The average FET SUVmax in HGG and LGG was 2.68 ± 0.86 and 1.36 ± 0.15, and the average FET TNR in HGG and LGG was 2.31 ± 0.73 and 1.27 ± 0.12, respectively. The differences of FET SUVmax and TNR between HGG and LGG were statistically significant (p=0.0129, p=0.0095). FET PET has higher sensitivity in detection of gliomas rather than FLT PET, but it seems that FLT PET is better than FET PET for noninvasive grading and predicting prognosis of newly diagnosed gliomas, considering high contrast of FLT and overlap of FET uptakes between HGG and LGG.

Monitoring Early Response to Taxane Therapy in Advanced Breast Cancer with Circulating Tumor Cells and [ 18 F] 3´-deoxy-3´-Fluorothymidine PET: A Pilot Study

Early markers of response to chemotherapy, measured by blood markers and imaging, may ultimately lead to tailored therapies that avoid cumulative toxicity. We performed a small pilot study to compare early changes in levels of circulatory tumor cells (CTCs) with changes in tumor proliferation, using metabolic imaging with [(18)F] 3´-deoxy-3´-fluorothymidine PET (FLT-PET) in women with advanced breast cancer, before and during docetaxel therapy. In those individuals in whom we could detect CTCs, a decrease in CTC count correlated with a decrease in FLT-PET signal, within 2 weeks. Combined, these two technologies are likely to provide a powerful, albeit expensive, tool to assess immediate responses to therapy.

Utility of F-18 Fluorothymidine PET Over F-18 Fluorodeoxyglucose PET/CT in Detection of a Recurrent Glioma

ABSTRACT Differentiation of postsurgical or postradiation necrosis from tumor recurrence is a clinical dilemma. Magnetic resonance imaging does not always perform well in this setting. Several nuclear medicine techniques are available that offer a solution in such a clinical situation. We report a case where F-18 flurodeoxyglucose (FDG) and F-18 fluorothymidine (FLT) PET/CT were used to identify recurrence of a glioma. How to cite this article Kashyap R, Tiwari MK, Senthil R, Bhattacharya A, Gupta V, Mittal BR. Utility of F-18 Fluorothymidine PET Over F-18 Fluorodeoxyglucose PET/CT in Detection of a Recurrent Glioma. J Postgrad Med Edu Res 2012;46(4):202-203.

ACRIN 6688 phase II study of fluorine-18 3′-deoxy-3′ fluorothymidine (FLT) in invasive breast cancer.

TPS125 Background: Neoadjuvant chemotherapy (NAC) prior to surgery provides enhanced options for locoregional management and has become an integral component of primary breast cancer management. Initial tumor response in patients receiving NAC is generally determined at therapy completion. This evaluation is determined by either the presence/absence of palpable tumor as a clinical response and/or presence/absence of invasive tumor cells in the breast and nodes as a pathological response. The ability to evaluate the effectiveness of neoadjuvant therapy early during treatment would be of significant importance. FDG PET imaging has been shown to be predictive of subsequent tumor response, but the tendency of FDG to accumulate in inflammatory tissues can complicate image interpretation. MRI changes have also been touted as predictors of response. Preliminary data suggest that early FLT PET is better able to predict response to therapy, as FLT uptake has been shown to correlate with cellular proliferation, and does not significantly accumulate in inflammatory tissue (Kenny et al, Eur J Nucl Med Mol Imaging 2007:1339-1347). Methods: In this phase II multi-institutional study, breast cancer patients with locally advanced disease with a tumor size ≥2cm (measured on imaging or estimated by physical exam) are eligible. Participants will receive standard of care NAC at their respective institutions. Participants will have 3 FLT imaging sessions to evaluate therapy response: at baseline, early-treatment (5-10 days after initiating treatment), and post-treatment. The primary objective is to correlate the percentage change in the standardized uptake value between baseline and early therapy FLT in the primary tumor with pathologic response. Correlatively, FLT PET parameters will be compared with proliferative indices from the initial biopsy and residual tumor surgical samples using Ki-67 staining, mitotic index, and residual cancer burden. Potential safety issues and the physiologic effects associated with FLT administration will also be evaluated. The analysis of these data may provide a better understanding of early treatment response and improve the clinical management of breast cancer in the future.

Abstract 1280: Preclinical and Clinical Evidence for MEK Pathway Inhibition by GDC-0973 using FDG-PET

Abstract Inhibitors of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) can cause potent growth arrest leading to tumor stasis or even regression, especially in BRAF mutant tumors. Seeking a pharmacodynamic marker of drug action, the effect of MEK inhibition on FDG PET signals was studied in rodent xenograft models using responsive and non-responsive cell lines. Colo205, HCT116, and A375 tumors showed substantial (30-50 %) signal (FDG flux, Ki, measured by a Patlak analysis) decreases within 72 h of beginning MEK inhibition and a rebound to baseline signal within 72 h of discontinuing treatment. BT474 tumors showed no effect. In MEK responsive tumors immunohistochemistry showed that glucose transporter GLUT1 redistributes away from the plasma membrane during treatment, which may explain the FDG PET findings. Fluorothymidine (FLT) uptake is also modulated by MEK inhibition, but the relative availability of clinical FDG PET centers and the robust preclinical results suggested the use of FDG PET, and not FLT PET, in clinic. FDG PET was implemented at all 4 Phase 1 study sites according to a standardized scanning charter. Scans were acquired at screening, at days 10-14 of cycle 1 (steady state drug concentration) and at days 26-28 of cycle 1 (trough drug concentration). Patients with RAS or RAF mutant tumors were treated at GDC-0973 MTD on the 21/7 and 14/14 dosing schedules. CT scans were acquired just prior to cycle 3 (∼ day 56) for response assessment. PET images were collected and read centrally. Up to 5 hypermetabolic lesions were assessed for mean and maximum standardized uptake value (SUV). A decrease of more than 20% in mean (across lesions) percentage change-from-baseline in SUVmax was considered a partial metabolic response (PMR). Compliance with the scanning guidelines across sites was generally good. Out of a total of 23 patients from both cohorts with PET scans read to date, 7 patients appeared to show a temporal profile of decreased FDG uptake at steady state with a rebound towards baseline at trough, mirroring the preclinical findings. Of 17 patients in the 21/7 MTD cohort whose PET scans were measured, 9 patients (∼53%) demonstrated a PMR at least one timepoint during cycle 1. Two of these patients demonstrated a PR per CT at 2 months (first tumor assessment) and also showed a robust PET response at both timepoints (Patient 1: -55% and -61% respectively; Patient 2: -63% and -53%). In addition, 2 other patients with a PMR at one or both timepoints had stable disease for at least 5 months. Of 6 patients in the 14/14 MTD cohort with PET scans read, 5 patients (83%) demonstrated a PMR at least one timepoint. Taken together, the preclinical PET evidence for a mechanistic effect of MEK inhibition on tumor glucose metabolism combined with the significant proportion of patients demonstrating PMR in this phase 1 study are consistent with hypothesis that GDC-0973 is achieving pathway modulation when given as single agent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1280. doi:10.1158/1538-7445.AM2011-1280

18F]Fluorothymidine PET imaging in the diagnosis of leptomeningeal involvement with diffuse large B-cell lymphoma

The diagnosis of leptomeningeal carcinomatosis remains difficult despite improvement in central nervous system (CNS) imaging and cytologic examination of the cerebral spinal fluid. False-negative results are common, providing obstacles in assessing both prophylactic and therapeutic efforts. As a result of increased survival of patients with a variety of systemic neoplasms it is likely that central nervous involvement will need to be addressed more often. This article presents a patient with a diffuse large B-cell lymphoma with polymorphic features. Imaging using 18F-labeled fluorodeoxythymidine (FLT) proved useful in demonstrating both parenchymal and leptomeningeal CNS involvement. The potential for FLT to identify proliferative tissue may make it uniquely suitable for detection of CNS malignant disease.

Correlation between FLT-PET and Ki-67 change in breast cancer during neoadjuvant chemotherapy.

TPS182 Background: [18F]-fluorothymidine (FLT) PET is an emerging imaging modality that measures change in cellular uptake of a radiolabeled thymidine analogue and may provide a more direct assessment of alterations in cell proliferation than changes in tumor size or glucose utilization. FLT-PET may be a useful tool in early clinical development for new oncology therapeutics. A high correlation between pre-treatment FLT uptake and Ki-67 expression in breast and lung cancer has been shown in small studies, but there have been no studies examining the correlation between change in FLT uptake and change in tissue-based measures of proliferation. The goal of this study is to determine whether a change in breast tumor FLT-PET standardized uptake value (SUV), pre- and post-treatment, correlates with the change in tumor Ki-67 labeling index (LI) during the same period. In addition, the correlation between change in tumor volume and the change in FLT uptake, Ki-67 LI, or a gene signature of cell proliferation wil...

3'-Deoxy-3'-[(18)F]fluorothymidine and O-(2-[(18)F]fluoroethyl)-L-tyrosine PET in Patients with Suspicious Recurrence of Glioma after Multimodal Treatment: Initial Results of a Retrospective Comparative Study.

The purpose of this study was to compare the uptakes and diagnostic accuracies between 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) and O-(2-[(18)F]fluoroethyl)-L-tyrosine (FET) PET in patients with a clinical suspicion of having a recurrence of glioma after multimodality treatment. Thirty-two patients who underwent FLT and FET PET due to abnormal enhancement on magnetic resonance (MR) images were included. According to surgical confirmation or follow-up results, patients were divided into those with therapy-related benign changes (TRBCs) and those with recurrence. Recurrences were divided again into initial low-grade glioma (LGG) and high-grade glioma (HGG). The uptakes of FLT and FET were compared with the maximum standardized uptake value (SUVmax) and lesion-to-normal ratio (LNR). The diagnostic accuracies were compared via a receiver-operating-characteristic (ROC) curve analysis. The LNRs of FLT in recurrences with initial HGG (8.26 ± 5.02) were significantly higher than those in recurrences with initial LGG (3.43 ± 2.14) and TRBC (1.81 ± 0.60). The LNRs of FET in recurrence with initial HGG (2.70 ± 0.48) and LGG (3.03 ± 1.32) were significantly higher than those in the TRBC (1.60 ± 0.47). The areas under the ROC curve (AUCs) of FLT and FET for initial LGG were 0.768 and 0.893, respectively. The AUCs of FLT and FET for initial HGG were 1.000 and 0.964. However, there were no statistical significances. The results for comparing with SUVmax were the same as those with LNR. Uptakes of FLT were different according to initial grade in patients with recurrent glioma, but those of FET were not. However, there were no statistical significances in the diagnostic accuracies according to initial grade between the two tracers in this study.

MO-E-AUD C-03: Use of FLT-PET Imaging to Assess Tumor and Normal Tissue Response to Radiotherapy

Purpose: In radiation therapy, use of 2‐Fluoro‐2‐deoxy‐D‐glucose (FDG) PET imaging to assess treatment response in tumors and normal tissues is suboptimal because of the confounding effects of radiation‐induced inflammation. We have investigated the feasibility of 3′‐Deoxy‐3′‐fluorothymidine (FLT) PET imaging, as a surrogate of cell proliferation, to assess treatment response in tumors and as well as normal tissues.Method and Materials: Patients receiving radiation therapy were imaged twice with FLT‐PET/CT: prior to therapy, and after receiving approximately 10–20 Gy of radiationdose. A 90 minute dynamic FLT‐PET image acquisition was initiated after the injection of FLT. The average standardized uptake values (SUV) between 60–90 minutes were used in the analysis. The CT data between the imaging sessions was co‐registered and the corresponding PET data compared and analyzed. Both, the tumor region as well as the surrounding normal tissues within the radiation field were analyzed for their response. Results: The FLT‐PET SUVs decreased approximately 20–50% within the first two weeks of radiation therapy, which provides an optimal timing window for treatment response assessment. Of the normal tissues,radiation effects were most notable in bone marrow, because of the high normal FLT uptake. Radiationdoses in excess of 10 Gy lead to complete bone marrow ablation, as assessed with FLT‐PET imaging. For doses below 10 Gy, an exponential cell‐kill relation correlates well with the observed decrease in FLT bone marrow uptake. Radiation effects were observed in other normal tissues as well. However, due to the low baseline FLT uptake, the changes were not readily detectable. Conclusion: FLT‐PET imaging was demonstrated as a powerful tool for early assessment of proliferative response to radiation therapy.Treatment assessment is possible as early as one week after the initiation of therapy. In addition to tumor response, FLT‐PET imaging also provides means to assess normal tissue damage.

18F]fluorothymidine (FLT) PET after 3 days of gefitinib treatment and tumor response in non-small cell lung cancer (NSCLC)

13031 Background: FLT has been developed as a PET tracer for imaging tumor proliferation. We evaluated whether FLT-PET could predict tumor response only after 3 days of gefitinib treatment. Methods: Nonsmokers with adenocarcinoma of the lung were eligible for this study. FLT-PET was performed at 1 day before and 3 days after the start of gefitinib (250 mg/d) therapy. The maximum standardized uptake value (SUVmax) of the main lung mass was measured, and changes in tumor SUVmax were calculated. After 6 weeks of therapy, response was assessed by chest CT according to WHO criteria. The cutoff value predicting subsequent CT response was obtained by receiver operating characteristic curve analysis. Results: Between Jun. 2005 and Nov. 2005, 22 patients were enrolled. CT response was partial response in 12 (54%), stable disease in 5 (23%), and progressive disease in 5 (23%). As early as 3 days after the initiation of therapy, significant difference in % changes of tumor SUVmax on FLT-PET was observed between responders and nonresponders (−32% v −2.3%, P = .002) ( Table ). When a reduction of tumor SUVmax ≥ 20% was used as a cutoff value for FLT-PET response, CT response could be predicted with positive and negative predictive values of 100% and 83%, respectively. Time to progression was significantly longer in FLT-PET responders than nonresponders (median 5.1 v 1.4 months, P = .011). Conclusions: Using FLT-PET obtained on days 0 and 3 of gefitinib therapy, the response could be early predicted in patients with NSCLC. [Table: see text] No significant financial relationships to disclose.

Use of 3′-deoxy-3′-[18F]fluorothymidine PET to monitor early responses to radiation therapy in murine SCCVII tumors

3'-Deoxy-3'-[(18)F]fluorothymidine (FLT) is a promising new radiopharmaceutical for imaging cell proliferation. We evaluated whether FLT PET can be used to monitor early responses to radiation treatment. C3H/HeN mice bearing murine squamous cell carcinomas were randomized to irradiation with 0, 10, or 20 Gy. Twenty-four hours later, the mice were sacrificed for histopathological and biological assessment such as cell cycle analysis, Hoechst staining, and clonogenic cell survival assay. PET scans were performed on other mice after injection of [(18)F]FLT or [(18)F]fluorodeoxyglucose (FDG) before and after radiation treatment, and tumor growth was assessed over 9 days. Histopathological examination detected no morphological changes 24 h after radiation treatment, but cell cycle analysis showed that irradiated tumors had a decreased fraction of cells in S phase and an increased fraction in G2-M phase, compared with nonirradiated tumors. Irradiated tumors also had a higher incidence of apoptotic features and reduced clonogenic cell survival. Tumor growth was significantly delayed in irradiated mice (p<0.001) compared with control mice. PET images showed increased tumoral uptake of both FLT and FDG before radiation treatment. Following irradiation, FLT uptake differed significantly (p=0.020) from that in control mice. In contrast, FDG uptake after irradiation did not differ significantly from that in control mice. Our finding that tumor uptake of FLT was reduced at 24 h after radiation treatment suggests that FLT PET may be a promising imaging modality for monitoring the early effects of radiation therapy.

Early Detection of Chemoradiotherapy Response in Esophageal Carcinoma by Fluorothymidine (FLT) PET Imaging

Early Detection of Chemoradiotherapy Response in Esophageal Carcinoma by Fluorothymidine (FLT) PET Imaging

&lt;SUP&gt;18&lt;/SUP&gt;F]3′-Deoxy-3′-Fluorothymidine–PET in NHL Patients: Whole-Body Biodistribution and Imaging of Lymphoma Manifestations—a Pilot Study

&lt;SUP&gt;18&lt;/SUP&gt;F]3′-Deoxy-3′-Fluorothymidine–PET in NHL Patients: Whole-Body Biodistribution and Imaging of Lymphoma Manifestations—a Pilot Study

The biology of lung cancer- FDG and fluorothymidine PET

The biology of lung cancer- FDG and fluorothymidine PET