Dataset Information

Prospective Study of 3'-Deoxy-3'-18F-Fluorothymidine PET for Early Interim Response Assessment in Advanced-Stage B-Cell Lymphoma.

ABSTRACT: Current clinical and imaging tools remain suboptimal for early assessment of prognosis and treatment response in aggressive lymphomas. PET with 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) can be used to measure tumor cell proliferation and treatment response. In a prospective study in patients with advanced-stage B-cell lymphoma, we investigated the prognostic and predictive value of (18)F-FLT PET in comparison to standard imaging with (18)F-FDG PET and clinical outcome.Sixty-five patients were treated with an induction/consolidation regimen consisting of 4 cycles of R-CHOP-14 (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) followed by 3 cycles of ICE (ifosfamide, carboplatin, etoposide). (18)F-FLT PET was performed at baseline and at interim (iPET) after 1-2 cycles of therapy. (18)F-FDG PET was performed at baseline, after cycle 4, and at the end of therapy. The relationship between PET findings, progression-free survival (PFS) and overall survival (OS) was investigated.With a median follow-up of 51 mo, PFS and OS were 71% and 86%, respectively. (18)F-FLT iPET, analyzed visually (using a 5-point score) or semiquantitatively (using SUV and ?SUV) predicted both PFS and OS (P < 0.01 for all parameters). Residual (18)F-FLT SUVmax on iPET was associated with an inferior PFS (hazard ratio, 1.26, P = 0.001) and OS (hazard ratio, 1.27, P = 0.002). When (18)F-FDG PET was used, findings in the end of treatment scan were better predictors of PFS and OS than findings on the interim scan. Baseline PET imaging parameters, including SUV, proliferative volume, or metabolic tumor volume, did not correlate with outcome.(18)F-FLT PET after 1-2 cycles of chemotherapy predicts PFS and OS, and a negative (18)F-FLT iPET result may potentially help design risk-adapted therapies in patients with aggressive lymphomas. In contrast, the positive predictive value of (18)F-FLT iPET remains too low to justify changes in patient management.

SUBMITTER: Schoder H

PROVIDER: S-EPMC4854760 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Prospective Study of 3'-Deoxy-3'-18F-Fluorothymidine PET for Early Interim Response Assessment in Advanced-Stage B-Cell Lymphoma.

Schöder Heiko H Zelenetz Andrew D AD Hamlin Paul P Gavane Somali S Horwitz Steven S Matasar Matthew M Moskowitz Alison A Noy Ariela A Palomba Lia L Portlock Carol C Straus David D Grewal Ravinder R Migliacci Jocelyn C JC Larson Steven M SM Moskowitz Craig H CH

Journal of nuclear medicine : official publication, Society of Nuclear Medicine 20151230 5

<h4>Unlabelled</h4>Current clinical and imaging tools remain suboptimal for early assessment of prognosis and treatment response in aggressive lymphomas. PET with 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) can be used to measure tumor cell proliferation and treatment response. In a prospective study in patients with advanced-stage B-cell lymphoma, we investigated the prognostic and predictive value of (18)F-FLT PET in comparison to standard imaging with (18)F-FDG PET and clinical outcome.<h4> ...[more]

PMID: 26719374

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Project description:Selective inhibition of oncogenic targets and associated signaling pathways forms the basis of personalized cancer medicine. The clinical success of (V600E)BRAF inhibition in melanoma, coupled with the emergence of acquired resistance, underscores the importance of rigorously validating quantitative biomarkers of treatment response in this and similar settings. Because constitutive activation of BRAF leads to proliferation in tumors, we explored 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET to noninvasively quantify changes in tumor proliferation that are associated with pharmacologic inhibition of (V600E)BRAF downstream effectors and that precede changes in tumor volume.Human colorectal cancer (CRC) cell lines expressing (V600E)BRAF were used to explore relationships between upregulation of p27 and phosphorylation of BRAF downstream effectors on small-molecule (V600E)BRAF inhibitor exposure. Athymic nude mice bearing (V600E)BRAF-expressing human CRC cell line xenografts were treated with a small-molecule (V600E)BRAF inhibitor (or vehicle) daily for 10 d. Predictive (18)F-FLT PET was conducted before changes in tumor volume occurred. Correlations were evaluated among PET, inhibition of phosphorylated MEK (p-MEK) and phosphorylated-ERK (p-ERK) by Western blot, tumor proliferation by histology, and small-molecule exposure by matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS).Treatment of CRC cell lines with PLX4720 reduced proliferation associated with target inhibition and upregulation of p27. In vivo, PLX4720 treatment reduced (18)F-FLT uptake, but not (18)F-FDG uptake, in Lim2405 xenografts before quantifiable differences in xenograft volume. Reduced (18)F-FLT PET reflected a modest, yet significant, reduction of Ki67 immunoreactivity, inhibition of p-MEK and p-ERK, and elevated tumor cell p27 protein levels. Both (18)F-FLT PET and (18)F-FDG PET accurately reflected a lack of response in HT-29 xenografts, which MALDI imaging mass spectrometry suggested may have stemmed from limited PLX4720 exposure.We used preclinical models of CRC to demonstrate (18)F-FLT PET as a sensitive predictor of response to (V600E)BRAF inhibitors. Because (18)F-FLT PET predicted reduced proliferation associated with attenuation of BRAF downstream effectors, yet (18)F-FDG PET did not, these data suggest that (18)F-FLT PET may represent an alternative to (18)F-FDG PET for quantifying clinical responses to BRAF inhibitors.

Project description:Our objective was to determine whether early change in standardized uptake values (SUVs) of 3'deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) using PET with CT could predict pathologic complete response (pCR) of primary breast cancer to neoadjuvant chemotherapy (NAC). The key secondary objective was to correlate SUV with the proliferation marker Ki-67 at baseline and after NAC.This prospective, multicenter phase II study did not specify the therapeutic regimen, thus, NAC varied among centers. All evaluable patients underwent (18)F-FLT PET/CT at baseline (FLT1) and after 1 cycle of NAC (FLT2); 43 patients were imaged at FLT1, FLT2, and after NAC completion (FLT3). The percentage change in maximum SUV (%?SUVmax) between FLT1 and FLT2 and FLT3 was calculated for the primary tumors. The predictive value of ?SUVmax for pCR was determined using receiver-operating-characteristic curve analysis. The correlation between SUVmax and Ki-67 was also assessed.Fifty-one of 90 recruited patients (median age, 54 y; stage IIA-IIIC) met the eligibility criteria for the primary objective analysis, with an additional 22 patients totaling 73 patients for secondary analyses. A pCR in the primary breast cancer was achieved in 9 of 51 patients. NAC resulted in a significant reduction in %SUVmax (mean ?, 39%; 95% confidence interval, 31-46). There was a marginal difference in %?SUVmax_FLT1-FLT2 between pCR and no-pCR patient groups (Wilcoxon 1-sided P = 0.050). The area under the curve for ?SUVmax in the prediction of pCR was 0.68 (90% confidence interval, 0.50-0.83; Delong 1-sided P = 0.05), with slightly better predictive value for percentage mean SUV (P = 0.02) and similar prediction for peak SUV (P = 0.04). There was a weak correlation with pretherapy SUVmax and Ki-67 (r = 0.29, P = 0.04), but the correlation between SUVmax and Ki-67 after completion of NAC was stronger (r = 0.68, P < 0.0001).(18)F-FLT PET imaging of breast cancer after 1 cycle of NAC weakly predicted pCR in the setting of variable NAC regimens. Posttherapy (18)F-FLT uptake correlated with Ki-67 on surgical specimens. These results suggest some efficacy of (18)F-FLT as an indicator of early therapeutic response of breast cancer to NAC and support future multicenter studies to test (18)F-FLT PET in a more uniformly treated patient population.

Project description:PURPOSE In studies of diffuse large B-cell lymphoma, positron emission tomography with [(18)F]fluorodeoxyglucose (FDG-PET) performed after two to four cycles of chemotherapy has demonstrated prognostic significance. However, some patients treated with immunochemotherapy experience a favorable long-term outcome despite a positive interim FDG-PET scan. To clarify the significance of interim FDG-PET scans, we prospectively studied interim FDG-positive disease within a risk-adapted sequential immunochemotherapy program. PATIENTS AND METHODS From March 2002 to November 2006, 98 patients at Memorial Sloan-Kettering Cancer Center received induction therapy with four cycles of accelerated R-CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by an interim FDG-PET scan. If the FDG-PET scan was negative, patients received three cycles of ICE (ifosfamide, carboplatin, and etoposide) consolidation therapy. If residual FDG-positive disease was seen, patients underwent biopsy; if the biopsy was negative, they also received three cycles of ICE. Patients with a positive biopsy received ICE followed by autologous stem-cell transplantation. RESULTS At a median follow-up of 44 months, overall and progression-free survival were 90% and 79%, respectively. Ninety-seven patients underwent interim FDG-PET scans; 59 had a negative scan, 51 of whom are progression free. Thirty-eight patients with FDG-PET-positive disease underwent repeat biopsy; 33 were negative, and 26 remain progression free after ICE consolidation therapy. Progression-free survival of interim FDG-PET-positive/biopsy-negative patients was identical to that in patients with a negative interim FDG-PET scan (P = .27). CONCLUSION Interim or post-treatment FDG-PET evaluation did not predict outcome with this dose-dense, sequential immunochemotherapy program. Outside of a clinical trial, we recommend biopsy confirmation of an abnormal interim FDG-PET scan before changing therapy.

Project description:BackgroundWe tested interim positron-emission tomography-computed tomography (PET-CT) as a measure of early response to chemotherapy in order to guide treatment for patients with advanced Hodgkin's lymphoma.MethodsPatients with newly diagnosed advanced classic Hodgkin's lymphoma underwent a baseline PET-CT scan, received two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy, and then underwent an interim PET-CT scan. Images were centrally reviewed with the use of a 5-point scale for PET findings. Patients with negative PET findings after two cycles were randomly assigned to continue ABVD (ABVD group) or omit bleomycin (AVD group) in cycles 3 through 6. Those with positive PET findings after two cycles received BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone). Radiotherapy was not recommended for patients with negative findings on interim scans. The primary outcome was the difference in the 3-year progression-free survival rate between randomized groups, a noninferiority comparison to exclude a difference of 5 or more percentage points.ResultsA total of 1214 patients were registered; 937 of the 1119 patients (83.7%) who underwent an interim PET-CT scan according to protocol had negative findings. With a median follow-up of 41 months, the 3-year progression-free survival rate and overall survival rate in the ABVD group were 85.7% (95% confidence interval [CI], 82.1 to 88.6) and 97.2% (95% CI, 95.1 to 98.4), respectively; the corresponding rates in the AVD group were 84.4% (95% CI, 80.7 to 87.5) and 97.6% (95% CI, 95.6 to 98.7). The absolute difference in the 3-year progression-free survival rate (ABVD minus AVD) was 1.6 percentage points (95% CI, -3.2 to 5.3). Respiratory adverse events were more severe in the ABVD group than in the AVD group. BEACOPP was given to the 172 patients with positive findings on the interim scan, and 74.4% had negative findings on a third PET-CT scan; the 3-year progression-free survival rate was 67.5% and the overall survival rate 87.8%. A total of 62 patients died during the trial (24 from Hodgkin's lymphoma), for a 3-year progression-free survival rate of 82.6% and an overall survival rate of 95.8%.ConclusionsAlthough the results fall just short of the specified noninferiority margin, the omission of bleomycin from the ABVD regimen after negative findings on interim PET resulted in a lower incidence of pulmonary toxic effects than with continued ABVD but not significantly lower efficacy. (Funded by Cancer Research UK and Others; ClinicalTrials.gov number, NCT00678327.).

Project description:Access to diverse PET tracers for preclinical and clinical research remains a major obstacle to research in cancer and other disease research. The prohibitive cost and limited availability of tracers could be alleviated by microfluidic radiosynthesis technologies combined with a high-yield microscale radiosynthetic method. In this report, we demonstrate the multistep synthesis of 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) with high yield on an electrowetting-on-dielectric (EWOD) microfluidic radiosynthesizer, previously developed in our group. We have identified and established several parameters that are most critical in the microscale radiosynthesis, such as the reaction time, reagent concentration, and molar ratios, to successfully synthesize (18)F-FLT in this compact platform.(18)F-FLT was synthesized from the 3-N-Boc-1-[5-O-(4,4'-dimethoxytrityl)-3-O-nosyl-2-deoxy-?-D-lyxofuranosyl] thymine precursor on the EWOD chip starting from the first solvent exchange and (18)F-fluoride ion activation step to the final deprotection step. The fluorination reaction was performed in a mixture of thexyl alcohol and dimethyl sulfoxide. The crude product after deprotection was collected from the chip and purified on a custom-made solid-phase extraction cartridge and subjected to quality control testing. The purified (18)F-FLT was suitable for small-animal PET studies in multiple nude mice xenografted with the A431 carcinoma cell line.(18)F-FLT was successfully synthesized on the EWOD microdevice coupled with an off-chip solid-phase extraction purification with a decayed-corrected radiochemical yield of 63% ± 5% (n = 5) and passed all of the quality control tests required by the U.S. Pharmacopeia for radiotracers to be injected into humans. We have successfully demonstrated the synthesis of several batches of (18)F-FLT on EWOD, starting with approximately 333 MBq of radioactivity and obtained up to 52 MBq (non-decay-corrected) of (18)F-FLT on cartridge purification. The specific activity of 2 representative preparations of (18)F-FLT synthesized on the EWOD chip were measured to be 1,800 and 2,400 GBq/?mol.The EWOD microchip and optimized synthesis method in combination represent an effective platform for synthesizing (18)F-FLT with high yield and of good quality for imaging. This compact platform, with configurable synthesis steps, could potentially form the basis of a stand-alone system that decouples PET probe production from the cyclotron and specialized radiochemistry facilities and increases diversity and flexibility in probe production.

Dataset Information

Prospective Study of 3'-Deoxy-3'-18F-Fluorothymidine PET for Early Interim Response Assessment in Advanced-Stage B-Cell Lymphoma.

Publications

Prospective Study of 3'-Deoxy-3'-18F-Fluorothymidine PET for Early Interim Response Assessment in Advanced-Stage B-Cell Lymphoma.

Similar Datasets

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