Human biodistribution and radiation dosimetry of novel PET probes targeting the deoxyribonucleoside salvage pathway.

PURPOSE: Deoxycytidine kinase (dCK) is a rate-limiting enzyme in deoxyribonucleoside salvage, a metabolic pathway involved in the production and maintenance of a balanced pool of deoxyribonucleoside triphosphates (dNTPs) for DNA synthesis. dCK phosphorylates and therefore activates nucleoside analogs such as cytarabine, gemcitabine, decitabine, cladribine, and clofarabine that are used routinely in cancer therapy. Imaging probes that target dCK might allow stratifying patients into likely responders and nonresponders with dCK-dependent prodrugs. Here we present the biodistribution and radiation dosimetry of three fluorinated dCK substrates, (18)F-FAC, L: -(18)F-FAC, and L: -(18)F-FMAC, developed for positron emission tomography (PET) imaging of dCK activity in vivo. METHODS: PET studies were performed in nine healthy human volunteers, three for each probe. After a transmission scan, the radiopharmaceutical was injected intravenously and three sequential emission scans acquired from the base of the skull to mid-thigh. Regions of interest encompassing visible organs were drawn on the first PET scan and copied to the subsequent scans. Activity in target organs was determined and absorbed dose estimated with OLINDA/EXM. The standardized uptake value was calculated for various organs at different times. RESULTS: Renal excretion was common to all three probes. Bone marrow had higher uptake for L: -(18)F-FAC and L: -(18)F-FMAC than (18)F-FAC. Prominent liver uptake was seen in L: -(18)F-FMAC and L: -(18)F-FAC, whereas splenic activity was highest for (18)F-FAC. Muscle uptake was also highest for (18)F-FAC. The critical organ was the bladder wall for all three probes. The effective dose was 0.00524, 0.00755, and 0.00910 mSv/MBq for (18)F-FAC, L: -(18)F-FAC, and L: -(18)F-FMAC, respectively. CONCLUSION: The biodistribution of (18)F-FAC, L: -(18)F-FAC, and L: -(18)F-FMAC in humans reveals similarities and differences. Differences may be explained by different probe affinities for nucleoside transporters, dCK, and catabolic enzymes such as cytidine deaminase (CDA). Dosimetry demonstrates that all three probes can be used safely to image the deoxyribonucleoside salvage pathway in humans.

Treatment response evaluation using 18F-FDOPA PET in patients with recurrent malignant glioma on bevacizumab therapy.

PURPOSE: This study compares the value of 3,4-dihydroxy-6-[(18)F]-fluoro-l-phenylalanine ((18)F-FDOPA) positron emission tomography (PET) and MRI in assessing outcome during antiangiogenic treatment in patients with recurrent high-grade gliomas. EXPERIMENTAL DESIGN: Thirty patients were prospectively studied with (18)F-FDOPA PET scans immediately before, and two and six weeks after start of bevacizumab therapy. (18)F-FDOPA metabolic tumor volumes (MTV) as well as max and mean standardized uptake values (SUV) within this MTV were obtained. MRI treatment response was assessed at six weeks. The predictive ability of (18)F-FDOPA PET and MRI response assessment were evaluated with regard to progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 30, 28, and 24 (18)F-FDOPA PET scans at baseline, two weeks, and six weeks, were available for analysis, respectively. (18)F-FDOPA PET SUVs as well as their changes through therapy were not predictive of outcome. However, MTV parameters such as MTV changes were highly prognostic. Interestingly, absolute MTV at the first follow up scan provides the most significant prediction for increased OS (P < 0.0001) as well as PFS (P = 0.001). This surprising result was scrutinized with cross-validation and simulation analysis. Responders based on (18)F-FDOPA PET data survived 3.5 times longer (12.1 months vs. 3.5 months, median OS, P < 0.001) than nonresponders (17 patients vs. 11 patients, respectively). In comparison, responders based on MRI data lived 1.5 times longer (11.4 months vs 7.7 months, P = 0.03) than nonresponders (22 patients vs. 7 patients, respectively). CONCLUSIONS: (18)F-FDOPA PET identifies treatment responders to antiangiogenic therapy as early as two weeks after treatment initiation.

3'-deoxy-3'-18F-fluorothymidine PET and MRI for early survival predictions in patients with recurrent malignant glioma treated with bevacizumab.

UNLABELLED: With the dismal prognosis for malignant glioma patients, survival predictions become key elements in patient management. This study compares the value of 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET and MRI for early outcome predictions in patients with recurrent malignant glioma on bevacizumab therapy. METHODS: Thirty patients treated with bevacizumab combination therapy underwent (18)F-FLT PET immediately before and at 2 and 6 wk after the start of treatment. A metabolic treatment response was defined as a decrease of equal to or greater than 25% in tumor (18)F-FLT uptake (standardized uptake values) from baseline using receiver-operating-characteristic analysis. MRI treatment response was assessed at 6 wk according to the Response Assessment in Neurooncology criteria. (18)F-FLT responses at different times were compared with MRI response and correlated with progression-free survival and overall survival using Kaplan-Meier analysis. Metabolic response based on (18)F-FLT was further compared with other outcome predictors using Cox regression analysis. RESULTS: Early and late changes in tumor (18)F-FLT uptake were more predictive of overall survival than MRI criteria (P < 0.001 and P = 0.01, respectively). (18)F-FLT uptake changes were also predictive of progression-free survival (P < 0.001). The median overall survival for responders was 3.3 times longer than for nonresponders based on (18)F-FLT PET criteria (12.5 vs. 3.8 mo, P < 0.001) but only 1.4 times longer using MRI assessment (12.9 vs. 9.0 mo, P = 0.05). On the basis of the 6-wk (18)F-FLT PET response, there were 16 responders (53%) and 14 nonresponders (47%), whereas MRI identified 9 responders (7 partial response, 2 complete response, 31%) and 20 nonresponders (13 stable disease, 7 progressive disease, 69%). In 7 of the 8 discrepant cases between MRI and PET, (18)F-FLT PET was able to demonstrate response earlier than MRI. Among various outcome predictors, multivariate analysis identified (18)F-FLT PET changes at 6 wk as the strongest independent survival predictor (P < 0.001; hazard ratio, 10.051). CONCLUSION: Changes in tumor (18)F-FLT uptake were highly predictive of progression-free and overall survival in patients with recurrent malignant glioma on bevacizumab therapy. (18)F-FLT PET seems to be more predictive than MRI for early treatment response.