A B S T R A C T PurposeEvaluation of treatment effects in malignant brain tumors is challenging because of the lack of reliable response predictors of tumor response. This study examines the predictive value of positron emission tomography (PET) using [18 F] fluorothymidine (FLT), an imaging biomarker of cell proliferation, in patients with recurrent malignant gliomas treated with bevacizumab in combination with irinotecan. Patients and MethodsPatients with recurrent malignant gliomas treated with biweekly cycles of bevacizumab and irinotecan were prospectively studied with FLT-PET at baseline, after 1 to 2 weeks, and after 6 weeks from start of treatment. A more than 25% reduction in tumor FLT uptake as measured by standardized uptake value was defined as a metabolic response. FLT responses were compared with response as shown by magnetic resonance imaging (MRI) and patient survival. ResultsTwenty-one patients were included, and 19 were assessable for metabolic response evaluation with FLT-PET. There were nine responders (47%) and 10 nonresponders (53%). Metabolic responders survived three times as long as nonresponders (10.8 v 3.4 months; P ϭ .003), and tended to have a prolonged progression-free survival (P ϭ .061). Both early and later FLT-PET responses were more significant predictors of overall survival (1 to 2 weeks, P ϭ .006; 6 weeks, P ϭ .002), compared with the MRI responses (P ϭ .060 for both 6-week and best responses). ConclusionFLT-PET as an imaging biomarker seems to be predictive of overall survival in bevacizumab and irinotecan treatment of recurrent gliomas. Whether FLT-PET performed as early as 1 to 2 week after starting treatment is as predictive as the study indicates at 6 weeks warrants further investigation.

Post-chemotherapy treated cancer patients frequently report cognitive difficulties. The biology of this phenomenon is poorly understood, with uncertainty about possible direct toxic effects on the brain, secondary effects from systemic inflammation, host factors/genetic predisposition to cognitive complaints, or hormonal changes influencing cognitive function. To elucidate possible mechanisms associated with post-treatment cognitive dysfunction among breast cancer survivors, in 2007 we established a prospective, longitudinal, observational cohort study of early stage breast cancer patients, recruited at the end of initial treatments (primary treatment exposure included surgery, ± radiation, ± chemotherapy), and prior to the initiation of adjuvant endocrine therapy. We assessed cognitive complaints, neuropsychological (NP) test performance, markers of inflammation, and brain imaging at baseline, 6 months and 12 months after enrollment. In this analysis of data from the first 93 patients enrolled in the cohort study, we focus on the relationship of circulating levels of proinflammatory cytokines to cerebral functioning and chemotherapy exposure. Among the proinflammatory cytokines tested (IL-1ra, sTNF-RII, CRP, and IL-6) at baseline, only sTNF-RII was increased among chemotherapy exposed patients, with a significant decline in the year after treatment (p=0.003). Higher baseline sTNF-RII was significantly associated with increased memory complaints. In chemotherapy exposed patients, the longitudinal decline in sTNF-RII was significantly correlated with fewer memory complaints over 12 months (r=-0.34, p=0.04). Higher baseline sTNF-RII was also associated with relatively diminished brain metabolism in the inferior frontal cortex (r=-0.55, p=0.02), as well as relatively increased inferior frontal metabolism after one year, in chemotherapy-exposed subjects. These preliminary findings suggest that post-chemotherapy increases in TNF-α may be playing an important role in the manifestations of cognitive complaints in breast cancer survivors.

6-18 F-fluoro-L-dopa ( 18 F-FDOPA) measured with PET as a biomarker of amino acid uptake has been investigated in brain tumor imaging. The aims of the current study were to determine whether the degree of 18 F-FDOPA uptake in brain tumors predicted tumor grade and was associated with tumor proliferative activity in newly diagnosed and recurrent gliomas. Methods: Fifty-nine patients (40 men, 19 women; mean age 6 SD, 44.4 6 12.3 y) with newly diagnosed (n 5 22) or recurrent (n 5 37) gliomas underwent 18 F-FDOPA PET perioperatively. Tumor tissue was obtained by resection or biopsy in all patients. The tumor grade and Ki-67 proliferation index were obtained by standard pathology assays. Tumor 18 F-FDOPA uptake was quantified by determining various standardized uptake value (SUV) parameters (mean SUV, maximum SUV [SUVmax], mean values of voxels with top 20% SUVs, and tumor-to-normal-brain tissue ratios) that were then correlated with histopathologic grade and Ki-67 proliferation index. Results: Fifty-nine lesions in 59 patients were analyzed. 18 F-FDOPA uptake was significantly higher in high-grade than in low-grade tumors for newly diagnosed tumors (SUVmax, 4.22 6 1.30 vs. 2.34 6 1.35, P 5 0.005) but not for recurrent tumors that had gone through treatment previously (SUVmax, 3.36 6 1.26 vs. 2.67 6 1.18, P 5 0.22). An SUVmax threshold of 2.72 differentiated low-grade from high-grade tumors, with a sensitivity and specificity of 85% and 89%, respectively, using receiver-operating-characteristic curve analysis (area under the curve, 0.86). 18 F-FDOPA PET uptake correlated significantly with Ki-67 tumor proliferation index in newly diagnosed tumors (r 5 0.66, P 5 0.001) but not in recurrent tumors (r 5 0.14, P 5 0.41). Conclusion: 18 F-FDOPA uptake is significantly higher in high-grade than in low-grade tumors in newly diagnosed but not recurrent tumors that had been treated previously. A significant correlation between 18 F-FDOPA uptake and tumor proliferation in newly diagnosed tumors was observed, whereas this correlation was not identified for recurrent tumors. Thus, 18 F-FDOPA PET might serve as a noninvasive marker of tumor grading and might provide a useful surrogate of tumor proliferative activity in newly diagnosed gliomas.

Purpose This study compares the value of 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-FDOPA) PET and MRI in assessing outcome during antiangiogenic treatment in patients with recurrent high-grade gliomas. Experimental Design Thirty patients were prospectively studied with 18F-FDOPA PET scans immediately before, and two and six weeks after start of bevacizumab therapy. 18F-FDOPA metabolic tumor volumes (MTV) as well as max and mean SUVs within this MTV were obtained. MRI treatment response was assessed at 6 weeks. The predictive ability of 18F-FDOPA PET and MRI response assessment were evaluated with regard to progression-free survival (PFS) and overall survival (OS). Results 30, 28, and 24 18F-FDOPA PET scans at baseline, 2 weeks, and 6 weeks, were available for analysis, respectively. 18F-FDOPA PET SUVs as well as their changes through therapy were not predictive of outcome. However, metabolic tumor volume (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 18F-FDOPA PET data survived 3.5 times longer (12.1 vs. 3.5 months median OS, P < 0.001) than non-responders (17 vs. 11 patients, respectively). In comparison, responders based on MRI data lived 1.5 times longer (11.4 vs 7.7 mo, P = 0.03) than non-responders (22 vs. 7 patients, respectively). Conclusions 18F-FDOPA PET identifies treatment responders to antiangiogenic therapy as early as two weeks after treatment initiation.

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′-18F-fluorothymidine (18F-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 18F-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 18F-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. 18F-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 18F-FLT was further compared with other outcome predictors using Cox regression analysis. Results Early and late changes in tumor 18F-FLT uptake were more predictive of overall survival than MRI criteria (P < 0.001 and P = 0.01, respectively). 18F-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 18F-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 18F-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, 18F-FLT PET was able to demonstrate response earlier than MRI. Among various outcome predictors, multivariate analysis identified 18F-FLT PET changes at 6 wk as the strongest independent survival predictor (P < 0.001; hazard ratio, 10.051). Conclusion Changes in tumor 18F-FLT uptake were highly predictive of progression-free and overall survival in patients with recurrent malignant glioma on bevacizumab therapy. 18F-FLT PET seems to be more predictive than MRI for early treatment response.