A Phase III study of radiation therapy (RT) and O6-benzylguanine + BCNU versus RT and BCNU alone and methylation status in newly diagnosed glioblastoma and gliosarcoma: Southwest Oncology Group (SWOG) study S0001.

AIMS: To determine the efficacy of methylguanine methyltransferase (MGMT) depletion + BCNU [1,3-bis(2-chloroethyl)-1- nitrosourea: carmustine] therapy and the impact of methylation status in adults with glioblastoma multiforme (GBM) and gliosarcoma. METHODS: Methylation analysis was performed on GBM patients with adequate tissue samples. Patients with newly diagnosed GBM or gliosarcoma were eligible for this Phase III open-label clinical trial. At registration, patients were randomized to Arm 1, which consisted of therapy with O(6)-benzylguanine (O(6)-BG) + BCNU 40 mg/m(2) (reduced dose) + radiation therapy (RT) (O6BG + BCNU arm), or Arm 2, which consisted of therapy with BCNU 200 mg/m(2) + RT (BCNU arm). RESULTS: A total of 183 patients with newly diagnosed GBM or gliosarcoma from 42 U.S. institutions were enrolled in this study. Of these, 90 eligible patients received O(6)-BG + BCNU + RT and 89 received BCNU + RT. The trial was halted at the first interim analysis in accordance with the guidelines for stopping the study due to futility (<40 % improvement among patients on the O6BG + BCNU arm). Following adjustment for stratification factors, there was no significant difference in overall survival (OS) or progression-free survival (PFS) between the two groups (one sided p = 0.94 and p = 0.88, respectively). Median OS was 11 [95 % confidence interval (CI) 8-13] months for patients in the O6BG + BCNU arm and 10 (95 % CI 8-12) months for those in the BCNU arm. PFS was 4 months for patients in each arm. Adverse events were reported in both arms, with significantly more grade 4 and 5 events in the experimental arm. CONCLUSIONS: The addition of O(6)-BG to the standard regimen of radiation and BCNU for the treatment patients with newly diagnosed GBM and gliosarcoma did not provide added benefit and in fact caused additional toxicity.

A phase 1/2 study of orally administered synthetic hypericin for treatment of recurrent malignant gliomas.

BACKGROUND: Hypericin is a potent inhibitor of glioma growth in vitro. To examine whether synthetic oral hypericin can be tolerated by patients with recurrent malignant gliomas (anaplastic astrocytoma and glioblastoma) and to investigate its efficacy against these tumors, the authors undertook an open-label, sequential dose escalation/de-escalation tolerance study. METHODS: Patients with documented recurrent or progressive malignant gliomas who had received standard radiation therapy with or without chemotherapy were included. Patients were excluded for previous treatment with agents known to contain hypericin or treatment within 30 days with medications known to cause photosensitivity. Enrolled patients were given gradually increasing dosages of oral synthetic hypericin (0.05-0.50 mg/kg) for up to 3 months if no toxicity was observed, and patient response to treatment was noted. The patients were examined each month and underwent magnetic resonance imaging to evaluate tumor status at 3 months. RESULTS: Synthetic hypericin administered orally appeared to provide stabilization or a slight (<50%) decrease in tumor volume (coded as stable disease) at 3 months for 7 of 42 patients (17%) and produced a tumor reduction >50% (partial response) in 2 patients (5%). Seventeen patients (40%) survived for 3 months on daily synthetic hypericin at dose levels of 0.33 ± 0.070 mg/kg daily. The mean maximum tolerated dose was 0.40 ± 0.098 mg/kg daily. Twelve patients continued on hypericin therapy beyond 3 months. The median survival was 26 weeks (Kaplan-Meier method). CONCLUSIONS: The results of this study indicated that synthetic, oral hypericin is well tolerated in this patient group. The response results were comparable to those reported from other studies of salvage therapies for recurrent malignant brain tumors.

Complementary but distinct roles for MRI and 18F-fluoromisonidazole PET in the assessment of human glioblastomas.

UNLABELLED: Glioblastoma multiforme is a primary brain tumor known for its rapid proliferation, diffuse invasion, and prominent neovasculature and necrosis. This study explores the in vivo link between these characteristics and hypoxia by comparing the relative spatial geometry of developing vasculature inferred from gadolinium-enhanced T1-weighted MRI (T1Gd), edematous tumor extent revealed on T2-weighted MRI (T2), and hypoxia assessed by 18F-fluoromisonidazole PET (18F-FMISO). Given the role of hypoxia in upregulating angiogenic factors, we hypothesized that the distribution of hypoxia seen on 18F-FMISO is correlated spatially and quantitatively with the amount of leaky neovasculature seen on T1Gd. METHODS: A total of 24 patients with glioblastoma underwent T1Gd, T2, and 18F-FMISO-11 studies preceded surgical resection or biopsy, 7 followed surgery and preceded radiation therapy, and 11 followed radiation therapy. Abnormal regions seen on the MRI scan were segmented, including the necrotic center (T0), the region of abnormal blood-brain barrier associated with disrupted vasculature (T1Gd), and infiltrating tumor cells and edema (T2). The 18F-FMISO images were scaled to the blood 18F-FMISO activity to create tumor-to-blood ratio (T/B) images. The hypoxic volume (HV) was defined as the region with T/Bs greater than 1.2, and the maximum T/B (T/Bmax) was determined by the voxel with the greatest T/B value. RESULTS: The HV generally occupied a region straddling the outer edge of the T1Gd abnormality and into the T2. A significant correlation between HV and the volume of the T1Gd abnormality that relied on the existence of a large outlier was observed. However, there was consistent correlation between surface areas of all MRI-defined regions and the surface area of the HV. The T/Bmax, typically located within the T1Gd region, was independent of the MRI-defined tumor size. Univariate survival analysis found the most significant predictors of survival to be HV, surface area of HV, surface area of T1Gd, and T/Bmax. CONCLUSION: Hypoxia may drive the peripheral growth of glioblastomas. This conclusion supports the spatial link between the volumes and surface areas of the hypoxic and MRI regions; the magnitude of hypoxia, T/Bmax, remains independent of size.

Regional hypoxia in glioblastoma multiforme quantified with [18F]fluoromisonidazole positron emission tomography before radiotherapy: correlation with time to progression and survival.

PURPOSE: Hypoxia is associated with resistance to radiotherapy and chemotherapy and activates transcription factors that support cell survival and migration. We measured the volume of hypoxic tumor and the maximum level of hypoxia in glioblastoma multiforme before radiotherapy with [(18)F]fluoromisonidazole positron emission tomography to assess their impact on time to progression (TTP) or survival. EXPERIMENTAL DESIGN: Twenty-two patients were studied before biopsy or between resection and starting radiotherapy. Each had a 20-minute emission scan 2 hours after i.v. injection of 7 mCi of [(18)F]fluoromisonidazole. Venous blood samples taken during imaging were used to create tissue to blood concentration (T/B) ratios. The volume of tumor with T/B values above 1.2 defined the hypoxic volume (HV). Maximum T/B values (T/B(max)) were determined from the pixel with the highest uptake. RESULTS: Kaplan-Meier plots showed shorter TTP and survival in patients whose tumors contained HVs or tumor T/B(max) ratios greater than the median (P < or = 0.001). In univariate analyses, greater HV or tumor T/B(max) were associated with shorter TTP or survival (P < 0.002). Multivariate analyses for survival and TTP against the covariates HV (or T/B(max)), magnetic resonance imaging (MRI) T1Gd volume, age, and Karnovsky performance score reached significance only for HV (or T/B(max); P < 0.03). CONCLUSIONS: The volume and intensity of hypoxia in glioblastoma multiforme before radiotherapy are strongly associated with poorer TTP and survival. This type of imaging could be integrated into new treatment strategies to target hypoxia more aggressively in glioblastoma multiforme and could be applied to assess the treatment outcomes.

Positron emission tomography-guided conformal fast neutron therapy for glioblastoma multiforme.

Glioblastoma multiforme (GBM) continues to be a difficult therapeutic challenge. Our study was conducted to determine whether improved survival and tumor control could be achieved with modern delivery of fast neutron radiation using three-dimensional treatment planning. Ten patients were enrolled. Eligibility criteria included pathologic diagnosis of GBM, age >or=18 years, and KPS >or=60. Patients underwent MRI and (18)F-fluorodeoxyglucose PET (FDG PET) as part of initial three-dimensional treatment planning. Sequential targets were treated with noncoplanar fields to a total dose of 18 Gy in 16 fractions over 4 weeks. Median and 1-year overall survival were 55 weeks and 60%, respectively. One patient remains alive at last follow-up 255 weeks after diagnosis. Median progression-free survival was 16 weeks, and all patients had tumor progression by 39 weeks. Treatment was clinically well tolerated, but evidence of mild to moderate gliosis and microvascular sclerosis consistent with radiation injury was observed at autopsy in specimens taken from regions of contralateral brain that received approximately 6-10 Gy. Fast neutron radiation using modern imaging, treatment planning, and beam delivery was feasible to a total dose of 18 Gy, but tumor control probability was poor in comparison to that predicted from a dose-response model based on older studies. Steep dose-response curves for both tumor control and neurotoxicity continue to present a challenge to establishing a therapeutic window for fast neutron radiation in GBM, even with modern techniques.

NCI-sponsored trial for the evaluation of safety and preliminary efficacy of FLT as a marker of proliferation in patients with recurrent gliomas: safety studies.

PURPOSE: 3'-[F-18]Fluoro-3'-deoxythymidine (FLT) is an analog of thymidine that is being developed for imaging cellular proliferation. The goal of this study was to prove that the dose of FLT used for positron emission tomography imaging produces no significant toxicity. PROCEDURES: Twelve patients with gliomas with either recurrence or suspected radionecrosis were imaged with FLT. Before and at several time points after imaging, subjects underwent general physical and neurological examinations with review of systems and tests of hematologic, hepatic, renal, and several other metabolic parameters. Vital signs and electrocardiograms were monitored during and after the imaging session. RESULTS: There were no significant adverse effects from FLT injected at a dose of 0.07 mCi/kg (maximum of 5 mCi) at specific activities of 1.25 Ci/micromol or higher. The FLT mass administered for imaging was 0.0001% to 0.0009% of the least toxic cumulative dose administered in clinical trials of FLT as an antiretroviral agent. CONCLUSIONS: FLT is a safe radiotracer for quantifying proliferation in the human cancer setting.

Tumor-specific positron emission tomography imaging in patients: [18F] fluorodeoxyglucose and beyond.

Biochemical and molecular imaging of cancer using positron emission tomography (PET) plays an increasing role in the care of cancer patients. Most clinical work to date uses the glucose analogue [(18)F]fluorodeoxyglucose (FDG) to detect accelerated and aberrant glycolysis present in most tumors. Although clinical FDG PET has been used largely to detect and localize cancer, more detailed studies have yielded biological insights and showed the utility of FDG as a prognostic marker and as a tool for therapeutic response evaluation. As cancer therapy becomes more targeted and individualized, it is likely that PET radiopharmaceuticals other than FDG, aimed at more specific aspects of cancer biology, will also play a role in guiding cancer therapy. Clinical trials designed to test and validate new PET agents will need to incorporate rigorous quantitative image analysis and adapt to the evolving use of imaging as a biomarker and will need to incorporate cancer outcomes, such as survival into study design.

Challenges in clinical studies with multiple imaging probes.

This article addresses two related issues: (a) When a new imaging agent is proposed, how does the imager integrate it with other biomarkers, either sampled or imaged? (b) When we have multiple imaging agents, is the information additive or duplicative and how is this objectively determined? Molecular biology is leading to new treatment options with reduced normal tissue toxicity, and imaging should have a role in objectively evaluating new treatments. There are two roles for molecular characterization of disease. Molecular imaging measurements before therapy help predict the aggressiveness of disease and identify therapeutic targets and, therefore, help choose the optimal therapy for an individual. Measurements of specific biochemical processes made during or after therapy should be sensitive measures of tumor response. The rules of evidence are not fully developed for the prognostic role of imaging biomarkers, but the potential of molecular imaging provides compelling motivation to push forward with convincing validation studies. New imaging procedures need to be characterized for their effectiveness under realistic clinical conditions to improve the management of patients and achieve a better outcome. The purpose of this article is to promote a critical discussion within the molecular imaging community because our future value to the overall biomedical community will be in supporting better treatment outcomes rather than in detection.

[F-18]-fluorodeoxyglucose positron emission tomography for targeting radiation dose escalation for patients with glioblastoma multiforme: clinical outcomes and patterns of failure.

PURPOSE: [F-18]-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging for brain tumors has been shown to identify areas of active disease. Radiation dose escalation in the treatment of glioblastoma multiforme may lead to improved disease control. Based on these premises, we initiated a prospective study of FDG-PET for the treatment planning of radiation dose escalation for the treatment of glioblastoma multiforme. METHODS AND MATERIALS: Forty patients were enrolled. Patients were treated with standard conformal fractionated radiotherapy with volumes defined by MRI imaging. When patients reached a dose of 45-50.4 Gy, they underwent FDG-PET imaging for boost target delineation, for an additional 20 Gy (2 Gy per fraction) to a total dose of 79.4 Gy (n = 30). RESULTS: The estimated 1-year and 2-year overall survival (OS) for the entire group was 70% and 17%, respectively, with a median overall survival of 70 weeks. The estimated 1-year and 2-year progression-free survival (PFS) was 18% and 3%, respectively, with a median of 24 weeks. No significant improvements in OS or PFS were observed for the study group in comparison to institutional historical controls. CONCLUSIONS: Radiation dose escalation to 79.4 Gy based on FDG-PET imaging demonstrated no improvement in OS or PFS. This study establishes the feasibility of integrating PET metabolic imaging into radiotherapy treatment planning.

Kinetic analysis of 3'-deoxy-3'-18F-fluorothymidine in patients with gliomas.

UNLABELLED: 3'-Deoxy-3'-fluorothymidine (FLT), a thymidine analog, is under investigation for monitoring cellular proliferation in gliomas, a potential measure of disease progression and response to therapy. Uptake may result from retention in the biosynthetic pathway or leakage via the disrupted blood-tumor barrier. Visual analysis or static measures of 18F-FLT uptake are problematic as transport and retention cannot be distinguished. METHODS: Twelve patients with primary brain tumors were imaged for 90 min of dynamic 18F-FLT PET with arterial blood sampling. Total blood activity was corrected for labeled metabolites to provide an FLT input function. A 2-tissue compartment, 4-rate-constant model was used to determine blood-to-tissue transport (K1) and metabolic flux (K(FLT)). Modeling results were compared with MR images of blood-brain barrier (BBB) breakdown revealed by gadolinium (Gd) contrast enhancement. Parametric image maps of K1 and K(FLT) were produced by a mixture analysis approach. RESULTS: Similar to prior work with 11C-thymidine, identifiability analysis showed that K1 (transport) and K(FLT) (flux) could be estimated independently for sufficiently high K1 values. However, estimation of K(FLT) was less robust at low K1 values, particularly those close to normal brain. K1 was higher for MRI contrast-enhancing (CE) tumors (0.053 +/- 0.029 mL/g/min) than noncontrast-enhancing (NCE) tumors (0.005 +/- 0.002 mL/g/min; P < 0.02), and K(FLT) was higher for high-grade tumors (0.018 +/- 0.008 mL/g/min, n = 9) than low-grade tumors (0.003 +/- 0.003 mL/g/min, n = 3; P < 0.01). The flux in NCE tumors was indistinguishable from contralateral normal brain (0.002 +/- 0.001 mL/g/min). For CE tumors, K1 was higher than K(FLT). Parametric images matched region-of-interest estimates of transport and flux. However, no patient has 18F-FLT uptake outside of the volume of increased permeability defined by MRI T1+Gd enhancement. CONCLUSION: Modeling analysis of 18F-FLT PET data yielded robust estimates of K1 and K(FLT) for enhancing tumors with sufficiently high K1 and provides a clearer understanding of the relationship between transport and retention of 18F-FLT in gliomas. In tumors that show breakdown of the BBB, transport dominates 18F-FLT uptake. Transport across the BBB and modest rates of 18F-FLT phosphorylation appear to limit the assessment of cellular proliferation using 18F-FLT to highly proliferative tumors with significant BBB breakdown.

True tracers: comparing FDG with glucose and FLT with thymidine.

As PET metabolic imaging becomes routine in clinical practice, there is a tendency to make imaging and data analysis fast and simple, but interpretation of these pictures by visual inspection does not do justice to the power of PET technology. Tissue data and blood data can be analyzed mathematically to provide parametric images of the PET tracer's biochemistry in terms of a transport parameter and a metabolic flux. The methods for parametric imaging with (11)C tracers of glucose and thymidine have been validated, but the short half-life of this radionuclide and the rapid metabolism of these labeled substrates to [(11)C]CO(2) have led investigators to develop (18)F analogs. While (18)F substitution at critical positions in the natural substrate can block metabolism, it has other effects on the transport and metabolism of the analog tracer. The fidelity with which analog tracers mimic tracers of the authentic substrate is critically evaluated for [(18)F]-2-fluoro-2-deoxyglucose and [(18)F]-3'-fluoro-3'-deoxythymidine.

Apurinic endonuclease activity in adult gliomas and time to tumor progression after alkylating agent-based chemotherapy and after radiotherapy.

PURPOSE: Apurinic/apyrimidinic endonuclease (Ap endo) is a key DNA repair enzyme that cleaves DNA at cytotoxic abasic sites caused by alkylating agents and radiation. We have observed that human glioma cells deficient in Ap endo activity are hypersensitive to clinically used alkylators (Silber et al., Clin Cancer Res 2002;8:3008.). Here we examine the association of glioma Ap endo activity with clinical response after alkylating agent-based chemotherapy or after radiotherapy. EXPERIMENTAL DESIGN: Cox proportional hazards regression models were used to analyze the relationship of Ap endo activity with time to tumor progression (TTP). RESULTS: In a univariate model with Ap endo activity entered as a continuous variable, the hazard ratio (HR) for progression after alkylator therapy in 30 grade III gliomas increased by a factor of 1.061 for every 0.01 increase in activity (P = 0.013). Adjusting for age, gender, extent of resection, and prior treatment strengthened slightly the association (HR = 1.094; P = 0.003). Similarly, the HR for progression after radiotherapy in 44 grade II and III tumors increased by a factor of 1.069 (P = 0.008). Adjusting for the aforementioned variables had little effect on the association. In contrast, we observed no association between activity and TTP in grade IV gliomas after either alkylator therapy in 34 tumors or radiotherapy in 26 tumors. CONCLUSIONS: Our data suggest that Ap endo activity mediates resistance to alkylating agents and radiation and may be a useful predictor of progression after adjuvant therapy in a subset of gliomas.

Hypoxia and glucose metabolism in malignant tumors: evaluation by [18F]fluoromisonidazole and [18F]fluorodeoxyglucose positron emission tomography imaging.

PURPOSE: The aim of this study is to compare glucose metabolism and hypoxia in four different tumor types using positron emission tomography (PET). (18)F-labeled fluorodeoxyglucose (FDG) evaluates energy metabolism, whereas the uptake of (18)F-labeled fluoromisonidazole (FMISO) is proportional to tissue hypoxia. Although acute hypoxia results in accelerated glycolysis, cellular metabolism is slowed in chronic hypoxia, prompting us to look for discordance between FMISO and FDG uptake. EXPERIMENTAL DESIGN: Forty-nine patients (26 with head and neck cancer, 11 with soft tissue sarcoma, 7 with breast cancer, and 5 with glioblastoma multiforme) who had both FMISO and FDG PET scans as part of research protocols through February 2003 were included in this study. The maximum standardized uptake value was used to depict FDG uptake, and hypoxic volume and maximum tissue:blood ratio were used to quantify hypoxia. Pixel-by-pixel correlation of radiotracer uptake was performed on coregistered images for each corresponding tumor plane. RESULTS: Hypoxia was detected in all four patient groups. The mean correlation coefficients between FMISO and FDG uptake were 0.62 for head and neck cancer, 0.47 for breast cancer, 0.38 for glioblastoma multiforme, and 0.32 for soft tissue sarcoma. The correlation between the overall tumor maximum standardized uptake value for FDG and hypoxic volume was small (Spearman r = 0.24), with highly significant differences among the different tumor types (P < 0.005). CONCLUSIONS: Hypoxia is a general factor affecting glucose metabolism; however, some hypoxic tumors can have modest glucose metabolism, whereas some highly metabolic tumors are not hypoxic, showing discordance in tracer uptake that can be tumor type specific.

2-[(18)F]Fluoro-2-deoxyglucose and glucose uptake in malignant gliomas before and after radiotherapy: correlation with outcome.

PURPOSE: To examine whether quantitative 1-[(11)C]glucose- or 2-[(18)F]fluoro-2-deoxyglucose (FDG)-positron emission tomography performed before and/or after radiotherapy (RT) of malignant gliomas correlates with treatment outcome. Changes in metabolism between the start and finish of RT, and immediate post-RT studies have received little attention. EXPERIMENTAL DESIGN: Adults with malignant gliomas were imaged within 2 weeks before and/or 2 weeks after RT. Four patients were imaged only before RT, 12 only after RT, and 14 both before and after RT. Each 1-[(11)C]glucose and FDG study included arterial plasma sampling. Kinetic parameters, glucose metabolic rate (MRGlc), and FDG metabolic rate (MRFDG) were estimated by an optimization program based on a three compartment, four rate constant model. Changes in MRGlc or MRFDG from pre-RT to post-RT were calculated for the 14 patients studied at both times. Overall survival was examined, and survival was computed relative to historical controls in matched prognostic classes. RESULTS: Low pre-RT MRGlc (P < 0.02) or MRFDG (P < 0.03), or an increase from pre- to post-RT in MRGlc (P < 0.004) or MRFDG (P < 0.006) are correlating with longer survival (4 patients still alive). Strikingly, the post-RT studies (n = 26) showed no correlation between MRGlc or MRFDG and survival (P = 0.73 and P = 0.46 respectively). CONCLUSIONS: Low MRGlc or MRFDG before RT probably indicates less aggressive disease. An increase in MRGlc or MRFDG from pre- to post-RT in the tumors of patients with longer survival could be because of one or more of the following or other reasons: (a) apoptosis of tumor cells in response to RT requires energy; (b) decreased tumor cell density by the RT leaving normal cells with higher metabolism; or (c) inflammatory cells infiltrate and take up glucose or FDG where tumor cells are dying. Quantitative 1-[(11)C]glucose or FDG uptake in the early weeks post-RT correlates poorly with survival.

The FDG lumped constant in normal human brain.

UNLABELLED: The lumped constant (LC) is a correction factor used to infer glucose metabolic rate (MR(glc)) from FDG metabolic rate (MR(FDG)). METHODS: LC was determined in normal brain in 10 subjects (4 male, 6 female) by measuring regional MR(glc) and MR(FDG) independently using 1-(11)C-glucose and (18)F-FDG with dynamic positron tomographic imaging, arterial blood sampling, and region-of-interest time-activity curve analysis with appropriate compartmental models. RESULTS: The mean LC (+/-SD) for normal brain was found to be 0.89 +/- 0.08. The value for cerebellum was slightly lower, 0.78 +/- 0.11 (P = 0.006; 2-tailed paired t test). CONCLUSION: The LC values determined in this study are considerably higher than older values in the literature, probably because of methodologic differences, but agree with a recent study by Hasselbalch.

18F-FDG PET of gliomas at delayed intervals: improved distinction between tumor and normal gray matter.

UNLABELLED: We hypothesized that delineation of gliomas from gray matter with 18F-FDG PET could be improved by extending the interval between 18F-FDG administration and PET data acquisition. The purposes of this study were, first, to analyze standard and delayed 18F-FDG PET images visually and quantitatively to determine whether definition of tumor improved at later imaging times and, second, to investigate the dynamics of model-derived kinetic rate constants, particularly k4. METHODS: Nineteen adult patients with supratentorial gliomas were imaged from 0 to 90 min and once or twice later at 180-480 min after injection. In 15 patients, arterial sampling provided the early input function. Venous sampling provided the remaining curve to the end of the imaging sequence. Standardized uptake value (SUV) was calculated as tissue concentration of tracer per injected tracer dose per body weight. Ratios of tumor SUV relative to the SUV of gray matter, brain (including gray and white matter), or white matter were calculated at each imaging time point. Dynamic image data from tumor, gray matter, brain, or white matter were analyzed using a 2-compartment, 4-parameter model applied for the entire duration of imaging, in which delay, K1, distribution volume, k3, and k4 were optimized using a nonlinear optimization method. Parameter estimation for each region included both an early subset of data from a conventional dynamic imaging period (0-60 min) and the full, extended dataset for each region. RESULTS: In 12 of the 19 patients, visual analysis showed that the delayed images better distinguished the high uptake in tumors relative to uptake in gray matter. SUV comparisons also showed greater uptake in the tumors than in gray matter, brain, or white matter at the delayed times. The estimated k4 values for tumors were not significantly different from those for gray matter in early imaging analysis but were lower (P < 0.01) using the extended-time data. CONCLUSION: The kinetic parameter results confirm the visual and SUV interpretation that tumor enhancement is greater than enhancement of surrounding brain regions at later imaging times, consistent with a greater effect of FDG-6-phosphate degradation on normal brain relative to glioma.

Volumetric analysis of 18F-FDG PET in glioblastoma multiforme: prognostic information and possible role in definition of target volumes in radiation dose escalation.

UNLABELLED: The use of (18)F-FDG PET for brain tumors has been shown to be accurate in identifying areas of active disease. Radiation dose escalation in the treatment of glioblastoma multiforme (GBM) may lead to improved disease control. On the basis of these premises, we initiated a pilot study to investigate the use of (18)F-FDG PET for the guidance of radiation dose escalation in the treatment of GBM. METHODS: Patients were considered eligible to participate in the study if they had a diagnosis of GBM, were at least 18 y old, and had a score of at least 60 on the Karnofsky Scale. Patients were treated with standard conformal fractionated radiotherapy (1.8 Gy per fraction, to 59.4 Gy), with volumes defined by MRI. At a dose of 45-50.4 Gy, patients underwent (18)F-FDG PET for boost target delineation. Final noncoplanar fields (3-4) were designed to treat the volume of abnormal (18)F-FDG uptake plus a 0.5-cm margin for an additional 20 Gy (2 Gy per fraction), to a total dose of 79.4 Gy. If no abnormal (18)F-FDG uptake was observed, treatment was stopped after the conventional course of 59.4 Gy. Age, Karnofsky score, MRI-based volumes, and (18)F-FDG PET volume were analyzed as prognostic variables for time to tumor progression (TTP) and overall survival. (18)F-FDG PET volumes and MRI-based volumes were compared to assess concordance. RESULTS: For the 27 patients who could be evaluated, median actuarial TTP was 43 wk, and median actuarial survival was 70 wk. On univariate analysis, (18)F-FDG PET, T1-weighted MRI gadolinium enhancement (excluding nonenhancing resection cavity), and T2-weighted MRI volumes were significantly predictive of TTP. On multivariate analysis, only (18)F-FDG PET volume retained significance for predicting TTP. Similar results were obtained on analysis of these variables as prognostic factors for survival. When (18)F-FDG PET-based volumes were compared with MRI-based volumes, a difference of at least 25% was detected in all patients, with all but 2 having smaller (18)F-FDG PET volumes. Of patients in whom (18)F-FDG uptake was initially present but treatment subsequently failed, 83% demonstrated the first tumor progression within the region of abnormal (18)F-FDG uptake. CONCLUSION: In comparison with MRI, (18)F-FDG PET defined unique volumes for radiation dose escalation in the treatment of GBM. (18)F-FDG PET volumes were predictive of survival and time to tumor progression in the treatment of patients with GBM.

[18F]-2-fluoro-2-deoxyglucose transport kinetics as a function of extracellular glucose concentration in malignant glioma, fibroblast and macrophage cells in vitro.

FDG-PET is used to measure the metabolic rate of glucose. Transport and phosphorylation determine the amount of hexose analog that is phosphorylated and trapped. Competition occurs for both events, such that extracellular glucose concentration affects the FDG image. This study investigated the effect of glucose concentration on the rate of FDG accumulation in three cell lines. The results show that extracellular glucose concentration has a greater impact on the rate of FDG accumulation than the relative abundance of GLUT transporter subtypes.

Positron emission tomography imaging of brain tumors.

Energy metabolism and amino acid transport and incorporation are important components of the pathophysiology of gliomas, about which molecular imaging is providing regional biologic information that is useful to clinical practice. Imaging hypoxia is straightforward and proliferation imaging with FLT shows significant promise. Neither has been exploited thoroughly enough to allow judgement of their potential benefit to the practice of neuro-oncology. Although cell division is the most distinguishing function of growth in tumors, probing membrane biosynthesis with PET and 1-[11C]acetate or a choline tracer may yield information as helpful as protein or DNA synthesis. Because astrocytic gliomas frequently carry epidermal growth factor receptor mutations at a frequency that is related to grade, a PET tracer that is specific for this mutated receptor could be useful for grading and prognosis [35]. Methods for imaging angiogenesis are being developed; 18F-labeling of a cyclic RGD-containing glycopeptide, cyclo(-Arg-Gly-Asp-D-Phe-Lys(sugar amino acid)-), with 4-nitro-phenyl 2-[18F]fluoropropionate has been reported [136]. 18F-labeled annexin V is being tested as a new PET agent for quantitating tumor cell death and predicting response to therapy. Annexin V binds to surface membranes that have exposed phosphatidyl serine residues resulting from programmed cell destruction. Recently, a Tc-99m-labeled derivative has been shown to accumulate in late stage lung cancer and lymphoma in response to chemotherapy [137]. As molecular pathways leading to and sustaining neoplasia become better understood, so will our capacity improve to measure them in vivo and intervene to the patient's advantage.

VOXEL-LEVEL MAPPING OF TRACER KINETICS IN PET STUDIES: A STATISTICAL APPROACH EMPHASIZING TISSUE LIFE TABLES.

Most radiotracers used in dynamic positron emission tomography (PET) scanning act in a linear time-invariant fashion so that the measured time-course data are a convolution between the time course of the tracer in the arterial supply and the local tissue impulse response, known as the tissue residue function. In statistical terms the residue is a life table for the transit time of injected radiotracer atoms. The residue provides a description of the tracer kinetic information measurable by a dynamic PET scan. Decomposition of the residue function allows separation of rapid vascular kinetics from slower blood-tissue exchanges and tissue retention. For voxel-level analysis, we propose that residues be modeled by mixtures of nonparametrically derived basis residues obtained by segmentation of the full data volume. Spatial and temporal aspects of diagnostics associated with voxel-level model fitting are emphasized. Illustrative examples, some involving cancer imaging studies, are presented. Data from cerebral PET scanning with 18F fluoro-deoxyglucose (FDG) and 15O water (H2O) in normal subjects is used to evaluate the approach. Cross-validation is used to make regional comparisons between residues estimated using adaptive mixture models with more conventional compartmental modeling techniques. Simulations studies are used to theoretically examine mean square error performance and to explore the benefit of voxel-level analysis when the primary interest is a statistical summary of regional kinetics. The work highlights the contribution that multivariate analysis tools and life-table concepts can make in the recovery of local metabolic information from dynamic PET studies, particularly ones in which the assumptions of compartmental-like models, with residues that are sums of exponentials, might not be certain.