Preclinical Applications of 3'-Deoxy-3'-[18F]Fluorothymidine in Oncology - A Systematic Review.

The positron emission tomography (PET) tracer 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) has been proposed to measure cell proliferation non-invasively in vivo. Hence, it should provide valuable information for response assessment to tumor therapies. To date, [18F]FLT uptake has found limited use as a response biomarker in clinical trials in part because a better understanding is needed of the determinants of [18F]FLT uptake and therapy-induced changes of its retention in the tumor. In this systematic review of preclinical [18F]FLT studies, comprising 174 reports, we identify the factors governing [18F]FLT uptake in tumors, among which thymidine kinase 1 plays a primary role. The majority of publications (83 %) report that decreased [18F]FLT uptake reflects the effects of anticancer therapies. 144 times [18F]FLT uptake was related to changes in proliferation as determined by ex vivo analyses. Of these approaches, 77 % describe a positive relation, implying a good concordance of tracer accumulation and tumor biology. These preclinical data indicate that [18F]FLT uptake holds promise as an imaging biomarker for response assessment in clinical studies. Understanding of the parameters which influence cellular [18F]FLT uptake and retention as well as the mechanism of changes induced by therapy is essential for successful implementation of this PET tracer. Hence, our systematic review provides the background for the use of [18F]FLT in future clinical studies.

An exploratory study of volumetric analysis for assessing tumor response with (18)F-FAZA PET/CT in patients with advanced non-small-cell lung cancer (NSCLC).

BACKGROUND: Hypoxia is associated with resistance to chemotherapy and radiotherapy and is randomly distributed within malignancies. Characterization of changes in intratumoral hypoxic regions is possible with specially developed PET tracers such as (18)F-fluoroazomycin arabinoside ((18)F-FAZA) while tumor metabolism can be measured with 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG). The purpose of this study was to study the effects of chemotherapy on (18)F-FAZA and (18)F-FDG uptake simultaneously in non-small-cell lung cancer (NSCLC) patients METHODS: At baseline and after the second chemotherapy cycle, both PET/CT with (18)F-FDG and (18)F-FAZA was performed in seven patients with metastasized NSCLC. (18)F-FAZA and (18)F-FDG scans were aligned with deformable image registration using Mirada DBx. The primary tumors were contoured, and on the (18)F-FDG scan, volumes of interest (VOI) were drawn using a 41 % adaptive threshold technique. Subsequently, the resulting VOI was transferred to the (18)F-FAZA scan. (18)F-FAZA maximum tumor-to-background (T/Bgmax) ratio and the fractional hypoxic volume (FHV) were assessed. Measurements were corrected for partial volume effects. Finally, a voxel-by-voxel analysis of the primary tumor was performed to assess regional uptake differences. RESULTS: In the primary tumor of all seven patients, median (18)F-FDG standard uptake value (SUVmax) decreased significantly (p = 0.03). There was no significant decrease in (18)F-FAZA uptake as measured with T/Bgmax (p = 0.24) or the FHV (p = 0.35). Additionally, volumetric voxel-by-voxel analysis showed that low hypoxic tumors did not significantly change in hypoxic status between baseline and two cycles of chemotherapy, whereas highly hypoxic tumors did. Individualized volumetric voxel-by-voxel analysis revealed that hypoxia and metabolism were not associated before and after 2 cycles of chemotherapy. CONCLUSIONS: Tumor hypoxia and metabolism are independent dynamic events as measured by (18)F-FAZA PET and (18)F-FDG PET, both prior to and after treatment with chemotherapy in NSCLC patients.

Assessment of hypoxic subvolumes in laryngeal cancer with (18)F-fluoroazomycinarabinoside ((18)F-FAZA)-PET/CT scanning and immunohistochemistry.

BACKGROUND AND PURPOSE: (18)F-fluoroazomycinarabinoside ((18)F-FAZA) is a promising hypoxia radiopharmaceutical agent with outstanding biokinetic parameters. We aimed to determine the accuracy of (18)F-FAZA-PET/CT scan in detecting hypoxic regions within the tumor using immunohistochemical markers in a pilot study. PATIENTS AND METHODS: Eleven patients with primary or recurrent laryngeal squamous cell carcinoma were indicated for total laryngectomy (TLE). Patients underwent (18)F-FAZA-PET/CT scan before TLE. Hypoxic regions inside the laryngeal tumor were determined. After TLE, regions with high uptake on (18)F-FAZA-PET scan were selected for immunohistochemical examination for exogenous (pimonidazole) and endogenous (HIF1α, CA-IX and GLUT-1) hypoxia markers. To assess the accuracy of (18)F-FAZA-PET scanning, radiopharmacon accumulation was related with immunohistochemical expression of hypoxia markers. RESULTS: Inter- and intratumoral heterogeneity of tumor hypoxia was observed on (18)F-FAZA-PET scan. Nine of the eleven tumors were hypoxic with (18)F-FAZA-PET. Hypoxia could also be detected with pimonidazole, HIF1α, CA-IX and GLUT-1 expression in some tumors. No clear association was observed between (18)F-FAZA uptake and hypoxia markers. CONCLUSIONS: This pilot study could not prove the accuracy of (18)F-FAZA-PET in determining hypoxic subvolumes in laryngeal cancer. Further study is required to investigate the benefit of (18)F-FAZA-PET imaging in radiotherapy planning.

Dynamics of tumor hypoxia assessed by 18F-FAZA PET/CT in head and neck and lung cancer patients during chemoradiation: possible implications for radiotherapy treatment planning strategies.

INTRODUCTION: To define the optimal time point for the integration of hypoxia (18)F-FAZA-PET/CT information into radiotherapy treatment planning to benefit from hypoxia modification or dose escalation treatment. Therefore, we performed a prospective cohort study, using serial hypoxic imaging ((18)F-FAZA-PET/CT) prior to and at several time-points during (chemo)radiotherapy (CHRT) in six head and neck squamous cell (HNSCC) and six non-small cell lung cancer (NSCLC) patients. METHODS: The spatio-temporal dynamics of tumor hypoxia and fractional hypoxic volumes (FHV) were evaluated using a voxel-by-voxel analysis based on a (18)F-FAZA-T/B ratio of 1.4 at four time points in HNSCC patients, at baseline (FAZA-BL), at week one (FAZA-W1), two (FAZA-W2), and four (FAZA-W4) during CHRT and at three time points in NSCLC patients (baseline; W2, W4). RESULTS: Ten out of twelve patients showed a substantial pre-treatment tumor hypoxia representing a FHV⩾1.4 assessed by (18)F-FAZA-PET/CT. The median FHV was 38% (FAZA-BL), 15% (FAZA-W1), 17% (FAZA-W2) and 1.5% (FAZA-W4) in HNSCC patients, and 34% (FAZA-BL), 26% (FAZA-W2) and 26% (FAZA-W4) in NSCLC patients, respectively. Stable tumor hypoxia was observed in three HNSCC patients and two NSCLC patients at FAZA-W2. In three HNSCC patients and two NSCLC patients FHVs declined to non-detectable hypoxia levels at FAZA-W4 during CHRT, while two NSCLC patients, showed increasing FHVs. CONCLUSION: Our results indicate that, instead of using the FAZA-BL scan as the basis for the dose escalation, FAZA-W2 of CHRT is most suitable and might provide a more reliable basis for the integration of (18)F-FAZA-PET/CT information into radiotherapy treatment planning for hypoxia-directed dose escalation strategies.

PET imaging of tumor hypoxia using 18F-fluoroazomycin arabinoside in stage III-IV non-small cell lung cancer patients.

UNLABELLED: Tumor hypoxia hampers the efficacy of radiotherapy because of its increased resistance to ionizing radiation. The aim of the present study was to estimate the potential added clinical value of the specific hypoxia tracer (18)F-fluoroazomycin arabinoside ((18)F-FAZA) over commonly used (18)F-FDG in the treatment of advanced-stage non-small cell lung cancer (NSCLC). METHODS: Eleven patients with stage III or stage IV NSCLC underwent (18)F-FDG and (18)F-FAZA PET before chemoradiotherapy. The maximum standardized uptake value (SUVmax) was used to depict (18)F-FDG uptake, and the tumor-to-background (T/B) ratio and tumor fractional hypoxic volume (FHV) were used to quantify hypoxia. The spatial correlation between (18)F-FDG and (18)F-FAZA uptake values was investigated using voxel-based analysis. Partial-volume correction was applied. RESULTS: All 11 patients showed clear uptake of (18)F-FAZA in the primary tumor. However, different patterns of (18)F-FDG and (18)F-FAZA uptake distributions were observed and varied widely among different tumors. No significant correlation was observed between (18)F-FDG SUVmax and (18)F-FAZA T/B ratio (P = 0.055). The median FHV of 1.4 was 48.4% (range, 5.0-91.5). A significant positive correlation was found between the (18)F-FAZA T/B ratio and FHV of 1.4 (P < 0.001). There was no correlation between the lesion size and FHV or between the (18)F-FDG SUVmax and FHV. The pattern of tumoral (18)F-FDG uptake was rather homogeneous, whereas (18)F-FAZA uptake was more heterogeneous, suggesting that (18)F-FAZA identifies hypoxic areas within metabolically active areas of tumor. A significant correlation between (18)F-FDG SUVmax and lesion size (P = 0.002) was observed. CONCLUSION: (18)F-FAZA PET imaging is able to detect heterogeneous distributions of hypoxic subvolumes out of homogeneous (18)F-FDG background in a clinical setting. Therefore, (18)F-FAZA might be considered a tool for guiding dose escalation to the hypoxic fraction of the tumor.