Purpose: To characterize proliferative changes in tumors during the sunitinib malate exposure/withdrawal using 3′-deoxy-3′-[¹⁸F]fluorothymidine (FLT) positron emission tomography (PET)/computed tomography (CT) imaging. Patients and Methods: Patients with advanced solid malignancies and no prior anti-VEGF exposure were enrolled. All patients had metastatic lesions amenable to FLT PET/CT imaging. Sunitinib was initiated at the standard dose of 50 mg p.o. daily either on a 4/2 or 2/1 schedule. FLT PET/CT scans were obtained at baseline, during sunitinib exposure, and after sunitinib withdrawal within cycle #1 of therapy. VEGF levels and sunitinib pharmacokinetic (PK) data were assessed at the same time points. Results: Sixteen patients (8 patients on 4/2 schedule and 8 patients on 2/1 schedule) completed all three planned FLT PET/CT scans and were evaluable for pharmacodynamic imaging evaluation. During sunitinib withdrawal (change from scans 2 to 3), median FLT PET standardized uptake value (SUV_mean) increased +15% (range: −14% to 277%; P = 0.047) for the 4/2 schedule and +19% (range: −5.3% to 200%; P = 0.047) for the 2/1 schedule. Sunitinib PK and VEGF ligand levels increased during sunitinib exposure and returned toward baseline during the treatment withdrawal. Conclusions: The increase of cellular proliferation during sunitinib withdrawal in patients with renal cell carcinoma and other solid malignancies is consistent with a VEGF receptor (VEGFR) tyrosine kinase inhibitor (TKI) withdrawal flare. Univariate and multivariate analysis suggest that plasma VEGF is associated with this flare, with an exploratory analysis implying that patients who experience less clinical benefit have a larger withdrawal flare. This might suggest that patients with a robust compensatory response to VEGFR TKI therapy experience early “angiogenic escape.” Clin Cancer Res; 17(24); 7634–44. ©2011 AACR.

Molecular imaging plays a central role in the management of radiation oncology patients. Specific uses of imaging, particularly to plan radiotherapy and assess its efficacy, require an additional level of reproducibility and image quality beyond what is required for diagnostic imaging. Specific requirements include proper patient preparation, adequate technologist training, careful imaging protocol design, reliable scanner technology, reproducible software algorithms, and reliable data analysis methods. As uncertainty in target definition is arguably the greatest challenge facing radiation oncology, the greatest impact that molecular imaging can have may be in the reduction of interobserver variability in target volume delineation and in providing greater conformity between target volume boundaries and true tumor boundaries. Several automatic and semiautomatic contouring methods based on molecular imaging are available but still need sufficient validation to be widely adopted. Biologically conformal radiotherapy (dose painting) based on molecular imaging–assessed tumor heterogeneity is being investigated, but many challenges remain to fully exploring its potential. Molecular imaging also plays increasingly important roles in both early (during treatment) and late (after treatment) response assessment as both a predictive and a prognostic tool. Because of potentially confounding effects of radiation-induced inflammation, treatment response assessment requires careful interpretation. Although molecular imaging is already strongly embedded in radiotherapy, the path to widespread and all-inclusive use is still long. The lack of solid clinical evidence is the main impediment to broader use. Recommendations for practicing physicians are still rather scarce. ¹⁸F-FDG PET/CT remains the main molecular imaging modality in radiation oncology applications. Although other molecular imaging options (e.g., proliferation imaging) are becoming more common, their widespread use is limited by lack of tracer availability and inadequate reimbursement models. With the increasing presence of molecular imaging in radiation oncology, special emphasis should be placed on adequate training of radiation oncology personnel to understand the potential, and particularly the limitations, of quantitative molecular imaging applications. Similarly, radiologists and nuclear medicine specialists should be sensitized to the special need of the radiation oncologist in terms of quantification and reproducibility. Furthermore, strong collaboration between radiation oncology, nuclear medicine/radiology, and medical physics teams is necessary, as optimal and safe use of molecular imaging can be ensured only within appropriate interdisciplinary teams.

Parathyroid adenomas, the most common cause of primary hyperparathyroidism, are benign tumours which autonomously produce and secrete parathyroid hormone. [(18)F]-fluorocholine (FCH), PET marker of cellular proliferation, was recently demonstrated to accumulate in lesions representing enlarged parathyroid tissue; however, the optimal time to perform FCH PET/CT after FCH administration is not known. The aim of this study was to determine the optimal scan time of FCH PET/CT in patients with primary hyperparathyroidism. 43 patients with primary hyperparathyroidism were enrolled in this study. A triple-phase PET/CT imaging was performed five minutes, one and two hours after the administration of FCH. Regions of interest (ROI) were placed in lesions representing enlarged parathyroid tissue and thyroid tissue. Standardized uptake value (SUVmean), retention index and lesion contrast for parathyroid and thyroid tissue were calculated. Accumulation of FCH was higher in lesions representing enlarged parathyroid tissue in comparison to the thyroid tissue with significantly higher SUVmean in the second and in the third phase (p < 0.0001). Average retention index decreased significantly between the first and the second phase and increased significantly between the second and the third phase in lesions representing enlarged parathyroid tissue and decreased significantly over all three phases in thyroid tissue (p< 0.0001). The lesion contrast of lesions representing enlarged parathyroid tissue and thyroid tissue was significantly better in the second and the third phase compared to the first phase (p < 0.05). According to the results the optimal scan time of FCH PET/CT for localization of lesions representing enlarged parathyroid tissue is one hour after administration of the FCH.

Tumour hypoxia is a major cause of radiation resistance, often present in various solid tumours. Dynamic [¹⁸F]-fluoromisonidazole (FMISO) PET imaging is able to reliably assess tumour hypoxia. Comprehensive characterization of tumour microenvironment through FMISO-PET and dynamic contrast enhanced (DCE) MR multimodality imaging might be a valuable alternative to the dynamic FMISO-PET acquisition. The aim of this work was to explore the correlation between the FMISO-PET and DCE-MRI kinetic parameters. This study was done on N=6 head and neck cancer patients, who were imaged dynamically with FMISO-PET and DCE-MRI on the same day. Images were registered and analysed for kinetics on a voxel basis. FMISO-PET images were analysed with the two-tissue compartment three rate-constant model. Additionally, tumour-to-muscle ratio (TMR) maps were evaluated. DCE-MRI was analysed with the extended Tofts model. Voxel-wise Pearson coefficients were calculated for each patient to assess pairwise parameter correlations. Median correlations between FMISO uptake parameters and DCE-MRI kinetic parameters varied across the parameter pairs in the range from -0.05 to 0.71. The highest median correlation of r=0.71 was observed for the pair V_b-v_p, while the K₁-K^trans median correlation was r=0.45. Median correlation coefficients for the K₁-v_p and the K_i-K^trans pairs were r=0.42 and r=0.32, respectively. Correlations between FMISO uptake rate parameter K_i and DCE-MRI kinetic parameters varied substantially across the patients, whereas correlations between the FMISO and DCE-MRI vascular parameters were consistently high. Median TMR-K₁ and TMR-K^trans correlations were r=0.52 and r=0.46, respectively, but varied substantially across the patients. Based on this clinical evidence, we can conclude that the vascular fraction parameters obtained through DCE-MRI kinetic analysis or FMISO kinetic analysis measure the same biological property, while other kinetic parameters are unrelated. These results might be useful in the design of future clinical trials involving FMISO-PET/DCE-MR multimodality imaging for the assessment of tumour microenvironment.