[18F]DCFPyL PET-MRI/CT for unveiling a molecularly defined oligorecurrent prostate cancer state amenable for curative-intent ablative therapy: study protocol for a phase II trial.

INTRODUCTION: The oligometastatic (OM) disease hypothesis of an intermediate metastatic state with limited distant disease deposits amenable for curative therapies remains debatable. Over a third of prostate cancer (PCa) patients treated with radical prostatectomy and postoperative radiotherapy experience disease recurrence; these patients are considered incurable by current standards. Often the recurrence cannot be localised by conventional imaging (CT and bone scan). Combined anatomical imaging with CT and/or MR with positron emission tomography (PET) using a novel second-generation prostate-specific membrane antigen (PSMA) probe, [18F]DCFPyL, is a promising imaging modality to unveil disease deposits in these patients. A new and earlier molecularly defined oligorecurrent (OR) state may be amenable to focal-targeted ablative curative-intent therapies, such as stereotactic ablative radiotherapy (SABR) or surgery, thereby significantly delaying or completely avoiding the need for palliative therapies in men with recurrent PCa after maximal local treatments. METHODS AND ANALYSIS: This ongoing single-institution phase II study will enrol up to 75 patients total, to include up to 37 patients with response-evaluable disease, who have rising prostate-specific antigen (range 0.4-3.0 ng/mL) following maximal local therapies with no evidence of disease on conventional imaging. These patients will undergo [18F]DCFPyL PET-MR/CT imaging to detect disease deposits, which will then be treated with SABR or surgery. The primary endpoints are performance of [18F]DCFPyL PET-MR/CT, and treatment response rates following SABR or surgery. Demographics and disease characteristics will be summarised and analysed descriptively. Response rates will be described with waterfall plots and proportions. ETHICS AND DISSEMINATION: Ethics approval was obtained from the institutional Research Ethics Board. All patients will provide written informed consent. [18F]DCFPyL has approval from Health Canada. The results of the study will be disseminated by the principal investigator. Patients will not be identifiable as individuals in any publication or presentation of this study. TRIAL REGISTRATION NUMBERS: NCT03160794.

A prospective study of DWI, DCE-MRI and FDG PET imaging for target delineation in brachytherapy for cervical cancer.

BACKGROUND AND PURPOSE: We examined the utility of dynamic contrast-enhanced MRI (DCE-MRI), diffusion-weighted MRI (DWI), and FDG-PET imaging for brachytherapy target delineation in patients with locally advanced cervical cancer. MATERIALS AND METHODS: Twenty-two patients had DWI, DCE-MRI, and FDG-PET/CT scans after brachytherapy applicator insertion, in addition to standard T2-weighted (T2w) 3T MRI. Gross tumor volume (GTVB) and high-risk clinical target volume (HRCTV) were contoured first on T2w images, and then modified if indicated upon review of DWI/DCE-MRI/FDG-PET images by two observers. The primary endpoint was utility, determined by the number of patients whose volumes were modified, and interobserver variability. RESULTS: Eleven patients' T2w-GTVB were modified based on DWI/DCE-MRI/FDG-PET by observer 1, due to clearer demarcation (7) and residual disease not well visualized on T2w MRI (4). GTVB was modified in 17 patients by observer 2 (11 and 6, respectively). Incorporation of functional imaging improved the conformity index (CI) for GTVB from 0.54 (T2w alone) to 0.65 (P=0.003). HRCTV was modified in 3 and 8 patients by observers 1 and 2, respectively, with a trend toward higher CI using functional imaging (0.71 to 0.76, P=0.06). CONCLUSIONS: DWI/DCE-MRI/FDG-PET imaging as a supplement to T2w MRI decreased interobserver variability in GTVB delineation.

Biodistribution and radiation dosimetry of the serotonin transporter ligand 11C-DASB determined from human whole-body PET.

UNLABELLED: 11C-Labeled 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) is a selective radioligand for the in vivo quantitation of serotonin transporters (SERTs) using PET. The goal of this study was to provide dosimetry estimates for 11C-DASB based on human whole-body PET. METHODS: Dynamic whole-body PET scans were acquired for 7 subjects after the injection of 669 +/- 97 MBq (18.1 +/- 2.6 mCi) of 11C-DASB. The acquisition for each subject was obtained at 14 time points for a total of 115 min after injection of the radioligand. Regions of interest were placed over compressed planar images of source organs that could be visually identified to generate time-activity curves. Radiation burden to the body was calculated from residence times of these source organs using the MIRDOSE3.1 program. RESULTS: The organs with high radiation burden included the lungs, urinary bladder wall, kidneys, gallbladder wall, heart wall, spleen, and liver. The activity peaked within 10 min after the injection of 11C-DASB for all these organs except two--the excretory organs gallbladder and urinary bladder wall, which had peak activities at 32 and 22 min, respectively. Monoexponential fitting of activity overlying the urinary bladder suggested that approximately 12% of activity was excreted via the urine. Simulations in which the urinary voiding interval was decreased from 4.8 to 0.6 h produced only modest effects on the dose to the urinary bladder wall. With a 2.4-h voiding interval, the calculated effective dose was 6.98 microGy/MBq (25.8 mrem/mCi). CONCLUSION: The estimated radiation burden of 11C-DASB is relatively modest and would allow multiple PET examinations of the same research subject per year.

Efficacy of combining GMX1777 with radiation therapy for human head and neck carcinoma.

PURPOSE: Rapidly metabolizing tumor cells have elevated levels of nicotinamide phosphoribosyltransferase, an enzyme involved in NAD(+) biosynthesis, which serves as an important substrate for proteins involved in DNA repair. GMX1777, which inhibits nicotinamide phosphoribosyltransferase, was evaluated in two human head and neck cancer models in combination with radiotherapy. EXPERIMENTAL DESIGN: Effects of GMX1777-mediated radiosensitization were examined via metabolic and cytotoxicity assays in vitro; mechanism of action, in vivo antitumor efficacy, and radiosensitization were also investigated. RESULTS: IC(50) values of GMX1777 for FaDu and C666-1 cells were 10 and 5 nmol/L, respectively, which interacted synergistically with radiotherapy. GMX1777 induced a rapid decline in intracellular NAD(+) followed by ATP reduction associated with significant cytotoxicity. These metabolic changes were slightly increased with the addition of radiotherapy, although poly(ADP-ribose) polymerase activity was significantly reduced when GMX1777 was combined with radiotherapy, thereby accounting for the synergistic cytotoxicity of these two modalities. Systemic GMX1777 administration with local tumor radiotherapy caused complete disappearance of FaDu and C666-1 tumors for 50 and 20 days, respectively. There was also significant reduction in tumor vascularity, particularly for the more sensitive FaDu model. [(18)F]FDG-positron emission tomography/computed tomography images showed reduction in [(18)F]FDG uptake after GMX1777 administration, showing decreased glucose metabolism in vivo. CONCLUSIONS: Our data represent the first report showing that GMX1777 plus radiotherapy is an effective therapeutic strategy for head and neck cancer, mediated via pleiotropic effects of inhibition of DNA repair and tumor angiogenesis, while sparing normal tissues. Therefore, GMX1777 combined with radiotherapy definitely warrants clinical evaluation in human head and neck cancer patients.