Methods
bone disease, tumor, lymphadenopathy, castration-resistant prostate cancer, adenocarcinoma of the prostate, castration-resistant disease, visceral disease
BONE DISEASE, TUMOR, LYMPHADENOPATHY, CASTRATION-RESISTANT PROSTATE CANCER, ADENOCARCINOMA OF THE PROSTATE, BLOOD, METASTASES
REASURE was a phase 2, multicenter, noncomparative, randomized study of radium-223 in men with chemotherapy-naive, bone-only, progressive metastatic castration-resistant prostate cancer incorporating whole-body DWI and positron emission tomography (PET) imaging as well as biological samples, with the primary objective of identifying potential imaging response biomarkers. The PET data will be reported separately. The trial was registered [ISRCTN17805587 (Patients were identified through oncology clinics at 3 participating sites in the United Kingdom. Inclusion criteria were histologically or cytologically confirmed adenocarcinoma of the prostate with castration-resistant disease, serum PSA of 2 ng/mL or more, ECOG performance status of 0 to 2, life expectancy beyond 6 months, and multiple skeletal metastases (≥2 hotspots) on bone scintigraphy within the previous 12 weeks. Exclusion criteria were visceral disease; lymphadenopathy greater than 1.5 cm in diameter; inadequate hematologic, kidney, or liver function; prior chemotherapy for castration-resistant prostate cancer; and any prior radioisotope therapy.Eligible participants were allocated to 1 of 2 dose levels—55 or 88 kBq/kg—of radium-223 (1:1 allocation ratio). Treatment allocation was through minimization with a random element; balancing factors included patient weight, total ALP level, and current bisphosphonate use. Dose allocation was not blinded. Patients received treatment with radium-223 at the allocated dose by intravenous administration every 4 weeks for up to 6 cycles. Whole-body DWI scans were done at baseline, at cycles 2 and 4, and 1 month after treatment. Blood tests, including full blood count, routine biochemistry, and PSA, were done at 4-week intervals during radium-223 treatment. During the follow-up period, patients were evaluated every 4 months for 1 year, during which time imaging was done according to routine clinical practice.Whole-body DWI was performed axially from the skull vertex to midthigh using a free-breathing, single-shot, echo-planar DWI technique on a 1.5 T MR system (Siemens Aera and Avanto systems, Siemens Healthineers, Erlangen, Germany). Imaging parameters included short τ inversion recovery fat suppression (inversion time = 180 ms), partition thickness of 5 mm, matrix size of 150 × 144, partial Fourier transform of 6 of 8, time to echo of 64.8 ms, repetition time of 14.6 s, receiver bandwidth of 1961 Hz/pixel, For each whole-body DWI examination, metastatic bone disease segmentation was performed using OsiriX MD 2016 software (Pixmeo, Bernex, Switzerland). One junior radiologist (A.C., who had less than 3 years of experience) outlined all sites of metastatic bone disease based on all available sequences; the volumes were then checked and modified as necessary by an experienced radiologist (>10 years of experience with whole-body DWI). The outlined segmentations were then transferred to the apparent diffusion coefficient map to record the individual lesions and global (total tumor burden) apparent diffusion coefficient value for each patient at each imaging time point. In addition, up to 5 representative target lesions larger than 2 cm (1 each from the cervical spine, thoracic spine, lumbar spine, thorax, and pelvis) were selected by the same experienced radiologist (N.T.) and their individual apparent diffusion coefficient values recorded for each patient at each imaging time point.