The efficacy of Ra-223-dichloride treatment for bone-metastatic lesions in patients with castration-resistant prostatic cancer

Background: Ra-223-dichloride treatment of castration-resistant prostatic cancer has an alpha radiation-induced radiotherapeutic effect on bone metastases and prolongs the prognosis, but the mechanism by which the prognosis is prolonged is not well understood.

Objectives: The purpose of this study was to observe the changes in bone accumulation using bone scintigraphy during Ra-223-dichloride therapy with a precise single-photon emission computed tomography (CT)/CT (SPECT/CT) device.Subjects and Methods: The subjects were 28 patients with Ra-223-dichloride therapy for castration-resistant prostate cancer bone metastases who provided consent to participate in the study. Using Symbia Intevo (Siemens Healthineers K.K., Japan), a whole-body bone scan, and SPECT/CT were performed before treatment, 1 and 2 months after the initiation of treatment, 1 month after the completion of treatment, and 6 months after the completion of treatment approximately 3 h after the administration of Tc-99m-methyl diphosphonate. For bone scintigraphy, the bone scan index (BSI), maximum standardized uptake value (SUV_max), SUV_peak, SUV_mean, metabolic bone volume (MBV), and total bone uptake (TBU) were obtained in the automated analysis application with a cut-off SUV of 12. We also compared blood cell counts and biochemical tests for bone metastases, including white blood cells (WBCs), platelets, hemoglobin, serum prostate-specific antigen (PSA), lactate dehydrogenase, alkaline phosphatase (ALP), bone-specific alkaline phosphatase (BAP), type I collagen cross-linked C-telopeptide (1-CTP), and calcium. Statistical analyses were performed with the Kruskal-Wallis test and post-hoc Dunn's multiple comparisons test. Same analyses were performed for a percent change in each value.

Results: During the course, significant changes were evident in SUV_max (p = 0.026), SUV_peak (p = 0.013), SUV_mean (p = 0.0099), and percent changes in SUV, including %SUV_max (p = 0.0004), %SUV_peak (p = 0.0010), and %SUV_mean (p = 0.0081), indicating a decrease after the end of treatment compared to the value before the start of treatment. However, there were no significant changes in the index scores reflecting bone metastasis, including BSI (p = 0.88), MBV (p = 0.73), TBU (p = 0.59), %BSI (p = 0.18), %MBV (p = 0.18), and %TBU (p = 0.31). Blood biochemistry revealed significant increases in %PSA (p <0.0001), which is considered to represent the rate of bone metastasis change, 1-CTP (p = 0.02), and %1-CTP (p <0.0001), which represent osteolytic bone metastasis activity. In %ALP (p<0.0001) and %BAP (p = 0.0012), which represent osteogenic activity, a significant decrease was observed during treatment, but it tended to increase after the end of treatment. WBCs (p = 0.094) and platelets (p = 0.50), which reflect the myelosuppressive effect of radiation, did not change significantly while hemoglobin (p = 0.0003) tended to decrease significantly.

Conclusions: Although the elevation of PSA and hemoglobin may lead to the progression of bone marrow lesions during Ra-223-dichloride treatment, elevations of SUVs, ALP, and BAP suggest that areas with a high osteoblastic activity had a high-absorbed dose of alpha radiation and suppressed osteoblastic activity. The amount of bone metastatic lesions demonstrated by BSI, MBV, or TBU did not significantly change, and 1-CTP of osteolytic bone metastases had increased during the treatment. Therefore, the Ra-223-dichloride therapy was considered to have little inhibitory effect on osteolytic metastases and a therapeutic effect mainly on osteoblastic bone metastatic lesions, leading to little effect on the burden of bone metastatic lesions. These results suggest that bone SUV_max may be more useful than BSI in evaluating the efficacy of Ra-233-dichloride therapy.