Radium-223 Dichloride in Combination with Vascular Endothelial Growth Factor–Targeting Therapy in Advanced Renal Cell Carcinoma with Bone Metastases

Abstract

This study investigates the biologic activity of radium-223 with VEGF-targeted therapy in patients with advanced renal cell carcinoma (aRCC) and bone metastases. Fifteen treatment-naïve patients ( = 15) received pazopanib 800 mg orally once daily, and 15 previously treated patients received sorafenib 400 mg orally twice daily. Radium-223 55 kilobecquerel/kg was administered concurrently every 4 weeks for up to six infusions in both cohorts. The primary endpoint was decline in bone turnover markers (Procollagen I Intact N-Terminal, N-telopeptide, C-telopeptide, osteocalcin, and bone-specific alkaline phosphatase) compared with baseline. Secondary endpoints included safety, rate of symptomatic skeletal event (SSE) and time to first SSE, objective response rate, change in analgesic use, and quality of life. Exploratory analysis of tumor genomic alterations was performed. Of the 30 patients enrolled, 83% had IMDC intermediate- or poor-risk disease, 33% had liver metastases, and 83% had a history of SSE prior to enrollment. No dose-limiting toxicity was observed. All bone turnover markers significantly declined from baseline at week 8 and 16. Forty percent of patients experienced treatment-related grade ≥3 adverse events. Response rates were 15% and 18% per RECIST v1.1 and bone response was 50% and 30% per MD Anderson criteria, in the pazopanib and sorafenib cohort, respectively. Median SSE-free interval was 5.8 months and not reached, respectively. Analgesic use remained stable over the study time. Radium-223 combined with VEGF-targeted therapy is biologically active and safe. Randomized-controlled trials are needed to define the role of radium-223 in aRCC with skeletal metastases. .

Radiographical efficacy of systemic treatment for bone metastasis from renal cell carcinoma

“…Therefore, the present study adopted the MD Anderson bone response criteria, which can be used to evaluate the treatment efficacy for bone lesions by considering the size and sclerotic changes ( 17 ). While these criteria were originally developed for evaluating bone metastases from breast cancer, they have been used in translational research to evaluate the effect of radium-223 dichloride combined with targeting therapy on bone metastases of RCC ( 18 ).…”

“…For example, Hamaoka et al ( 17 ) proposed the MD Anderson bone response criteria, in which not only a size reduction, but also osteoblastic changes are considered evidence of treatment efficacy for bone lesions. These criteria were originally developed for bone metastases from breast cancer, but have been adopted during a clinical trial evaluating the efficacy of radium-223 dichloride for RCC bone metastasis ( 18 ).…”

Utility of FDG-PET/CT in Patients with Advanced Renal Cell Carcinoma with Osseous Metastases: Comparison with CT and 99mTc-MDP Bone Scan in a Prospective Clinical Trial

“…This is a retrospective analysis of imaging data prospectively collected as part of a two-cohort trial of radium-223 and anti-VEGF therapy in mRCC [15]. The trial was conducted in full concordance with Declaration of Helsinki principles and Good Clinical Practice (NCT02406521) and approved by our institutional review board.…”

“…Patients had histologically-proven renal cell cancer, ≥1 bone metastasis on imaging and non-measurable bone-only disease was allowed. Eligibility criteria, treatment data, and the safety and efficacy results of the therapeutic clinical trial have been reported [15].…”

“…Response assessments were performed for the published clinical trial [15] [18] by a board-certified radiologist (KK) and board-certified nuclear medicine physician (HJ) in consensus. FDG-PET/CT at baseline and after 8 weeks of treatment (PET2) were reviewed for abnormal FDG uptake, defined as increased uptake greater than background not consistent with normal anatomy or physiology.…”