Elba C. Etchebehere, MD, PhD
Bone marrow failure (BMF) may occur following treatment with radium-223 (Xofigo) in a portion of patients with metastatic castration-resistant prostate cancer (CRPC) who have high skeletal tumor burden, according to a study presented at the 2015 ASCO Annual Meeting by Elba C. Etchebehere, MD, PhD.1
The findings suggest that whole-body 18F sodium fluoride PET/CT (Fluoride PET/CT) could be used as an imaging biomarker for selecting the best candidates for treatment with radium-223.
In 41 patients evaluable in the trial, radium-223 was found to significantly reduce the risk of death; however, this benefit was most pronounced in those who did not experience BMF. In 16 patients who developed BMF the median OS was 5.78 months compared with a median that was not yet reached in 25 patients who did not experienced this adverse event.
"Radium-223 is beneficial and reduces the risk of death, even in patients with high skeletal tumor burden," Etchebehere and colleagues at the MD Anderson Cancer Center wrote. "However, high skeletal tumor burden is a significant risk factor for developing BMF and Fluoride PET/CT is a useful imaging biomarker that is able to predict BMF and help select the best candidates for radium-223."
Radium-223 is a first-in-class alpha-emitting radiopharmaceutical agent approved for treatment of patients with metastatic CRPC and bone metastases. In clinical studies, radium-223 was found to deliver cytotoxic radiation with minimal myelosuppression by selectively targeting the area with increased bone turnover. In the pivotal 921-patient phase III ALSYMPCA trial, treatment with radium-223 demonstrated a median OS of 14 months compared with 11.2 months with placebo.
In the study presented in a poster at ASCO, Etchebehere and colleagues retrospectively reviewed data from 76 patients (mean age, 71 ± 9 years) with hormone-refractory prostate cancer and bone metastases who underwent Fluoride PET/CT prior to, during, or within 3 months after receiving radium-223. BMF, the primary endpoint, was defined as either the development of hematologic toxicity with no recovery after 6 weeks or death due to BMF after the last dose of radium-223.
Of the 76 patients reviewed, 41 were eligible for analysis. The median age of patients examined was 71.1 years and the median PSA was 54. An initial Gleason score of 8-10 was detected in 61.9% of patients and most patients with clinical stage III/IV at the time of diagnosis (85.4%).
A total of 16 patients developed BMF. By univariate analysis, the investigators found an increased risk of developing BMF in patients with higher skeletal tumor burden, indicated as fluoride skeletal metastatic lesion uptake (TLF10
) of <12,000. Additionally, BMF was associated with fewer doses of radium-223, lower serum hemoglobin concentration, and higher serum alkaline phosphatase levels. The use of chemotherapy during or after radium-223 and PSA levels were not associated with an increase in the risk of BMF.
In a multivariate analysis, skeletal tumor burden was the only independent predictor of BMF. High skeletal tumor burden was found to be highly specific for BMF (96%) but not as sensitive (62.5%), as a predictive biomarker.
levels and tumor burden were found to be an independent predictor of OS (HR = 5.99; 95%CI, 1.306- 27.475; P
= .0212), in a separate analysis from the study published in the Journal of Nuclear Medicine
In this analysis of 42 patients, a TLF10
cutoff value of 8000 effectively predicted long-term outcomes. In those with a TLF10
below 8000 the median OS was not reached versus 6.67 months in those with a level above 8000. Average standardized uptake value (SUV) of disease was found to be a significant univariate predictor of a skeletal related event (odds ratio = 1.30; 95%CI, 1.006- 1.681; P
Etchebehere EC, Araujo JC, Milton D, et al. Skeletal tumor burden on baseline 18F-fluoride PET/CT to predict bone marrow failure after radium-223. J Clin Oncol. 2015;33 (suppl; abstr 11012).
Etchebehere E, Araujo JC, Fox PS, et al. Prognostic factors in patients treated with radium-223: the role of skeletal tumor burden on baseline 18F-fluoride-PET/CT in predicting overall survival. J Nucl Med. 2015 Jun 11. pii: jnumed.115.158626. [Epub ahead of print]