Fosbøl Marie Øbro, Jørgensen Niklas Rye, Petersen Peter Meidahl, Kjaer Andreas, Mortensen Jann
Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
Cluster for Molecular Imaging, Department of Biomedical Sciences, Copenhagen University Hospital - Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
EJNMMI Res. 2024 Oct 3;14(1):90. doi: 10.1186/s13550-024-01155-w.
The alpha-emitting radionuclide therapy [Ra]RaCl (Radium-223) improves overall survival (OS) and time to symptomatic skeletal event (SSE) in patients with metastatic castration-resistant prostate cancer (mCRPC). Evidence suggests that the effect of Radium-223 is partly exerted through an impact on the surrounding bone matrix. We hypothesized that bone metabolism markers (BMM) could provide predictive information regarding response to Radium-223. Accordingly, the aim of this study was to investigate changes in BMM during Radium-223 therapy and evaluate association with clinical outcome.
Prospective study of BMM in patients with mCRPC receiving Radium-223. Blood samples were collected before each administration of Radium-223 and the following BMM were quantified; bone-specific alkaline phosphatase (BALP), osteocalcin, procollagen type I N-propeptide (PINP), C-terminal telopeptide of type I collagen (CTX), C-terminal cross-linking telopeptide of type I collagen generated by matrix metalloproteinases (CTX-MMP), tartrate-resistant acid phosphatase isoform 5b (TRACP5b), receptor-activated nuclear factor κB ligand (RANKL), osteoprotegerin (OPG), and sclerostin. Clinical outcomes were scintigraphic progression during/after therapy, change in bone scan index (BSI), occurrence of SSE, and OS.
A total of 55 mCRPC patients were included. There was a significant linear association between skeletal extent of disease and CTX-MMP, PINP, BALP, and osteocalcin. No significant association between dynamics in BSI and BMM were detected. Median OS for the cohort was 14 months (95% CI: 10.7-16.8). Baseline levels of Log2-CTX-MMP (HR = 2.15 (95%CI: 1.1-4.1)) and Log2-BALP (HR = 1.59 (95%CI: 1.1-2.1)) were associated with OS. Patients with increasing CTX-MMP during therapy had significantly shorter OS (Median OS = 4 mo. (95%CI: 2.3-5.7)) than patients with stable or decreasing CTX-MMP (Median OS = 12 mo. (95%CI: 10.1-13.9), P < 0.001).
BMM are significantly associated with scintigraphic extent of skeletal disease and OS in patients with mCRPC. Particularly, the bone resorption marker CTX-MMP is a promising surrogate marker for prediction of outcome in patients receiving Radium-223 therapy and could potentially improve selection of patients for therapy and assessment of response.
Clinicaltrials.gov, NCT03247010. Registered 10th of August 2017, https://clinicaltrials.gov/study/NCT03247010?term=NCT03247010&rank=1 .
发射α粒子的放射性核素疗法[镭]RaCl（镭 - 223）可改善转移性去势抵抗性前列腺癌（mCRPC）患者的总生存期（OS）及出现有症状骨相关事件（SSE）的时间。有证据表明，镭 - 223的作用部分是通过对周围骨基质的影响来发挥的。我们推测骨代谢标志物（BMM）可提供有关对镭 - 223反应的预测信息。因此，本研究的目的是调查镭 - 223治疗期间BMM的变化，并评估其与临床结局的关联。
对接受镭 - 223治疗的mCRPC患者的BMM进行前瞻性研究。在每次给予镭 - 223之前采集血样，并对以下BMM进行定量分析；骨特异性碱性磷酸酶（BALP）、骨钙素、I型前胶原N端前肽（PINP）、I型胶原C端肽（CTX）、基质金属蛋白酶产生的I型胶原C端交联肽（CTX - MMP）、抗酒石酸酸性磷酸酶同工酶5b（TRACP5b）、核因子κB受体活化配体（RANKL）、骨保护素（OPG）和硬化蛋白。临床结局包括治疗期间/治疗后的骨闪烁显像进展、骨扫描指数（BSI）变化、SSE的发生情况及OS。
共纳入55例mCRPC患者。疾病的骨骼范围与CTX - MMP、PINP、BALP和骨钙素之间存在显著的线性关联。未检测到BSI动态变化与BMM之间的显著关联。该队列的中位OS为14个月（95%CI：10.7 - 16.8）。Log2 - CTX - MMP（HR = 2.15（95%CI：1.1 - 4.1））和Log2 - BALP（HR = 1.59（95%CI：1.1 - 2.1））的基线水平与OS相关。治疗期间CTX - MMP升高的患者的OS（中位OS = 4个月（95%CI：2.3 - 5.7））显著短于CTX - MMP稳定或降低患者（中位OS = 12个月（95%CI：10.1 - 13.9），P < 0.001）。
BMM与mCRPC患者的骨闪烁显像疾病范围及OS显著相关。特别是，骨吸收标志物CTX - MMP是预测接受镭 - 223治疗患者结局的一个有前景的替代标志物，并且可能会改善治疗患者的选择及反应评估。
Clinicaltrials.gov，NCT03247010。于2017年8月10日注册，https://clinicaltrials.gov/study/NCT03247010?term=NCT03247010&rank=1 。
