Subbiah Vivek, Anderson Pete M, Kairemo Kalevi, Hess Kenneth, Huh Winston W, Ravi Vinod, Daw Najat C, Somaiah Neeta, Ludwig Joseph A, Benjamin Robert S, Chawla Sant, Hong David S, Meric-Bernstam Funda, Ravizzini Gregory, Kleinerman Eugenie, Macapinlac Homer, Rohren Eric
Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Clin Cancer Res. 2019 Jul 1;25(13):3802-3810. doi: 10.1158/1078-0432.CCR-18-3964. Epub 2019 Feb 7.
The prognosis of metastatic osteosarcoma continues to be poor. We hypothesized that alpha-emitting, bone-targeting radium 223 dichloride (RaCl) can be safely administered to patients with osteosarcoma and that early signals of response or resistance can be assessed by quantitative and qualitative correlative imaging studies and biomarkers.
A 3+3 phase I, dose-escalation trial of RaCl (50, 75, and 100 kBq/kg) was designed in patients with recurrent/metastatic osteosarcoma aged ≥15 years. Objective measurements included changes in standardized uptake values of positron emission tomography (PET; 18FDG and/or NaF-18) and single-photon emission CT/CT (99mTc-MDP) as well as alkaline phosphatase and bone turnover markers at baseline, midstudy, and the end of the study.
Among 18 patients enrolled (including 15 males) aged 15-71 years, tumor locations included spine ( = 12, 67%), pelvis ( = 10, 56%), ribs ( = 9, 50%), extremity ( = 7, 39%), and skull ( = 2, 11%). Patients received 1-6 cycles of RaCl; cumulative doses were 6.84-57.81 MBq. NaF PET revealed more sites of metastases than did FDG PET. One patient showed a metabolic response on FDG PET and NaF PET. Four patients had mixed responses, and one patient had a response in a brain metastasis. Bronchopulmonary hemorrhage from Grade 3 thrombocytopenia ( = 1) was a DLT. The median overall survival time was 25 weeks.
The first evaluation of the safety and efficacy of an alpha particle in high-risk osteosarcoma shows that the recommended phase II dose for RaCl in osteosarcoma is 100 kBq/kg monthly (twice the dose approved for prostate cancer), with minimal hematologic toxicity, setting the stage for combination therapies.
转移性骨肉瘤的预后仍然很差。我们假设，向骨靶向发射α粒子的二氯化镭（RaCl）可以安全地应用于骨肉瘤患者，并且可以通过定量和定性的相关成像研究及生物标志物评估反应或耐药的早期信号。
针对年龄≥15岁的复发性/转移性骨肉瘤患者，设计了一项3+3期I期剂量递增试验，使用RaCl（50、75和100 kBq/kg）。客观测量指标包括正电子发射断层扫描（PET；18FDG和/或NaF-18）以及单光子发射CT/CT（99mTc-MDP）的标准化摄取值变化，以及基线、研究中期和研究结束时的碱性磷酸酶和骨转换标志物。
18例入组患者（包括15例男性）年龄在15-71岁之间，肿瘤部位包括脊柱（n = 12，67%）、骨盆（n = 10，56%）、肋骨（n = 9，50%）、四肢（n = 7，39%）和颅骨（n = 2，11%）。患者接受了1-6个周期的RaCl治疗；累积剂量为6.84-57.81 MBq。NaF PET显示的转移部位比FDG PET更多。1例患者在FDG PET和NaF PET上显示出代谢反应。4例患者有混合反应，1例患者的脑转移灶有反应。3级血小板减少导致的支气管肺出血（n = 1）是剂量限制性毒性反应。中位总生存时间为25周。
对α粒子在高危骨肉瘤中的安全性和有效性进行的首次评估表明，骨肉瘤中RaCl的推荐II期剂量为每月100 kBq/kg（是前列腺癌批准剂量的两倍），血液学毒性最小，为联合治疗奠定了基础。
