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骨转移瘤最常见于晚期恶性肿瘤,包括肺癌、乳腺癌、前列腺癌(prostate cancer,PCa)、结直肠癌、甲状腺癌等[1]。骨转移瘤严重影响患者的生活质量,尤其是其引起的顽固性骨痛、病理性骨折、脊髓受压和高钙血症等骨相关事件(skeletal-related events,SRE)。
目前临床治疗骨转移瘤的常用方法包括手术、放化疗、激素治疗、中药治疗等[2]。但骨转移瘤并发症的发生率和病死率依旧较高,其中胃癌、肝癌、结直肠癌和肺癌患者发生骨转移后的总生存期(overall survival time,OS)均<6个月[3]。因此,骨转移瘤的早期诊断与有效治疗对提高患者生活质量和改善预后至关重要。随着基础医学与临床研究的发展,骨转移瘤的诊断方法和治疗策略也在不断更新和改进。近年来,放射性药物靶向治疗成为骨转移瘤的重要治疗方法之一。
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放射性核素靶向治疗是一种将辐射直接作用于靶肿瘤细胞或其微环境的治疗方式,其具有方法简单、不良反应少、疗效好等优点,已成为骨转移瘤的有效治疗方法之一。放射性药物释放的α、β粒子产生的电离辐射可以对肿瘤细胞产生直接杀伤作用、抑制痛感化学物质的分泌、破坏肿瘤组织周围的痛觉传出神经、减轻肿瘤组织对神经的压迫等[4]。放射性药物不仅可以治疗骨转移瘤,还可以从多个方面缓解骨转移瘤引起的顽固性骨痛[5]。
自20世纪40年代β粒子放射性核素131I首次应用于DTC骨转移的治疗以来[6],恶性肿瘤的放射性药物靶向治疗不断发展,如89SrCl2注射液为常用的骨转移瘤所致骨痛的经典治疗药物,其他用于治疗骨转移瘤的β粒子放射性核素还包括153Sm、188Rc、90Y、177Lu等。这些核素具有治疗骨转移瘤的良好物理特性,主要用于PCa、乳腺癌等晚期恶性肿瘤继发骨转移所致骨痛的缓解和部分病灶的清除[7]。但β粒子放射性药物治疗尚不能完全满足骨转移瘤患者的治疗需求。
与β粒子放射性药物治疗相比,α粒子放射性药物治疗体现出更大的优势。β粒子的电离能力较α粒子弱,β粒子主要通过产生自由基间接作用于肿瘤细胞导致其 DNA损伤,以 DNA单链断裂为主[8];而α粒子可直接作用于DNA,造成无法修复的 DNA双链断裂[9]。α粒子的穿透能力弱,能将更多的能量释放在更小的体积中,可以对肿瘤细胞造成更大的杀伤力,同时对邻近的正常组织产生较低的细胞毒性[10-11]。另外,在很大程度上,α粒子的辐射生物效应不受外在因素的影响,可以有效地对肿瘤细胞产生杀伤作用[12]。如肿瘤乏氧是放疗抵抗的一个重要因素[13],但由于α粒子具有很高的传能线密度,可直接作用于DNA导致其双链断裂,诱导细胞程序性凋亡,避免了乏氧导致的肿瘤放疗抵抗。因此,α粒子放射性药物在靶向治疗进展期肿瘤方面具有一定的优势和潜力。
目前,用于临床前和临床试验研究的α粒子放射性核素包括211At、212Pb、149Tb、227Th、225Ac、223Ra等,其中用于骨转移瘤治疗并取得良好疗效的核素有225Ac和223Ra,其半衰期分别为10.1 d和11.4 d,每次衰变均释放4个α粒子和2个β粒子,具有治疗肿瘤的良好物理特性。
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223Ra是一种发射α粒子的碱土金属元素,具有亲骨性。当患者静脉注射223RaCl2后,其会在骨质代谢活跃的区域(如骨转移灶)与羟基磷灰石形成复合物[14]。同时,223Ra也会浓聚在骨基质中发挥抗肿瘤作用[15]。由于具有以上优势和良好的临床试验效果,2013年5月15日,美国食品药品监督管理局(FDA)批准了223RaCl2(Xofigo™)用于PCa骨转移的姑息治疗[16]。
PCa是男性最常见的恶性肿瘤,经去势治疗后复发或进展的PCa会演变成转移性去势抵抗性前列腺癌(metastatic castration-resistant prostate cancer,mCRPC),而PCa的骨转移最为常见[17]。PCa骨转移患者较无骨转移患者的3年和5年生存率均显著降低(均P<0.0001)[18]。手术、化疗、内分泌治疗、细胞免疫治疗等均是PCa的有效治疗方法,但均存在一定的局限性。223RaCl2靶向治疗mCRPC骨转移显示出良好的应用前景[19]。研究结果显示,采用223RaCl2治疗mCRPC骨转移,患者的耐受性良好,其在缓解骨痛、降低SRE发生率、推迟SRE发生时间、延长OS、改善患者生活质量等方面均有优势[20]。
2013年,Wissing等[21]报道,采用223RaCl2治疗骨转移瘤可以延长mCRPC患者的OS。在一项Alpharadin治疗症状性PCa (ALSYMPCA)的Ⅲ期临床研究中,mCRPC骨转移患者接受了安慰剂或223RaCl2治疗,结果显示,经223RaCl2治疗的患者的中位OS较安慰剂治疗的患者延长了3.6个月(P<0.001)[21]。此外,Terrisse等[22]的研究比较了α粒子和β粒子放射性药物的治疗疗效,结果显示,与β粒子放射性核素89Sr相比,α粒子放射性核素223Ra治疗的mCRPC患者的OS获益更大(P=0.004),但后者存在血液毒性(P=0.001)。
Sraieb等[23]评估了30例接受223RaCl2治疗的mCRPC骨转移患者的生活质量,结果显示,223RaCl2治疗不会明显降低患者的生活质量。此外,Caffo等[24]回顾性分析了94例mCRPC患者的资料,其中85.1%的患者接受了223RaCl2治疗,结果显示仅有4例发生3级贫血、2例3级白细胞减少和1例3级中性粒细胞减少,病理性骨折的发生率为2.1%。由此可见,223RaCl2对mCRPC骨转移患者的治疗是安全耐受的,但需要进一步的研究来优化剂量,将不良反应及并发症的发生率降至最低。
同时,使用223Ra联合激素、化疗等方法治疗骨转移瘤的临床试验也取得了明显的进展。已有研究结果显示,223RaCl2可以延长骨转移瘤患者的OS,但与治疗前使用化疗药物多西紫杉醇无关[25]。然而,Saad等[26]报道了223Ra联合阿比特龙或地诺舒单抗治疗可以延长mCRPC骨转移患者的OS。综上所述,223RaCl2治疗使mCRPC骨转移患者多重受益,不仅可以缓解顽固性骨痛,还可以降低SRE的发生率、延长OS。
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225Ac主要由229Ac衰变产生。前列腺特异性膜抗原(prostate specific membrane antigen,PSMA)在PCa中过度表达,其与肿瘤的Gleason评分和疾病分期相关[27]。68Ga-PMSA已被应用于PCa的诊断[28];225Ac-PSMA治疗PCa骨转移也显示了良好的应用前景。
多数PCa患者存在血清前列腺特异性抗原(prostate specific antigen,PSA)水平升高,因此血清PSA水平可作为225Ac-PSMA治疗PCa临床疗效评判的指标。Sathekge等[29]报道,在经225Ac-PSMA-617放射配体疗法(RLT)治疗的晚期PCa患者中,82%的患者血清PSA水平下降幅度≥90%。该研究团队后续还报道了73例接受225Ac-PSMA-617治疗的mCRPC患者,结果显示,82%的患者血清PSA水平下降,其中70%的患者血清PSA水平下降幅度≥50%;多因素分析结果显示,经225Ac-PSMA-617治疗后,血清PSA水平下降幅度≥50%的患者的OS和无进展生存期显著延长;但该研究中有27例患者出现贫血,5例有基础肾脏疾病的患者出现Ⅲ或Ⅳ级肾功能衰竭[30]。
此外,Azorín-Vega等[31]通过体外细胞生物动力学实验在简化的骨模型中评价177Lu-PSMA、225Ac-PSMA和223RaCl2对PCa细胞核的辐射剂量,结果表明,225Ac-PSMA释放的辐射剂量是177Lu-PSMA的900倍,是223RaCl2的14倍,这提示225Ac-PSMA可能是治疗PCa骨转移的最佳选择,但还需要更多的研究以明确其有效性和安全性。
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目前,骨转移瘤的治疗方向主要集中在如何缓解骨痛和降低SRE的发生风险上,全身治疗联合放射性药物靶向治疗可能使骨转移瘤患者获益更多并减少不良反应。此外,α粒子和β粒子放射性药物联合治疗有望实现优势互补,将骨转移瘤患者的临床获益最大化、不良反应最小化[32]。同时,已有学者正在研究一些新型药物(如程序性死亡受体1抑制剂、阿唑单抗等)与223Ra之间的协同性[33],未来有希望将其联合用于骨转移瘤的治疗。
综上所述,α粒子放射性药物靶向治疗不仅具有特异性强、精准高效等优点,在治疗恶性肿瘤骨转移中还可以从缓解顽固性骨痛、降低SRE的发生率、延长OS等方面使患者多重受益。α粒子放射性药物在骨转移瘤治疗中具有不可替代的优势,未来将在恶性肿瘤骨转移的治疗中发挥更大的作用。
利益冲突 所有作者声明无利益冲突
作者贡献声明 吴凡负责综述的撰写及修改;李林法负责综述的立题、框架的建立、审阅及修改;易贺庆负责综述的审阅及修改
α粒子放射性药物在骨转移瘤治疗中的应用进展
Application and progress of α-particle radiopharmaceuticals in the treatment of bone metastases
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摘要: 骨骼是晚期恶性肿瘤的常见转移部位之一,骨转移瘤不仅会导致顽固性骨痛、病理性骨折等骨相关事件(SRE)的发生,还会导致医疗费用的增加和死亡风险的上升。放射性药物内放射治疗具有疗效好、靶向性好和毒性低等优点。常用于治疗骨转移瘤的放射性药物主要是释放β粒子和α粒子的药物,其中释放β粒子的放射性药物的临床应用较成熟,但也具有一定的局限性。近年来,释放α粒子的放射性药物越来越多地用于骨转移瘤的治疗,其在缓解骨痛、降低SRE发生率、延长总生存期等方面具有更大的优势。笔者仅就α粒子放射性药物在骨转移瘤治疗中的应用进展进行综述。Abstract: Bone is one of the common metastatic sites of advanced malignant tumors. Bone metastases not only lead to bone-related events (SRE), such as intractable bone pain and pathological fractures, but also result in the increase of medical costs and the risk of death. Internal radiotherapy with radiopharmaceuticals has the advantages of good curative effect, good targeting, and low toxicity. The radiopharmaceuticals commonly used in the treatment of bone metastases are those that release β-particles and α-particles. The clinical application of radiopharmaceuticals releasing β-particles is mature but has some limitations. In recent years, radiopharmaceuticals releasing α-particles are increasingly used in the treatment of bone metastases, because they have greater advantages in relieving pain, reducing the incidence of SRE, and prolonging overall survival than radiopharmaceuticals releasing β-particles. In this work, the authors review the progress in the application of α-particle radiopharmaceuticals in the treatment of bone metastases.
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Key words:
- Alpha particles /
- Radiopharmaceuticals /
- Neoplasm metastasis /
- Bone
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