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前列腺癌是全球男性发病率第二的恶性肿瘤[1],也是成年男性癌症死亡的第二大原因[2]。目前,前列腺癌的主要治疗方法有手术、放疗、化疗、雄激素剥夺治疗等。然而,随着患者病情的进展,这些疗法的疗效会逐渐降低甚至完全无效[3]。在经过18~24个月的雄激素剥夺治疗后,几乎所有患者都会逐渐演变为去势抵抗性前列腺癌(castration-resistant prostate cancer,CRPC);其中约86%的CRPC发生转移,转变为转移性去势抵抗性前列腺癌(metastatic castration resistant prostate cancer,mCRPC),这是导致前列腺癌患者死亡的主要原因。目前缺少有效的治疗方法来治疗这一疾病阶段的患者,且患者预后差,现迫切需要找到治疗mCRPC的新方法。
近年来,放射性核素标记的前列腺特异性膜抗原(prostate specific membrane antigen,PSMA)配体已被用于前列腺癌的诊断和治疗。由于放射性配体治疗(radioligand therapy,RLT)转移性神经内分泌肿瘤患者已取得良好疗效[4],促进了177Lu标记的PSMA配体在前列腺癌诊疗中的应用研究。对常规治疗方法抵抗的mCRPC患者来说,177Lu标记的PSMA配体靶向治疗是一种极具希望的新的治疗方法。
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放射性核素标记的配体通常由3部分组成:放射性核素、载体和连接分子(螯合剂等)。
与其他常用的治疗性放射性核素相比,177Lu展现出有利的治疗特性:释放低能β射线可用于治疗,最大组织穿透直径<3 mm,能精确地破坏小的肿瘤及转移性病变,并且对周围正常组织的损伤较小;释放低能γ射线,可进行SPECT/CT显像和剂量测定;物理半衰期较长(6.7 d),能进行远距离运输;不良反应小,成本可以接受;生产潜力大,易于辐射防护。
PSMA(图1)是一种II型跨膜蛋白(双核膜结合锌蛋白酶),也被称作叶酸水解酶I或谷氨酸羧肽酶II,具有叶酸水解酶和N-乙酰基化α-酸性二肽酶两种酶的活性。PSMA含有750个氨基酸,包括3个部分:膜内段、跨膜段及膜外段(分别含19、24、707个氨基酸)。膜内段和膜外段含多个表位,可与多种单克隆抗体结合,特别是膜外段表位,是近年研究的热点。PSMA在大多数前列腺肿瘤细胞表面、肿瘤相关新血管上高表达[5,6],表达水平随着肿瘤去分化程度、转移性和激素抵抗性的增加而增加[7-9]。即使多次行RLT后转移灶中的PSMA仍保持高表达,进而能重复静脉注射放射性配体进行全身性RLT[10]。此外,PSMA在前列腺上皮、小肠、肝、肾和唾液腺等正常人体组织中低表达,表达水平仅为前列腺癌的1‰~1%[11]。PSMA的配体与PSMA亲和力高,结合后通过网格蛋白介导的胞吞作用内化。因此PSMA被认为是前列腺癌诊断和治疗的理想靶点。
PSMA配体主要包括PSMA的单克隆抗体(如7E11、J591等)和小分子抑制剂(如PSMA-11、PSMA-617、PSMA-I&T、MIP-1095、MIP-1072、MIP-1404、MIP-1405、DCFBC、DCFPyl、PAMA-1007)(PSMA-617、PSMA I&T结构式分别见图2、图3)。表1中主要介绍与治疗相关的PSMA配体。单克隆抗体显像剂具有固有局限性(抗体分子质量相对较大,肿瘤组织渗透性差,血液清除慢,显像所需时间延长,图像对比度不理想)。PSMA的小分子抑制剂:分子质量小,克服了抗体配体固有的局限性,对PSMA有较高的亲和力,组织内化率高,具有更快的组织分布和血液清除(肿瘤背景比高),成为PSMA高表达的前列腺癌诊疗药物开发的热点。近年来研究报道的177Lu-PSMA配体主要包括:177Lu-J591、177Lu-PSMA-617和177Lu-PSMA I&T。其中177Lu-PSMA-617、177Lu-PSMA I&T具有更好的应用前景,疗效更好、不良反应更小。
生物学性质 配体名称 常用可标记核素 结合部位 特点 单克隆抗体(鼠源性) 7E11(CYT356、
CYT5400)177Lu、90Y、111In、99Tcm、89Zr等 胞内域 单克隆抗体显像剂固有局限性;仅与PSMA表型阳性的坏死细胞结合,具有人鼠抗体反应 单克隆抗体(鼠源性、人源性) J591 177Lu、90Y、213Bi、111In、89Zr、等 胞外域 单克隆抗体显像剂固有局限性;允许靶向活的、完整的肿瘤细胞 PSMA的小分子抑制剂 PSMA-617
(DOTA偶联)177Lu、90Y、213Bi、225Ac、131I、68Ga、111In、64Cu、44Sc等 胞外域 PSMA-11的变异体,具有PSMA-11的特性,并进一步改善药代动力学,增强肿瘤摄取并减少肾脏示踪剂聚集。177Lu-PSMA-617体内、体外稳定性好。 PSMA小分子抑制剂 PSMA-I&T
(DOTAGA偶联)177Lu、90Y、131I、68Ga、64Cu等 胞外域 与PAMA-617相似。但与177Lu-PSMA-617相比,全身摄取较低,半衰期较短,肾脏摄取略高、排泄较慢。标记步骤繁琐 PSMA小分子配体 MIP-1095、MIP-1072 123I、124I、131I等 胞外域 肿瘤病变中迅速、高摄取并长时间滞留,肾脏摄取较高 注:表中,PSMA为前列腺特异性膜抗原。 表 1 前列腺癌治疗相关性前列腺特异性膜抗原配体的特点
Table 1. Characteristics of prostate specific membrane antigen ligands associated with prostate cancer treatment
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疗效评估主要根据PSA的变化,同时还可以通过影像学、生活质量来评估。使用前列腺癌第3工作组(PCWG3)标准,PSA作为评估疗效的主要标志物,根据PSA的变化分为:任何程度的PSA下降、PSA下降≥50%、PSA增加。RLT后从基线起至少2周PSA下降≥50%被认为对治疗具有反应(生化反应)[31],PSA增加表明病情进展。
与常规药物相比,放射性药物的不良反应和疗效主要取决于对正常组织和肿瘤组织的辐射吸收剂量。许多研究证明177Lu-PSMA RLT是安全、有效的[30,32-34]。
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表2列出了一些关于177Lu-PSMA的回顾性研究,行177Lu-PSMA RLT后约70%的患者PSA下降,半数患者PSA下降有望超过50%。
作者 例数 中位年龄(岁) 配体 中位剂量(GBq) PSA下降频率(%) PSA降>50%的频率(%) Rahbar[10] 145 73 617 5.9 60、66①、72② 45、40①、57②、65③④ Rathke[22] 40 − 617 4.0、6.0、7.4、9.3 四组分别为:90、70、70、80 四组分别为:40、30、50、30 Kulkarni[23] 119 − 617、I&T 6.0 76 58 Rahbar[24] 104 70 617 6.1 67①②③④ 33 Fendler[28] 15 73 617 3.7、6.0 80 47 Kratochwil[30] 30 73 617 − 70① 43① Yadav[32] 31 66 617 5.1 − 71 Rahbar[33] 28 73 617 − 59①、75② 32①、50② Rahbar[34] 82 73 617 5.9 64 31 Rahbar[35] 71 72 617 6.0 66 56 Ahmadzadehfar[36] 52 71 617 − 81①、73③ 44①、60③ Ferdinandus[40] 40 71 617 6.0 68 33 Bräuer[41] 59 72 617 6.1 91 53 Ahmadzadehfar[42] 100 − 617 6.0 69 38 Ahmadzadehfar[45] 49 − 617 − 67 53 Ahmadzadehfar[46] 10 74 617 5.6 70 50 注:表中,①、②、③、④分别表示:第一、二、三、四个治疗周期后;−:无此项数据。 表 2 177Lu-前列腺特异性膜抗原治疗转移性去势抵抗性前列腺癌的疗效
Table 2. Therapeutic effect of 177Lu-prostate specific membrane antigen on metastatic castration resistant prostate cancer
其中约30%的mCRPC患者对RLT没有任何反应。有研究表示初始PSA反应与治疗活度无关[22]。第一个周期治疗后无反应者中相当数量患者表现出延迟反应[35-36]。
Hofman等[37]报道了一项II期前瞻性试验,选择了30例标准治疗失败的进展性mCRPC患者,其中,97%的患者出现了不同程度的PSA下降,57%的患者PSA下降≥50%,43%的患者PSA下降≥80%。
von Eyben等[38]的一项Meta分析结果显示:对于mCRPC患者,177Lu-PSMA RLT治疗比三线治疗(包括恩杂鲁胺、卡巴他赛、阿比特龙)效果更好,不良反应更少。该研究分析了包括669例患者在内的12项177Lu-PSMA RLT研究报道(其中177Lu-J591、177Lu-PSMA-617、177Lu-PSMA-617分别为2、1、9篇),与三线治疗相比,177Lu-PSMA RLT具有更显著的PSA下降≥50%(平均比例为44%vs.22%),更高的客观缓解率(31/109vs.43/275),中位生存期更长(14个月vs.11个月),没有频繁地导致治疗中止(0/469vs.22/66)。
另一项Meta分析结果显示:共10项研究(其中177Lu-J591、177Lu-PSMA I&T、177Lu-PSMA-617分别为3、2、6篇,其中1篇同时包括177Lu-PSMA-617和177Lu-PSMA I&T)纳入分析,总样本量为369例(334例可分析),220例经历了PSA下降,其中PSA下降>50%的比例为37%[39]。
有研究结果显示碱性磷酸酶升高和内脏转移是负面预测因子,治疗周期数是生化反应的阳性预测因子[10]。另一项研究结果显示,在单因素分析中,年龄越小,γ-谷氨酰转移酶水平越高,治疗前血红蛋白水平越低,Gleason评分越高,血小板数量越多,C-反应蛋白越高,需止痛药物治疗及乳酸脱氢酶越高对治疗反应有负面影响;在多变量分析中,最重要的独立因素是血小板数量和经常需要止痛药。治疗反应与病灶吸收剂量、先前的治疗及测量因素无关[40]。
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177Lu-PSMA RLT有望延迟多数患者的总体生存期(overall survival,OS),还能提高患者的生活质量。
Rahbar等[33]的研究结果显示:177Lu-PSMA-617治疗组与历史最佳支持治疗组相比,中位OS明显更长(29.4周vs.19.7周),但没有对177Lu-PSMA-617治疗组中反应者和无反应者进行比较。
Ahmadzadehfar等[36]的一项研究结果显示,与无PSA下降者相比,RLT反应阳性者(无论PSA下降率程度如何)中位OS显著延长(第一个周期后中位OS为68周vs.33周)。Bräuer等[41]也得出了类似的结果:第一周期后PSA下降和初始碱性磷酸酶水平<220 U/L是终末期mCRPC患者较长中位OS的预测因子。
Ahmadzadehfar等[42]进一步的研究结果显示:无肝脏受累,白蛋白和血红蛋白水平高,谷草转氨酶水平低的患者的中位OS更长。PSA水平下降超过14%是OS最重要的反应参数。
Rahbar等[24]在一项关于OS的回顾性分析中发现:初始PSA下降≥50%、初始乳酸脱氢酶、内脏转移、二线化疗或223Ra放疗史对生存无影响,而任何初始PSA下降、初始碱性磷酸酶<220 U/L和累积注射活性≥18.8 GBq与更长OS相关。逐步分析显示PSA下降≥20.87%是预测更长OS最显著的临界值,其在多变量分析中仍然是改善OS的独立预测因子。
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根据常见毒性标准分析不良事件。不良反应主要包括:血液学毒性,贫血、血小板减少和白细胞减少;非血液学毒性,肝肾毒性、胃肠道症状(如恶心、呕吐)、干燥综合征、疲劳等。表3列出了一些关于177Lu-PSMA-617相关报道的不良反应。177Lu-PSMA RLT的不良反应更轻微,安全、耐受性更好,是mCRPC患者安全的选择。
总例数 3/4级血液学毒性 口腔干燥症(%) 非血液学毒性 血红蛋白(%) 白细胞(%) 血小板(%) Rahbar[10] 145 10 3 4 8 轻至中度恶心 Kulkarni[23] 119 3.4 − − 4.2 疲劳 Yadav[32] 31 3.2 0 0 − − Rahbar[33] 28 11 0 0 14 轻度恶心 Rahbar[34] 82 2.8 0 0 8.5 轻度恶心 Hofman[37] 30 0 0 13 87 轻度恶心、疲劳 Bräuer[41] 59 19 3 3 25 恶心、腹泻、疲劳 Ahmadzadehfar[45] 49 8.2 0 6.1 − − Ahmadzadehfar[46] 10 10 0 0 0 轻度恶心、疲劳 Ahmadzadehfar[47] 24 9 0 0 8.7 轻度恶心、疲劳 Yordanova[48] 55 0 0 0 − − 注:表中,−:无此项数据或内容。 表 3 177Lu-前列腺特异性膜抗原治疗转移性去势抵抗性前列腺癌的不良反应
Table 3. Adverse reactions of 177Lu-prostate specific membrane antigen in the treatment of metastatic castration resistant prostate cancer
177Lu-PSMA靶向治疗转移性去势抵抗性前列腺癌的研究进展
Progress in radioligand therapy with 177Lu-PSMA for the treatment of metastatic castration-resistant prostate cancer
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摘要: 前列腺癌是男性最常见的恶性肿瘤之一,尽管现有的治疗方法对多数前列腺癌患者可取得较好疗效,但对转移性去势抵抗性前列腺癌的治疗仍然极具挑战性,迫切需要发展更有效的治疗方法。目前,177Lu标记的前列腺特异性膜抗原靶向治疗是最有希望的新疗法之一,有望成为前列腺癌的标准治疗方案之一,该疗法安全、有效,可延长患者的总体生存期。
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关键词:
- 前列腺特异膜抗原 /
- 前列腺肿瘤 /
- 分子靶向治疗 /
- 转移性去势抵抗性前列腺癌 /
- 177Lu
Abstract: Prostate cancer is one of the most common malignancies worldwide. Many advances have been made over the past years, but the treatment of metastatic prostate cancer remains challenging. In many cases, existing therapies have become ineffective for controlling tumor progression. Thus, new approaches are urgently needed. Radioligand therapy with 177Lu-Prostate specific membrane antigen (PSMA) is an innovative and effective therapy for patients with castration-resistant metastatic prostate cancer. PSMA is expected to be a standard regimen for prostate cancer as it is well tolerated by patients and has high potential for improving overall survival. -
表 1 前列腺癌治疗相关性前列腺特异性膜抗原配体的特点
Table 1. Characteristics of prostate specific membrane antigen ligands associated with prostate cancer treatment
生物学性质 配体名称 常用可标记核素 结合部位 特点 单克隆抗体(鼠源性) 7E11(CYT356、
CYT5400)177Lu、90Y、111In、99Tcm、89Zr等 胞内域 单克隆抗体显像剂固有局限性;仅与PSMA表型阳性的坏死细胞结合,具有人鼠抗体反应 单克隆抗体(鼠源性、人源性) J591 177Lu、90Y、213Bi、111In、89Zr、等 胞外域 单克隆抗体显像剂固有局限性;允许靶向活的、完整的肿瘤细胞 PSMA的小分子抑制剂 PSMA-617
(DOTA偶联)177Lu、90Y、213Bi、225Ac、131I、68Ga、111In、64Cu、44Sc等 胞外域 PSMA-11的变异体,具有PSMA-11的特性,并进一步改善药代动力学,增强肿瘤摄取并减少肾脏示踪剂聚集。177Lu-PSMA-617体内、体外稳定性好。 PSMA小分子抑制剂 PSMA-I&T
(DOTAGA偶联)177Lu、90Y、131I、68Ga、64Cu等 胞外域 与PAMA-617相似。但与177Lu-PSMA-617相比,全身摄取较低,半衰期较短,肾脏摄取略高、排泄较慢。标记步骤繁琐 PSMA小分子配体 MIP-1095、MIP-1072 123I、124I、131I等 胞外域 肿瘤病变中迅速、高摄取并长时间滞留,肾脏摄取较高 注:表中,PSMA为前列腺特异性膜抗原。 表 2 177Lu-前列腺特异性膜抗原治疗转移性去势抵抗性前列腺癌的疗效
Table 2. Therapeutic effect of 177Lu-prostate specific membrane antigen on metastatic castration resistant prostate cancer
作者 例数 中位年龄(岁) 配体 中位剂量(GBq) PSA下降频率(%) PSA降>50%的频率(%) Rahbar[10] 145 73 617 5.9 60、66①、72② 45、40①、57②、65③④ Rathke[22] 40 − 617 4.0、6.0、7.4、9.3 四组分别为:90、70、70、80 四组分别为:40、30、50、30 Kulkarni[23] 119 − 617、I&T 6.0 76 58 Rahbar[24] 104 70 617 6.1 67①②③④ 33 Fendler[28] 15 73 617 3.7、6.0 80 47 Kratochwil[30] 30 73 617 − 70① 43① Yadav[32] 31 66 617 5.1 − 71 Rahbar[33] 28 73 617 − 59①、75② 32①、50② Rahbar[34] 82 73 617 5.9 64 31 Rahbar[35] 71 72 617 6.0 66 56 Ahmadzadehfar[36] 52 71 617 − 81①、73③ 44①、60③ Ferdinandus[40] 40 71 617 6.0 68 33 Bräuer[41] 59 72 617 6.1 91 53 Ahmadzadehfar[42] 100 − 617 6.0 69 38 Ahmadzadehfar[45] 49 − 617 − 67 53 Ahmadzadehfar[46] 10 74 617 5.6 70 50 注:表中,①、②、③、④分别表示:第一、二、三、四个治疗周期后;−:无此项数据。 表 3 177Lu-前列腺特异性膜抗原治疗转移性去势抵抗性前列腺癌的不良反应
Table 3. Adverse reactions of 177Lu-prostate specific membrane antigen in the treatment of metastatic castration resistant prostate cancer
总例数 3/4级血液学毒性 口腔干燥症(%) 非血液学毒性 血红蛋白(%) 白细胞(%) 血小板(%) Rahbar[10] 145 10 3 4 8 轻至中度恶心 Kulkarni[23] 119 3.4 − − 4.2 疲劳 Yadav[32] 31 3.2 0 0 − − Rahbar[33] 28 11 0 0 14 轻度恶心 Rahbar[34] 82 2.8 0 0 8.5 轻度恶心 Hofman[37] 30 0 0 13 87 轻度恶心、疲劳 Bräuer[41] 59 19 3 3 25 恶心、腹泻、疲劳 Ahmadzadehfar[45] 49 8.2 0 6.1 − − Ahmadzadehfar[46] 10 10 0 0 0 轻度恶心、疲劳 Ahmadzadehfar[47] 24 9 0 0 8.7 轻度恶心、疲劳 Yordanova[48] 55 0 0 0 − − 注:表中,−:无此项数据或内容。 -
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