Radioimmunotherapy of prostate cancer using 90Y- and 177Lu-labeled J591 monoclonal antibodies:: Effect of multiple treatments on myelotoxicity
Radioimmunotherapy of prostate cancer using 90Y- and 177Lu-labeled J591 monoclonal antibodies:: Effect of multiple treatments on myelotoxicity
复制标题
DOI：
10.1158/1078-0432.ccr-1004-0023
复制
发表时间：
2005-10-01
影响因子：
11.5
通讯作者：
Bander, NH
中科院分区：
文献类型：
--
作者：
Vallabhajosula, S;Goldsmith, SJ;Bander, NH
目的：骨髓是放射免疫治疗的剂量限制器官。分次给药方案可降低骨髓毒性并增加更大的总给药剂量。我们研究了Lu-177-J591和Y-90-J591单克隆抗体（mAb）两次或三次治疗对骨髓毒性的影响。实验设计：J591是一种去免疫的抗PSMA mAb。7组前列腺癌患者（n = 35）接受了10至75 mCi/m2的Lu-177-J591，另外5组（n = 28）接受了5至20 mCi/m2的90 Y-J591。15例患者接受了2 - 3次Lu-177-J591（30、45或60 mCi/m2）治疗，4例患者接受了2 - 3次90 Y-J591（17.5或20 mCi/m2）治疗。再治疗包括患者接受与其初始周期相同的Lu-177或Y-90剂量。结果：（177）Lu-J591单次给药的最大耐受剂量为70 mCi/m2，（90）Y-J591单次给药的最大耐受剂量为17.5 mCi/m2。Lu-177单次给药在低于60 mCi/m2时未观察到严重毒性。使用Lu-177，45或60 mCi/m（2）的两个剂量，总计90至120 mCi/m（2），被证明是相当有毒的。然而，三次剂量30 mCi/m2（总剂量为go mCi/m2）的耐受性良好。使用90 Y，4名患者耐受2至3次17.5或20 mCi/m2的剂量。血小板减少症在较高剂量和重复给药后增加。在较高剂量下，最低点较低，达到最低点的时间较长。结论：177Lu-J591（30 - 60 mCi/m2）或90Y-J591（17.5 mCi/m2）多次给药（2次或3次）4 - 6个月，血小板可控制的血小板减少症患者可耐受。虽然单次大剂量可以提供最佳的辐射剂量来杀死更大比例的肿瘤细胞，但分次治疗提供了较低的骨髓毒性和延长肿瘤反应的优势。对于177 Lu-J591，剂量分级联合紫杉烷应被视为在前列腺癌患者中实现最佳治疗效果的替代方法。
Purpose: Bone marrow is the dose-limiting organ in radioimmunotherapy. Fractionated dose regimens may decrease myelotoxicity and increase greater total administered dose. We have studied the effect of two or three treatments of Lu-177-J591 and Y-90-J591 monoclonal antibodies (mAb) on myelotoxicity.Experimental Design: J591 is a deimmunized anti-PSMA mAb. Seven groups of patients with prostate cancer (n = 35) received 10 to 75 mCi/m(2) of Lu-177-J591 and five additional groups (n = 28) received 5 to 20 mCi/m(2) of 90Y-J591. Fifteen patients received two to three treatments of Lu-177-J591 (30,45, or 60 mCi/m(2)) and four patients received two or three doses of 90Y-J591 (17.5 or 20 mCi/m(2)). Re-treatment consisted of patients receiving the same Lu-177 or Y-90 dose as their initial cycle. Time between treatments was 2 to 4 months.Results: The single dose maximum tolerated dose was 70 mCi/m(2) with (177) Lu-J591 and 17.5 mCi/m(2) with 90Y-J591. With a single dose of Lu-177, no severe toxicity was observed below 60 mCi/m(2). With Lu-177, two doses of 45 or 60 mCi/m(2), totaling 90 to 120 mCi/m(2), proved to be quite toxic. Three doses of 30 mCi/m(2) (total go mCi/m(2)), however, were well tolerated. With 90Y, four patients tolerated two to three doses of 17.5 or 20 mCi/m(2). Thrombocytopenia increased at higher doses and after repeat treatments. At higher doses, the nadir was lower and the time to reach nadir was longer. Time for recovery of platelets seems related to the total dose.Conclusions: Multiple (two or three) administrations of 177 Lu-J591 (30-60 mCi/m(2)) or 90Y-J591 (17.5 mCi/m(2)) over a 4- to 6 -month period were tolerated by the patients with manageable thrombocytopenia. Although a single large dose may deliver optimal radiation dose to kill a larger fraction of tumor cells, fractionated therapy offers the advantage of lower myelotoxicity and prolonged tumor response. With 177 Lu-J591, dose fractionation in combination with taxanes should be considered as an alternative approach to achieve optimal therapeutic efficacy in patients with prostate cancer.