肿瘤骨转移疼痛患者对^188Re-HEDP的耐受性研究

目的 评价^188Re-1-羟基-1,1-二膦酸钠乙烷（即依替膦酸盐,HEDP）治疗肿瘤骨转移疼痛患者的安全性.方法 符合入选标准的31例患者（前列腺癌10例,乳腺癌9例,肺癌3例,肝癌5例,直肠癌2例,食管癌1例,肾癌1例,均随时间顺序人选）知情同意后接受了按体质量肘静脉单次注射^188ReHEDP,据药物递增剂量分为4个组：20 MBq/kg组6例、30 MBq/kg组6例、40 MBq/kg组9例、50 MBq/kg组10例.低剂量组安全性分析结束并显示安全后,才开始下一剂量组试验.如果患者出现由于用药引起的不可耐受的、WHO公布的Ⅲ或Ⅳ级骨髓毒性,即终止剂量递增,并认为前一组剂量为最大可接受剂量.观察指标包括给药前及给药后8周内每例患者的生命体征（用药后1,6,12,24,48,72 h和1,2,3,4,6,8周）,血细胞计数（用药后1,2,3,4,6和8周）,心电图,肝、肾功能,ALP（用药后4,8周）,＂反跳痛＂以及不良反应等.统计分析主要针对符合方案集（PP）人群,包括统计描述和统计推断（t检验）.结果 31例患者中有27例属于PP人群：20 MBq/kg组5例、30 MBq/kg组5例、40 MBq/kg组8例、50 MBq/kg组9例.在受试剂量范围内,没有观察到188Re-HEDP对患者生命体征、心电图、肝肾功能和ALP的不良影响.20 MBq/kg组的5例患者中仅1例自细胞出现WHO Ⅰ级毒性;30 MBq/kg组5例患者中2例白细胞出现WHO Ⅰ级毒性,其中1例合并血小板Ⅲ级毒性,但给药后8周白细胞和血小板均恢复正常;40 MBq/kg组8例患者中2例白细胞和血小板同时出现毒性反应,分别为WHO Ⅰ级和Ⅱ级,表现为白细胞和血小板同时、同级减低;50 MBq/kg组9例患者中3例白细胞出现WHOⅡ级毒性.全部患者的血小板均在给药后4周达最低水平,平均为143.5×109/L;白细胞均在给药后6周达最低水平,平均为5.4×109/L（两者与给药前基线值比较,t值分别为3.1325和3.3156,P均＜0.05）,给药后8周自细胞和血小板均恢复到基线水平;而血红蛋白在给药后8周最低（与基线值比较,t值为3.4917,P＜0.05）.PP人群27例中有2例出现＂反跳痛＂,发生率7.41%（2/27）.结论 按体质量注射188Re-HEDP 20,30,40和50 MBq/kg对肿瘤骨转移患者均无明显毒性及不良反应,且随着用药剂量增加,188Re-HEDP对骨髓的抑制有增加趋势.

The tolerance to 188Re-HEDP treatment in patients with bone pain from osseous metastases

Objective To study the tolerance to 188Re-1-hydroxy-1 ,1-ethylidene disodium phosphonate(HEDP) in patients with bone pain caused by osseous metastases. Methods Thirty-one patients(10with prostate cancer, 9 with breast cancer, 3 with lung cancer, 5 with liver cancer, 2 with rectal cancer, 1with esophageal cancer and 1 with renal cancer) received a single injection dose of 188Re-HEDP. The patients were divided into four groups according to the injection dose: 20 MBq/kg (6 patients), 30 MBq/kg(6 patients), 40 MBq/kg (9 patients), and 50 MBq/kg (10 patients). Haematological toxicity (WHO grading) of grade Ⅲ- Ⅳ was considered unacceptable. Vital signs and adverse effects after injection were recorded for 8 weeks. Blood counts were measured weekly during a period of 8 weeks. Biochemical parameters and electrocardiogram were assayed at week 4 and 8. Statistical analysis was performed for per-protocol (pp) population (t-test). Results Twenty-seven patients belonged to PP population with 5 in the group of 20 MBq/kg, 5 in the group of 30 MBq/kg, 8 in the group of 40 MBq/kg and 9 in the group of 50 MBq/kg.No obvious adverse effects and no significant change of vital signs, electrocardiogram, liver and renal function were found after injection. Alkaline phosphatase was slightly higher than baseline at week 4 and 8 after therapy, but the difference was not statistically significant. In the 20 MBq/kg group, reversible grade Ⅰ leucopenia was noted in 1 patient. In the 30 MBq/kg group, 2 patients showed reversible grade Ⅰ leucopenia including 1 alone with reversible grade Ⅲ thrombopenia. In the 40 MBq/kg group, reversible grade Ⅰ leucopenia and thrombopenia was observed in 1 patient and reversible grade Ⅱ leucopenia and thrombopenia in another patient. In the .50 MBq/kg group, 3 patients showed reversible grade Ⅱ leucopenia. The lowest level of thrombopenia was at week 4(143.5 × 109/L), leucopenia at week 6 (5.4 × 109/L) and anaemia at week 8(t = 3.1325, 3.3156, 3.4917, all P ＜ 0. 05 compared with baseline). At week 8, the mean level of platelet and leucocyte recovered to baseline. "Bounce pain" was found in 2 of 27 patients (7.41%).Conclusions The dose of 20 MBq/kg, 30 MBq/kg, 40 MBq/kg or 50 MBq/kg of 188Re-HEDP do not cause significant side effects on cancer patients with bone metastases, though there is a tendency that the haematological toxicity may increase as the dose of 188Re-HEDP increases.