Tepler I, Cannistra S A, Frei E, Gonin R, Anderson K C, Demetri G, Niloff J, Goodman H, Muntz H, Muto M
Department of Medicine, Dana-Farber Cancer Institute, Boston, MA.
J Clin Oncol. 1993 Aug;11(8):1583-91. doi: 10.1200/JCO.1993.11.8.1583.
Attempts to increase dose-intensity in clinical practice have been limited by cumulative hematologic toxicity despite the use of hematopoietic growth factors. To address this problem, we designed a study to determine whether four cycles of dose-intensive chemotherapy with carboplatin could be administered in the outpatient setting using granulocyte-macrophage colony-stimulating factor (GM-CSF) and peripheral-blood progenitor cells (PBPCs) that had been harvested before initiation of treatment.
An initial cycle (cycle no. 0) of cyclophosphamide 4 g/m2 followed by GM-CSF was used to mobilize PBPCs harvested by leukapheresis for 6 consecutive days. Cycles no. 1 through 4 consisted of outpatient carboplatin 600 mg/m2 and cyclophosphamide 600 mg/m2 followed by GM-CSF 5 micrograms/kg subcutaneously (SC) twice per day every 28 days. In cycle no. 1, PBPC were not reinfused to assess the effects of GM-CSF alone. In cycles no. 2 through 4, PBPCs were reinfused on day 3 in an outpatient setting.
In eight assessable patients, the addition of PBPCs in cycle no. 2 resulted in a significant reduction in the median duration of thrombocytopenia less than 20,000/microL (6.5 v 1 day; P = .016), days to platelets more than 50,000/microL (20.5 v 15 days; P = .020), number of platelet transfusions (five v 1.5; P = .016), and duration of neutropenia (absolute neutrophil count [ANC] < 1,000/microL (7 v 2.5 days; P = .008) when compared with cycle no. 1. Dose-limiting hematologic toxicity, defined as more than 7 days of platelets less than 20,000/microL or ANC less than 500/microL, was observed in four of eight patients during cycle no. 1, but not during cycles no. 2, 3, and 4 of chemotherapy supported by PBPCs (a total of 19 cycles in eight patients). Five of eight patients completed all four cycles of high-dose therapy. Three patients did not complete four cycles due to late thrombocytopenia (n = 2) or tumor progression (n = 1).
These results indicate a benefit of PBPCs in addition to GM-CSF in alleviating myelosuppression of dose-intensive chemotherapy. Initial collection of PBPCs may allow administration of repetitive cycles of high-dose chemotherapy with acceptable toxicity to outpatients at disease onset.
尽管使用了造血生长因子，但在临床实践中试图提高剂量强度仍受到累积血液学毒性的限制。为解决这一问题，我们设计了一项研究，以确定是否可以在门诊环境中使用粒细胞-巨噬细胞集落刺激因子（GM-CSF）和治疗开始前采集的外周血祖细胞（PBPC）进行四个周期的卡铂剂量密集化疗。
初始周期（第0周期）使用4 g/m²环磷酰胺，随后使用GM-CSF，以动员通过白细胞分离术连续6天采集的PBPC。第1至4周期包括门诊给予600 mg/m²卡铂和600 mg/m²环磷酰胺，随后每28天皮下注射（SC）5微克/千克GM-CSF，每日两次。在第1周期，未回输PBPC以评估单独使用GM-CSF的效果。在第2至4周期，在门诊第3天回输PBPC。
在8例可评估患者中，与第1周期相比，第2周期添加PBPC导致血小板计数低于20,000/微升的中位持续时间显著缩短（6.5天对1天；P = 0.016），血小板计数超过50,000/微升的天数缩短（20.5天对15天；P = 0.020），血小板输注次数减少（5次对1.5次；P = 0.016），以及中性粒细胞减少的持续时间（绝对中性粒细胞计数[ANC]<1,000/微升）缩短（7天对2.5天；P = 0.008）。在第1周期的8例患者中有4例观察到剂量限制性血液学毒性，定义为血小板计数低于20,000/微升或ANC低于500/微升超过7天，但在PBPC支持的化疗第2、3和4周期（8例患者共19个周期）未观察到。8例患者中有5例完成了所有四个周期的高剂量治疗。3例患者未完成四个周期，原因是晚期血小板减少（n = 2）或肿瘤进展（n = 1）。
这些结果表明，除GM-CSF外，PBPC在减轻剂量密集化疗的骨髓抑制方面具有益处。在疾病发作时初始采集PBPC可能允许对门诊患者给予重复周期的高剂量化疗，且毒性可接受。
