Rusthoven J, Levin L, Eisenhauer E, Mazurka J, Carmichael J, O'Connell G, Bryson P, Hirte H, Koski B
Ontario Cancer Treatment and Research Foundation Clinics, Hamilton, Canada.
J Natl Cancer Inst. 1991 Dec 4;83(23):1748-53. doi: 10.1093/jnci/83.23.1748.
Recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) may reduce myelosuppression and, thus, allow dose escalation of certain chemotherapeutic agents. We conducted two sequential phase I trials of escalating doses of carboplatin and a fixed dose and schedule of rHuGM-CSF in ovarian cancer patients who had not previously had chemotherapy, i.e., chemotherapy-naive patients. In the first trial, patients were assigned to regimens of increasing dose levels of carboplatin (starting at 400 mg/m2) and fixed doses and schedules of cyclophosphamide (600 mg/m2) and rHuGM-CSF (10 micrograms/kg given subcutaneously once daily on days 2-11). Chemotherapy was given every 3 weeks (regimen A). In the subsequent trial, the design was the same except that cyclophosphamide was omitted (regimen B). Fifteen patients received regimen A, and seven patients received regimen B. In regimen A, all three patients treated at the first dose level tolerated five cycles at full doses. Hematologic toxicity was dose limiting at the 600-mg/m2 dose level. When 500 mg/m2 carboplatin was given, six of eight patients tolerated three or four cycles at full doses before requiring dose reductions or treatment delays. In regimen B, doses could not be escalated above the first dose level (600 mg/m2) because of severe hematological toxicity. Nonhematological toxicity was tolerable and managed with acetaminophen, antihistamines, and/or nonsteroidal, anti-inflammatory medication. Compliance was excellent. We conclude that (a) rHuGM-CSF can be given safely and reliably to chemotherapy-naive ovarian cancer patients receiving these treatment regimens, (b) early and severe thrombocytopenia was a major problem with or without cyclophosphamide with doses of carboplatin at or above 600 mg/m2, and (c) 500 mg/m2 carboplatin administered every 3 weeks is the highest dose in regimen A that can be given safely in the outpatient setting.
重组人粒细胞巨噬细胞集落刺激因子（rHuGM-CSF）可能会减轻骨髓抑制，从而使某些化疗药物能够增加剂量。我们对未曾接受过化疗的卵巢癌患者（即初治患者）进行了两项连续的I期试验，逐步增加卡铂剂量并给予固定剂量和疗程的rHuGM-CSF。在第一项试验中，患者被分配到卡铂剂量水平递增（从400mg/m²开始）、环磷酰胺（600mg/m²）和rHuGM-CSF（10μg/kg，第2 - 11天每日皮下注射一次）固定剂量和疗程的方案中。每3周进行一次化疗（方案A）。在随后的试验中，设计相同，但省略了环磷酰胺（方案B）。15名患者接受了方案A，7名患者接受了方案B。在方案A中，在第一个剂量水平接受治疗的所有3名患者均能耐受5个周期的全剂量治疗。在600mg/m²剂量水平时，血液学毒性成为剂量限制因素。给予500mg/m²卡铂时，8名患者中有6名在需要减量或延迟治疗前能耐受3或4个周期的全剂量治疗。在方案B中，由于严重的血液学毒性，剂量无法超过第一个剂量水平（600mg/m²）。非血液学毒性可以耐受，通过对乙酰氨基酚、抗组胺药和/或非甾体抗炎药进行处理。依从性良好。我们得出结论：（a）对于接受这些治疗方案的初治卵巢癌患者，可以安全可靠地给予rHuGM-CSF；（b）无论有无环磷酰胺，卡铂剂量达到或高于600mg/m²时，早期严重血小板减少是一个主要问题；（c）每3周给予500mg/m²卡铂是方案A中可在门诊安全给予的最高剂量。
