O'Shaughnessy J A, Venzon D J, Gossard M, Noone M H, Denicoff A, Tolcher A, Danforth D, Jacobson J, Keegan P, Miller L, Chow C, Goldspiel B, Cowan K H
Medicine Branch, National Institutes of Health, Bethesda, MD, USA.
Blood. 1995 Oct 15;86(8):2913-21.
Cumulative thrombocytopenia is a dose-limiting toxicity of dose-intensive chemotherapy for advanced breast cancer. In this phase I study, we have studied the hematologic toxicity associated with sequential interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF; molgramostim) administration after multiple cycles of FLAC (5-fluorouracil, leucovorin, doxorubicin, cyclophosphamide) chemotherapy compared with that after concurrent cytokine administration or to each cytokine administered alone. Ninety-three patients with advanced breast cancer were treated with five cycles of FLAC chemotherapy and either IL-3 alone, GM-CSF alone, sequential IL-3 and GM-CSF administered by schedule A (5 days of IL-3 followed by 10 days of GM-CSF) or schedule B (9 days of IL-3 followed by 6 days of GM-CSF), or concurrent administration of IL-3 and GM-CSF for 15 days. Cohorts of patients were treated with one of four dose levels of IL-3 (1,2.5, 5, and 10 micrograms/kg) administered subcutaneously for each schedule of cytokine administration. The GM-CSF dose in all schedules was 5 micrograms/kg/day. Sequential IL-3 and GM-CSF (schedule B) was associated with higher platelet nadirs, shorter durations of platelet counts less than 50,000/microL, and the need for fewer platelet transfusions over five cycles of FLAC chemotherapy compared with concurrent cytokines, sequential IL-3 and GM-CSF schedule A, and GM-CSF alone. Concurrent IL-3 and GM-CSF was associated with unexpected platelet toxicity. The duration of granulocytopenia after FLAC chemotherapy was significantly worse with IL-3 alone compared with each of the GM-CSF-containing cytokine regimens. Although no cycle 1 maximum tolerated dose for IL-3 was defined in this study, 5 micrograms/kg was well tolerated over multiple cycles of therapy and is recommended for future studies. The data from this phase I study suggest that sequential IL-3 and GM-CSF with IL-3 administered for 9 days before beginning GM-CSF may be superior to shorter durations of IL-3 administered sequentially with GM-CSF, to concurrent IL-3 and GM-CSF, and to either colony-stimulating factor alone in ameliorating the cumulative hematologic toxicity associated with multiple cycles of FLAC chemotherapy. Additional studies of sequential IL-3 and GM-CSF are warranted.
累积性血小板减少是晚期乳腺癌剂量密集化疗的剂量限制性毒性。在这项I期研究中，我们研究了在多周期FLAC（5-氟尿嘧啶、亚叶酸钙、阿霉素、环磷酰胺）化疗后，与同时给予细胞因子或单独给予每种细胞因子相比，序贯给予白细胞介素-3（IL-3）和粒细胞-巨噬细胞集落刺激因子（GM-CSF；莫拉司亭）相关的血液学毒性。93例晚期乳腺癌患者接受了5周期的FLAC化疗，并分别接受单独的IL-3、单独的GM-CSF、按方案A（5天IL-3随后10天GM-CSF）或方案B（9天IL-3随后6天GM-CSF）序贯给予IL-3和GM-CSF，或同时给予IL-3和GM-CSF 15天。每组患者接受四种剂量水平之一的IL-3（1、2.5、5和10微克/千克）皮下注射，用于每种细胞因子给药方案。所有方案中GM-CSF的剂量均为5微克/千克/天。与同时给予细胞因子、序贯给予IL-3和GM-CSF方案A以及单独给予GM-CSF相比，序贯给予IL-3和GM-CSF（方案B）与更低的血小板最低点、血小板计数低于50,000/微升的持续时间更短以及在5周期FLAC化疗中所需的血小板输注次数更少相关。同时给予IL-3和GM-CSF与意外的血小板毒性相关。与每种含GM-CSF的细胞因子方案相比，单独给予IL-3时FLAC化疗后粒细胞减少的持续时间明显更差。尽管本研究未确定IL-3的第1周期最大耐受剂量，但5微克/千克在多周期治疗中耐受性良好，建议用于未来研究。这项I期研究的数据表明，在开始给予GM-CSF前先给予9天IL-3的序贯IL-3和GM-CSF方案，在改善与多周期FLAC化疗相关的累积血液学毒性方面，可能优于序贯给予IL-3和GM-CSF时间较短的方案、同时给予IL-3和GM-CSF的方案以及单独给予任何一种集落刺激因子的方案。有必要对序贯IL-3和GM-CSF进行更多研究。
