Luikart S D, Herndon J E, Hollis D R, MacDonald M, Maurer L H, Crawford J, Clamon G H, Wright J, Perry M C, Ozer H, Green M R
Veterans Administration Medical Center and the University of Minnesota Medical Center, Minneapolis 55417, USA.
Am J Clin Oncol. 1997 Feb;20(1):24-30. doi: 10.1097/00000421-199702000-00006.
The maximum tolerated dose (MTD) of etoposide and carboplatin without growth factor support was previously defined by Cancer and Leukemia Group B (CALGB) as 200 and 125 mg/m2/day x 3, respectively, given every 28 days to previously untreated patients who have extensive, small-cell lung cancer (SCLC). Myelosuppression was dose-limiting. The purpose of this phase I trial was to determine if granulocyte macrophage colony-stimulating factor (GM-CSF) support allows the dosage of the combination of etoposide and carboplatin to be increased above the previously determined MTD. In this CALGB study of 44 evaluable patients with performance status 0-2, cohorts were treated with etoposide and carboplatin given intravenously on days 1-3 followed by GM-CSF (molgramostim) given subcutaneously on days 4-18. Four dose levels of bacteria-derived recombinant GM-CSF (5, 10, 20 microg/kg/day and 5 microg/kg every 12 h), three dose levels of etoposide (200, 250, and 300 mg/m2/day x 3), and two dose levels of carboplatin (125 and 150 mg/m2/day x 3) were evaluated. There was no chemotherapy dose escalation in individual patients. With 5 microg/kg/d GM-CSF, the first etoposide and carboplatin cycle of 300 and 150 mg/m2/day x 3, respectively, could be administered with acceptable toxicity. However, GM-CSF did not allow repeated administration of this dose-escalated regimen every 21 days, since delayed platelet and/or neutrophil recovery was dose limiting in later cycles. These results demonstrate that GM-CSF alone has limited capability to support the repeated administration of high doses of etoposide and carboplatin. CALGB currently is testing the ability of interleukin (IL)-6 given with GM-CSF to ameliorate the cumulative myelosuppression of this intense regimen.
在无生长因子支持的情况下，依托泊苷和卡铂的最大耐受剂量（MTD）先前已由癌症与白血病B组（CALGB）定义为，对于既往未接受过治疗的广泛期小细胞肺癌（SCLC）患者，分别为200和125mg/m²/天，连用3天，每28天给药一次。骨髓抑制是剂量限制性毒性。本I期试验的目的是确定粒细胞巨噬细胞集落刺激因子（GM-CSF）支持是否能使依托泊苷与卡铂联合用药的剂量增加至先前确定的MTD以上。在这项CALGB研究中，44例体能状态为0 - 2的可评估患者，在第1 - 3天静脉给予依托泊苷和卡铂，随后在第4 - 18天皮下给予GM-CSF（莫拉司亭）。评估了四种剂量水平的细菌衍生重组GM-CSF（5、10、20μg/kg/天以及每12小时5μg/kg）、三种剂量水平的依托泊苷（200、250和300mg/m²/天，连用3天）以及两种剂量水平的卡铂（125和150mg/m²/天，连用3天）。未对个体患者进行化疗剂量递增。对于5μg/kg/d的GM-CSF，首个分别为300和150mg/m²/天，连用3天的依托泊苷和卡铂周期能够以可接受的毒性给药。然而，GM-CSF并不允许每21天重复给予这种剂量递增方案，因为在后续周期中，血小板和/或中性粒细胞延迟恢复是剂量限制性的。这些结果表明，单独使用GM-CSF支持重复给予高剂量依托泊苷和卡铂的能力有限。CALGB目前正在测试GM-CSF联合白细胞介素（IL）-6改善这种强化方案累积骨髓抑制的能力。
