Phase I trial of granulocyte-macrophage colony-stimulating factor plus high-dose cyclophosphamide given every 2 weeks: a Cancer and Leukemia Group B study.
Phase I trial of granulocyte-macrophage colony-stimulating factor plus high-dose cyclophosphamide given every 2 weeks: a Cancer and Leukemia Group B study.
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DOI：
10.1093/jnci/85.16.1319
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发表时间：
1993-08
期刊：
影响因子：
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通讯作者：
S. Lichtman;M. Ratain;D. A. Echo;G. Rosner;M. Egorin;D. Budman;N. Vogelzang;L. Norton;R. Schilsky
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文献类型：
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作者：
S. Lichtman;M. Ratain;D. A. Echo;G. Rosner;M. Egorin;D. Budman;N. Vogelzang;L. Norton;R. Schilsky
化疗诱导的骨髓抑制通常限制癌症化疗剂量的增加。环磷酰胺是一种烷化剂，是剂量递增的理想候选药物：已证明细胞杀伤与剂量之间存在对数线性关系，并且该药物不影响造血干细胞。此外，研究表明，粒细胞-巨噬细胞集落刺激因子（GM-CSF）可以增强达到最佳剂量强度的能力，并改善化疗诱导的骨髓抑制。本研究的目的是确定在GM-CSF支持下每2周给予环磷酰胺的最大耐受剂量和毒性作用。方法：在癌症和白血病组B（CALGB）的这项试验中，患者队列接受环磷酰胺治疗，每14天静脉输注1小时; GM-CSF在第3-10天皮下注射。评价了4个剂量水平的环磷酰胺（1.5、3.0、4.5和6.0 g/m2）和3个剂量水平的GM-CSF（2.5、5.0和10.0 μ g/kg/天）。个体患者未进行剂量递增。51例CALGB体能状态为0或1且既往接受过最低限度放疗的实体瘤患者符合分析条件。在输注完成时以及输注开始后4小时和24小时估计药物清除率和血浆药物浓度x时间曲线下面积（AUC）。结果对95个疗程进行分析。在所有治疗周期中，以3.0 g/m2或更高剂量环磷酰胺治疗导致中性粒细胞减少症（中性粒细胞绝对计数< 100/μ L）。在这些剂量下，67%-85%的周期（中位数，16天）的血细胞计数恢复足以再次治疗。6.0 g/m2剂量与最大程度的骨髓抑制和频繁住院（88%的周期）相关;输血要求禁止进一步剂量递增。非血液学毒性反应是可耐受的，两次可逆性心脏毒性和四次出血性膀胱炎，排除了进一步治疗。骨髓抑制程度与环磷酰胺AUC或清除率无关。结论：环磷酰胺的推荐II期剂量为4.5 g/m2，每2周给药一次，GM-CSF的剂量为5.0 μ g/kg/天。我们的研究结果表明，在GM-CSF支持下，可以给予高累积剂量的环磷酰胺以达到最佳剂量强度，血细胞计数恢复可重现，并且不需要自体骨髓移植。目前正在CALGB中进行这种强化方案治疗对烷化剂敏感的恶性疾病的II期研究。
BACKGROUND Chemotherapy-induced myelosuppression often limits escalation of cancer chemotherapy doses. Cyclophosphamide, an alkylating agent, is an ideal candidate for dose escalation: A log-linear relationship between cell kill and dose has been demonstrated, and the drug spares hematopoietic stem cells. In addition, studies suggest that granulocyte-macrophage colony-stimulating factor (GM-CSF) can enhance the ability to achieve optimal dose intensity as well as ameliorating chemotherapy-induced myelosuppression. PURPOSE The purpose of this study was to determine the maximum tolerated dose and the toxic effects of cyclophosphamide administered every 2 weeks with GM-CSF support. METHODS For this trial by the Cancer and Leukemia Group B (CALGB), cohorts of patients were treated with cyclophosphamide as a 1-hour intravenous infusion every 14 days; GM-CSF was given subcutaneously on days 3-10. Four dose levels of cyclophosphamide (1.5, 3.0, 4.5, and 6.0 g/m2) and three dose levels of GM-CSF (2.5, 5.0, and 10.0 micrograms/kg per day) were evaluated. There was no dose escalation in individual patients. Fifty-one patients with solid tumors who had CALGB performance status 0 or 1 and minimal prior radiotherapy were eligible for analysis. Drug clearance and area under the curve for plasma drug concentration x time (AUC) were estimated at completion of the infusion and at 4 and 24 hours after the start of the infusion. RESULTS Ninety-five courses of therapy were analyzed. Treatment with cyclophosphamide at 3.0 g/m2 or more resulted in neutropenia (absolute neutrophil counts < 100/microL) in all cycles of therapy. At those doses, blood cell count recovery adequate for re-treatment occurred in 67%-85% of cycles (median, 16 days). Doses of 6.0 g/m2 were associated with the greatest degree of myelosuppression and frequent hospitalization (88% of cycles); requirements for blood transfusion prohibited further dose escalation. Nonhematologic toxic effects were tolerable, with two episodes of reversible cardiotoxicity and four episodes of hemorrhagic cystitis that precluded further therapy. Degree of myelosuppression was not correlated with cyclophosphamide AUC or clearance. CONCLUSIONS The recommended phase II dose of cyclophosphamide is 4.5 g/m2 administered every 2 weeks with GM-CSF given at 5.0 micrograms/kg per day of GM-CSF. Our results suggest that, with GM-CSF support, high cumulative doses of cyclophosphamide can be given to achieve optimal dose intensity, with reproducible blood cell count recovery and without the need for autologous bone marrow transplantation. IMPLICATIONS Phase II studies of this intensive regimen in malignant diseases sensitive to alkylating agents are currently being done in CALGB.