Lichtman S M, Ratain M J, Van Echo D A, Rosner G, Egorin M J, Budman D R, Vogelzang N J, Norton L, Schilsky R L
North Shore University Hospital, Cornell University Medical College, Manhasset, N.Y. 11030.
J Natl Cancer Inst. 1993 Aug 18;85(16):1319-26. doi: 10.1093/jnci/85.16.1319.
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.
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.
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.
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.
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.
Phase II studies of this intensive regimen in malignant diseases sensitive to alkylating agents are currently being done in CALGB.
化疗引起的骨髓抑制常常限制癌症化疗剂量的增加。环磷酰胺作为一种烷化剂，是剂量增加的理想选择：已证实细胞杀伤与剂量之间呈对数线性关系，且该药物可使造血干细胞免受损伤。此外，研究表明粒细胞 - 巨噬细胞集落刺激因子（GM - CSF）可增强达到最佳剂量强度的能力，并改善化疗引起的骨髓抑制。
本研究的目的是确定每2周给予GM - CSF支持下环磷酰胺的最大耐受剂量及毒性作用。
在癌症与白血病B组（CALGB）进行的这项试验中，患者队列每14天接受1小时静脉输注环磷酰胺治疗；GM - CSF在第3 - 10天皮下注射。评估了四个环磷酰胺剂量水平（1.5、3.0、4.5和6.0 g/m²）以及三个GM - CSF剂量水平（2.5、5.0和10.0微克/千克/天）。个体患者不进行剂量递增。51例实体瘤患者，其CALGB体能状态为0或1且既往放疗极少，符合分析条件。在输注结束时以及输注开始后4小时和24小时估计药物清除率和血浆药物浓度×时间曲线下面积（AUC）。
分析了95个疗程的治疗。3.0 g/m²及以上剂量的环磷酰胺治疗在所有治疗周期均导致中性粒细胞减少（绝对中性粒细胞计数<100/微升）。在这些剂量下，67% - 85%的周期（中位数为16天）血细胞计数恢复到足以再次治疗的水平。6.0 g/m²的剂量与最严重程度的骨髓抑制和频繁住院相关（88%的周期）；输血需求使进一步增加剂量受限。非血液学毒性作用可耐受，有两例可逆性心脏毒性和四例出血性膀胱炎导致进一步治疗中断。骨髓抑制程度与环磷酰胺AUC或清除率无关。
环磷酰胺的推荐II期剂量为每2周给予4.5 g/m²，同时给予GM - CSF 5.0微克/千克/天。我们的结果表明，在GM - CSF支持下，可给予高累积剂量的环磷酰胺以达到最佳剂量强度，血细胞计数可重复性恢复，且无需自体骨髓移植。
CALGB目前正在对这种强化方案在对烷化剂敏感的恶性疾病中进行II期研究。
