Tanosaki R, Okamoto S, Akatsuka N, Ishida A, Michikawa N, Masuda Y, Uchida H, Murata M, Kizaki M, Ikeda Y
Department of Internal Medicine, Keio University, School of Medicine, Tokyo, Japan.
Cancer. 1994 Oct 1;74(7):1939-44. doi: 10.1002/1097-0142(19941001)74:7<1939::aid-cncr2820740719>3.0.co;2-c.
Several uncontrolled trials have suggested that dose intensity of chemotherapy is a crucial determinant of treatment outcome for patients with non-Hodgkin's lymphoma (NHL). To explore the possibility of increasing dose intensity, a dose-escalation study of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) using recombinant human granulocyte colony stimulating factor (rhG-CSF) was initiated.
First, the feasibility of standard dose CHOP (750 mg/m2 cyclophosphamide intravenously [i.v.] on Day 1;50 mg/m2 doxorubicin i.v. on Day 1; 1.4 mg/m2 vincristine i.v. on Day 1; and 100 mg/body prednisolone orally on Days 1-5) repeated biweekly at the original dose was assessed. rhG-CSF was given subcutaneously at doses of 2-5 micrograms/kg every day or every other day on Days 3-13. The safety of increasing the dose of cyclophosphamide during biweekly CHOP then was tested. Besides the standard dose (750 mg/m2), two dose levels of cyclophosphamide were set (1200 mg/m2 and 1500 mg/m2 in patients younger than 61 years of age, and 1200 mg/m2 in patients 61-75 years old).
Twenty-seven patients with NHL who had received minimal or no previous treatment were enrolled in this study. In the 750 mg/m2 group, 9 patients received 3-6 cycles of treatment (mean, 3.9 cycles), in the 1200 mg/m2 group, 10 patients received 3-6 cycles (mean, 4.8), and in the 1500 mg/m2 group, all 8 patients received 6 cycles. No significant differences among the groups were observed in the extent and the duration of neutropenia in each cycle, and a leukocyte count of more than 3000/microliters on Day 15 was achieved in all 131 cycles. Hemoglobin values and platelet counts, however, decreased in the later cycles in the 1500 mg/m2 group. Two patients were hepatitis-B virus carriers, one of whom died of fulminant hepatitis after completion of six cycles. Another patient developed a transient increase of transaminases after the second cycle. One other patient developed Grade 4 mucositis (World Health Organization scale). The numbers of patients who achieved complete and partial responses, respectively, were 4 (50%) and 2 (25%) in the 750 mg/m2 group, 8 (80%) and 2 (20%) in the 1200 mg/m2 group, and 8 (100%) and 0 (0%) in the 1500 mg/m2 group.
The dose of cyclophosphamide in biweekly CHOP can be increased up to 1500 mg/m2 with no increase in the incidence of treatment-related early mortalities without any organ damage in younger patients. The efficacy of this dose intensification of CHOP currently is being investigated in a multicenter prospective randomized trial using three different dose levels of cyclophosphamide.
多项非对照试验表明，化疗剂量强度是非霍奇金淋巴瘤（NHL）患者治疗结局的关键决定因素。为探索提高剂量强度的可能性，开展了一项使用重组人粒细胞集落刺激因子（rhG-CSF）的环磷酰胺、阿霉素、长春新碱和泼尼松（CHOP）剂量递增研究。
首先，评估了标准剂量CHOP（第1天静脉注射750mg/m²环磷酰胺；第1天静脉注射50mg/m²阿霉素；第1天静脉注射1.4mg/m²长春新碱；第1 - 5天口服100mg/体泼尼松）每两周按原剂量重复使用的可行性。在第3 - 13天，rhG-CSF每天或隔天皮下注射，剂量为2 - 5μg/kg。然后测试了在每两周的CHOP方案中增加环磷酰胺剂量的安全性。除标准剂量（750mg/m²）外，设定了两个环磷酰胺剂量水平（61岁以下患者为1200mg/m²和1500mg/m²，61 - 75岁患者为1200mg/m²）。
27例既往未接受过治疗或仅接受过极少治疗的NHL患者入组本研究。750mg/m²组中，9例患者接受了3 - 6个周期的治疗（平均3.9个周期）；1200mg/m²组中，10例患者接受了3 - 6个周期（平均4.8个周期）；1500mg/m²组中，所有8例患者均接受了6个周期的治疗。各周期中性粒细胞减少的程度和持续时间在各组间未观察到显著差异，在所有131个周期中，第15天白细胞计数均达到了超过3000/μl。然而，1500mg/m²组在后续周期中血红蛋白值和血小板计数下降。2例患者为乙肝病毒携带者，其中1例在完成6个周期治疗后死于暴发性肝炎。另1例患者在第二个周期后转氨酶短暂升高。还有1例患者发生了4级黏膜炎（世界卫生组织分级）。750mg/m²组分别达到完全缓解和部分缓解的患者人数为4例（50%）和2例（25%）；1200mg/m²组为8例（80%）和2例（20%）；1500mg/m²组为8例（100%）和0例（0%）。
在年轻患者中，每两周CHOP方案中环磷酰胺剂量可增至1500mg/m²，而与治疗相关的早期死亡率无增加，且无任何器官损害。目前正在一项多中心前瞻性随机试验中研究这种CHOP剂量强化的疗效，该试验使用三种不同剂量水平的环磷酰胺。
