Ingle J N, Kardinal C G, Suman V J, Veeder M H, Schaefer P L, Kirschling R J, Mailliard J A
Mayo Clinic, Rochester, MN 55905, USA.
Breast Cancer Res Treat. 1997 May;43(3):193-200. doi: 10.1023/a:1005749115033.
Based on reports of substantial antitumor efficacy of the combination of mitoxantrone (DHAD), 5-fluorouracil (FU) and leucovorin (LV), a clinical trial was performed to attempt augmentation of the dose of DHAD with filgrastim support. The doses and schedules, all intravenous, were DHAD (total dose divided over days 1 and 2), level I, 16 mg/m2; II, 20 mg/m2; III, 24 mg/m2; IV, 32 mg/m2; and LV, 300 mg, followed by FU, 350 mg/m2, on days 1-3. Filgrastim was given at 5 micrograms/kg/day subcutaneously on days 4-13. The planned cycle length was 21 days. Three or 4 patients were to be entered at each dose level and the maximum tolerated dose (MTD) was defined as the dose immediately below that which resulted in 2 patients with dose-limiting toxicity (DLT) in cycle 1. Once an apparent MTD was identified, an additional 6 patients were to be entered. Twenty patients (pts) were entered: level I: 3 pts; II: 3 pts; III: 10 pts: IV: 4 pts. The major toxicity was found to be cumulative thrombocytopenia with platelet counts < or = 20,000/microL occurring after cycle 1 at all levels beyond level I and five pts (25%) were removed from treatment solely because of platelet toxicity. Additional serious toxicities included grade 4 stomatitis in one patient (level IV) and cardiac toxicity in 2 patients with prior doxorubicin exposure. Ten pts had measurable and 8 had evaluable disease, and in 17 pts assessed, 5 (29%) achieved an objective response. The response rates in this study are lower than reported in the literature for the combination of DHAD, 5FU, LV and this may be related to the fact that only 40% of the patients were removed from protocol treatment because of disease progression. On the basis of limited DHAD-dose augmentation, toxicities observed, and modest response rate, the filgrastim-supported DHAD, 5FU, LV regimen as utilized in this study cannot be recommended for further development for treatment of women with metastatic breast cancer.
基于有关米托蒽醌（DHAD）、5-氟尿嘧啶（FU）和亚叶酸钙（LV）联合使用具有显著抗肿瘤疗效的报告，开展了一项临床试验，尝试在非格司亭的支持下增加DHAD的剂量。给药剂量和方案均为静脉给药，其中DHAD（总剂量分第1天和第2天给药），I级剂量为16mg/m²；II级为20mg/m²；III级为24mg/m²；IV级为32mg/m²；LV为300mg，随后在第1 - 3天给予FU，剂量为350mg/m²。在第4 - 13天皮下注射非格司亭，剂量为5微克/千克/天。计划的周期时长为21天。每个剂量水平纳入3或4例患者，最大耐受剂量（MTD）定义为刚好低于在第1周期导致2例出现剂量限制性毒性（DLT）的剂量。一旦确定了明显的MTD，再纳入6例患者。共纳入20例患者：I级：3例；II级：3例；III级：10例；IV级：4例。发现主要毒性为累积性血小板减少，在I级以上所有剂量水平，第1周期后血小板计数≤20,000/微升，5例患者（25%）仅因血小板毒性而停止治疗。其他严重毒性包括1例患者（IV级剂量水平）出现4级口腔炎，2例曾接受过阿霉素治疗的患者出现心脏毒性。10例患者有可测量病灶，8例患者可进行疗效评估，在接受评估的17例患者中，5例（29%）获得客观缓解。本研究中的缓解率低于文献报道的DHAD、5FU、LV联合使用的缓解率，这可能与仅40%的患者因疾病进展而停止方案治疗这一事实有关。基于有限的DHAD剂量增加、观察到的毒性以及适度的缓解率，本研究中使用的非格司亭支持的DHAD、5FU、LV方案不推荐用于转移性乳腺癌女性患者治疗的进一步研发。
