Holmes F A, Madden T, Newman R A, Valero V, Theriault R L, Fraschini G, Walters R S, Booser D J, Buzdar A U, Willey J, Hortobagyi G N
Department of Breast Medical Oncology, University of Texas, M.D. Anderson Cancer Center, Houston.
J Clin Oncol. 1996 Oct;14(10):2713-21. doi: 10.1200/JCO.1996.14.10.2713.
To determine whether a schedule-dependent interaction occurs when paclitaxel and doxorubicin are administered sequentially.
Ten patients with metastatic breast cancer received paclitaxel 125 mg/m2 over 24 hours either immediately before or after doxorubicin 48 mg/m2 over 48 hours as the initial chemotherapy treatment. Two such courses were given, and the sequence of administration was reversed after course 1. In cohort 1, paclitaxel preceded doxorubicin for course 1. In cohort 2, doxorubicin preceded paclitaxel for course 1. Doxorubicin levels were measured serially during the infusion and for 24 hours following it. Patients were assessed clinically for the occurrence of stomatitis and infection and granulocyte counts were measured twice weekly.
Eight patients had complete pharmacokinetic sampling for both courses. The mean end-of-infusion plasma doxorubicin concentrations (Cmax) were 70% higher in the paclitaxel-doxorubicin sequence compared with the reverse sequence (45 +/- 8 ng/mL v 26 +/- 5 ng/ mL). The mean doxorubicin clearance was 32% lower in the paclitaxel-doxorubicin sequence (34.3 +/- 10.3 L/h v 51.6 +/- 16.1 L/h, P < .01). Clinically, hematologic and mucosal toxic effects were worse in the paclitaxel-doxorubicin sequence. The median absolute granulocyte count was 0.2/microL in the paclitaxel-doxorubicin sequence and 1.3/microL in the doxorubicin-paclitaxel sequence. Seven of 10 patients who received the paclitaxel-doxorubicin sequence had grade 2 (n = 4) or 3 (n = 3) stomatitis, while only one of 10 patients who received the doxorubicin-paclitaxel sequence had grade 2 stomatitis and none had grade 3.
When paclitaxel by 24-hour infusion precedes doxorubicin by 48-hour infusion, doxorubicin clearance is reduced by nearly one third, which results in grade 2 and 3 stomatitis. To prevent this effect when paclitaxel (by 24-hour infusion) and doxorubicin are administered sequentially, doxorubicin should be given first. The mechanisms for this effect are under investigation.
确定紫杉醇和阿霉素序贯给药时是否存在给药顺序依赖性相互作用。
10例转移性乳腺癌患者接受初始化疗，在48小时内给予阿霉素48mg/m²，在这之前或之后24小时内给予紫杉醇125mg/m²。给予两个这样的疗程，在第1个疗程后给药顺序颠倒。在队列1中，第1个疗程紫杉醇先于阿霉素给药。在队列2中，第1个疗程阿霉素先于紫杉醇给药。在输注期间及输注后24小时内连续测定阿霉素水平。对患者进行口腔炎和感染发生情况的临床评估，并每周两次测量粒细胞计数。
8例患者两个疗程均进行了完整的药代动力学采样。与给药顺序相反的情况相比，紫杉醇-阿霉素给药顺序时输注结束时阿霉素的平均血浆浓度（Cmax）高70%（45±8ng/mL对26±5ng/mL）。紫杉醇-阿霉素给药顺序时阿霉素的平均清除率低32%（34.3±10.3L/h对51.6±16.1L/h，P<.01）。临床上，紫杉醇-阿霉素给药顺序时血液学和黏膜毒性作用更严重。紫杉醇-阿霉素给药顺序时绝对粒细胞计数中位数为0.2/μL，阿霉素-紫杉醇给药顺序时为1.3/μL。接受紫杉醇-阿霉素给药顺序的10例患者中有7例发生2级（n=4）或3级（n=3）口腔炎，而接受阿霉素-紫杉醇给药顺序的10例患者中只有1例发生2级口腔炎，无3级口腔炎。
当24小时输注的紫杉醇先于48小时输注的阿霉素给药时，阿霉素清除率降低近三分之一，这会导致2级和3级口腔炎。当紫杉醇（24小时输注）和阿霉素序贯给药时，为防止这种效应，应先给予阿霉素。这种效应的机制正在研究中。
