Livingston R B, Ellis G K, Gralow J R, Williams M A, White R, McGuirt C, Adamkiewicz B B, Long C A
Division of Oncology, University of Washington, Seattle 98195-6043, USA.
J Clin Oncol. 1997 Apr;15(4):1395-400. doi: 10.1200/JCO.1997.15.4.1395.
We evaluated weekly single-agent intravenous (IV) vinorelbine as salvage therapy for metastatic breast cancer. After the first five patients, all received elective growth factor support with granulocyte colony-stimulating factor (G-CSF; filgrastim) in an attempt to maximize delivered dose-intensity (DDI). Objective tumor response, DDI, and toxicity were assessed, as well as time to progression (TTP) and survival.
This single-center nonrandomized trial enrolled 40 patients. Anthracycline exposure and subsequent progression were common to all patients, and 38 of 40 were paclitaxel-refractory. Vinorelbine was given initially at 30 mg/m2/wk, then at 35 mg/m2/wk in a phase I/II design, which involved first intermittent (6 days of 7) and then continuous (daily) administration of G-CSF at 5 micrograms/kg.
The maximum-tolerated starting dose was 35 mg/m2/wk with continuous G-CSF support. The mean DDI was 27.7 mg/m2/wk for all patients. There were two complete responses (CRs) and eight partial responses (PRs) in 40 assessable patients for an overall response rate of 25% (95% confidence interval [CI], 13% to 41%). The median TTP was 13 weeks and median survival time 33 weeks. The dose-limiting toxicity was neutropenia, with dose delay or reduction required in 14 of 27 patients entered at 35 mg/m2. Febrile neutropenia that required hospitalization was unusual (three of 40 patients, 8%). There were no treatment-related deaths. Grade 3/4 thrombocytopenia occurred in nine patients (23%) and 26 patients (65%) required RBC transfusions for anemia. Seven patients (18%) had reversible grade 3/4 nonhematologic complications, primarily related to neurotoxicity. Grade > or = 3 mucositis was absent.
Concurrent administration of weekly vinoralbine and daily G-CSF is feasible and permits an increase in DDI for vinorelbine of 43% to 76% over that reported in series without growth factor support. The response rate, TTP, and survival data are encouraging for therapy given to heavily pretreated patients with metastatic breast cancer. Vinorelbine is not cross-resistant with paclitaxel and should be considered for further trials in the dose-intensified mode made possible by G-CSF, alone or combined with other agents.
我们评估了每周一次单药静脉注射长春瑞滨作为转移性乳腺癌挽救治疗的疗效。在前5例患者之后，所有患者均接受了粒细胞集落刺激因子（G-CSF；非格司亭）的选择性生长因子支持治疗，以试图使给药剂量强度（DDI）最大化。评估了客观肿瘤反应、DDI和毒性，以及疾病进展时间（TTP）和生存期。
这项单中心非随机试验纳入了40例患者。所有患者均有蒽环类药物暴露史且随后出现疾病进展，40例中有38例对紫杉醇耐药。在I/II期设计中，长春瑞滨最初剂量为30mg/m²/周，之后为35mg/m²/周，其中G-CSF以5μg/kg的剂量先间歇给药（每周7天中的6天），然后连续给药（每日）。
在持续G-CSF支持下，最大耐受起始剂量为35mg/m²/周。所有患者的平均DDI为27.7mg/m²/周。在40例可评估患者中，有2例完全缓解（CR）和8例部分缓解（PR），总缓解率为25%（95%置信区间[CI]，13%至41%）。中位TTP为13周，中位生存时间为33周。剂量限制性毒性为中性粒细胞减少，在以35mg/m²剂量入组的27例患者中有14例需要延迟给药或降低剂量。需要住院治疗的发热性中性粒细胞减少并不常见（40例患者中有3例，8%）。无治疗相关死亡。9例患者（23%）发生3/4级血小板减少，26例患者（65%）因贫血需要输注红细胞。7例患者（18%）出现可逆性3/4级非血液学并发症，主要与神经毒性有关。无≥3级黏膜炎。
每周一次长春瑞滨与每日一次G-CSF联合给药是可行的，与无生长因子支持的系列报道相比，长春瑞滨的DDI可提高43%至76%。对于接受过大量治疗的转移性乳腺癌患者，其缓解率、TTP和生存数据令人鼓舞。长春瑞滨与紫杉醇无交叉耐药，应考虑在G-CSF单独或与其他药物联合应用实现的剂量强化模式下进行进一步试验。
