Lessons learned: The combination of irinotecan and etoposide showed modest efficacy in terms of response rate in the refractory setting for patients with metastatic breast cancer.The studied dose and schedule of irinotecan and etoposide is very toxic, with >70% grade 3 or 4 treatment-related adverse events.
Background: As single agents, both irinotecan and etoposide have documented activity against breast cancer among patients who have received multiple lines of prior chemotherapy. Irinotecan interacts with topoisomerase I (Topo I) to stabilize its cleavable complex, and etoposide has an analogous interaction with topoisomerase II (Topo II). This stabilization without rapid resealing of the cleavage point results in apoptotic cell death and accounts for the antitumor activity of these agents. Topo II levels may increase after administration of a Topo I inhibitor, thus providing a rationale for combining these agents in practice. Based on preclinical data, we conducted a phase II trial of the Topo I inhibitor irinotecan combined with the Topo II inhibitor etoposide in patients with metastatic breast cancer (MBC).
Methods: This was a single-arm phase II clinical trial in patients with MBC refractory to prior anthracycline, taxane, and capecitabine therapy. All patients were treated with oral etoposide at 50 mg/day on days 1-14 and intravenous irinotecan at 100mg/m2 on days 1 and 15. Treatment cycles were repeated every 28 days. The primary endpoint was median time to progression. Secondary end points included overall clinical response rate using RECIST criteria and assessing the toxicity and safety profile associated with this combination regimen.
Results: We enrolled 31 women with refractory MBC to our trial. Median age was 54 (range, 36-84), with the majority (64%) having hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2 neg) MBC. Median number of prior therapies was five (range, 3-14). Efficacy was evaluated in 24 patients. Seventeen percent had a partial response, and 38% had stable disease as best response. Median progression-free survival was 9 weeks (range, 3-59). All 31 patients were evaluable for toxicity assessment, and 22 patients (71 %) experienced treatment-related grade 3 or 4 adverse events (AEs; Table 1). The most common grade 3-4 AE was neutropenia. The study was terminated early based on interim analysis assessment that suggested toxicities outweighed the efficacy.
Conclusion: Irinotecan and etoposide demonstrated only modest clinical activity and poor tolerability in patients with MBC refractory to anthracycline, taxane, and capecitabine therapy. Further studies testing a lower dose and/or different schedule could be considered given ease of administration and responses seen.
• 伊立替康联合依托泊苷治疗的研究剂量和给药方案具有较大的毒性，>70% 的患者出现 3 级或 4 级治疗相关不良反应。
背景。在单药治疗时，伊立替康和依托泊苷均已证明对既往曾采用多线化疗方案的乳腺癌患者具有活性。伊立替康与拓扑异构酶 I (Topo I) 互相作用可以稳定其可裂解复合物，依托泊苷可以与拓扑异构酶 II (Topo II) 进行类似的互相作用。这种稳定作用不会快速地重新封闭裂解点，可以造成凋亡细胞死亡并导致这两种药物具有抗肿瘤活性。在 Topo I 抑制剂给药后，Topo II 水平可能会升高，从而为在实践中联合使用这两种药物提供了理论基础。基于临床前数据，我们开展了一项关于 Topo I 抑制剂伊立替康联合 Topo II 抑制剂依托泊苷治疗转移性乳腺癌 (MBC) 患者的 II 期试验。
方法。这是一项针对既往蒽环霉素、紫杉烷和卡培他滨治疗无效的MBC患者的单组 II 期临床试验。所有患者均在第 1–14 天按照 50 mg/日的剂量口服依托泊苷并在第 1 天和第 15 天按照 100mg/m2 的剂量接受静脉注射伊立替康。治疗周期每 28 天重复一次。主要终点为中位至进展时间。次要终点为利用实体瘤疗效评价标准 (RECIST) 获得总体临床缓解率以及评估与此联合治疗方案相关的毒性和安全性。
结果。我们在试验中招募了 31 名患有难治型MBC的女性。中位年龄为 54 岁(范围为 36‐84 岁)，大多数患者 (64%) 患有激素受体阳性 (HR+) 人类表皮生长因子受体 2 阴性 (HER2 neg) MBC。既往治疗的中位数为 5 次(范围为 3–14 次)。在 24 名患者中评估了疗效。17% 的患者表现出部分缓解，38% 的患者表现出病情稳定的最佳缓解。中位无进展生存期为 9 周(范围为 3–59 周)。所有 31 名患者均可接受毒性评估，22 名患者 (71%) 出现了治疗相关的 3 级或 4 级不良反应(AE；表 1)。最常见的 3–4 级不良反应为嗜中性粒细胞减少。鉴于中期分析评估表明毒性已超过疗效，本研究提前终止。
Trial registration: ClinicalTrials.gov NCT00693719.
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