Abstract
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.
Abstract
经验总结
• 伊立替康联合依托泊苷治疗难治型转移性乳腺癌患者在缓解率方面表现出适度的疗效。
• 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。
摘要
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。
结论。在既往蒽环霉素、紫杉烷和卡培他滨治疗无效的MBC患者中，伊立替康联合依托泊苷治疗仅表现出适度的临床活性和较差的耐受性。鉴于易于给药和观察到缓解的情况，可以考虑开展进一步研究，针对较低的剂量和/或不同给药方案进行测试。
Discussion
Combinations of Topo I and Topo II inhibitors have been suggested based on the preclinical data that Topo II levels may be upregulated after administration of a Topo I inhibitor. We enrolled women with MBC who were heavily pretreated on this trial evaluating combination of irinotecan and etoposide. Although the regimen was found to have modest clinical activity in terms of response rates and progression‐free survival (PFS), it had significant side effects, with a majority of patients experiencing a grade 3 or 4 treatment‐related adverse event, and the study was terminated early. Based on our experience, the studied combination regimen dose and schedule is not optimal for patients.
Trial Information
- Disease
Breast cancer
- Stage of Disease/Treatment
Metastatic / Advanced
- Prior Therapy
More than 2 prior regimens
- Type of Study – 1
Phase II
- Type of Study – 2
Single arm
- Primary Endpoint
Time to progression
- Secondary Endpoint
Overall response ate
- Secondary Endpoint
Safety
- Secondary Endpoint
Overall survival
- Investigator's Analysis
Active but too toxic as administered in this study
Drug Information
- Drug 1
- Generic/Working Name
Irinotecan
- Trade Name
Camptosar
- Company Name
Pfizer Oncology
- Drug Type
Biological
- Drug Class
Topoisomerase I
- Dose
100 mg/m2
- Route
IV
- Schedule of Administration
100 mg/m2 every 2 weeks in a 28‐day cycle
- Drug 2
- Generic/Working Name
Etoposide
- Trade Name
VePesid
- Drug Class
Topoisomerase II
- Dose
50 mg per flat dose
- Route
p.o.
- Schedule of Administration
50 mg per day for 14 days, then off 2 weeks for a 28‐day cycle
Patient Characteristics
- Number of Patients, Male
0
- Number of Patients, Female
31
- Stage
Metastatic breast cancer, prior exposure to anthracycline, taxane, and capecitabine therapy
- Age
Median (range): 54 (36–84)
- Number of Prior Systemic Therapies
Median (range): 5 (3–14)
- Performance Status: ECOG
-
0 — 16
1 — 14
2 — 1
0
0
- Other
- Tumor Biology (Number)
-
Triple‐negative breast cancer = 5
HR+/HER2 neg = 20
HER2 pos = 3
Unknown = 3
- Cancer Types or Histologic Subtypes
-
Invasive ductal carcinoma, 24
Invasive lobular carcinoma, 3
Inflammatory, 2
Unknown, 2
Primary Assessment Method
- Title
Time to progression
- Number of Patients Enrolled
31
- Number of Patients Evaluable for Toxicity
31
- Number of Patients Evaluated for Efficacy
24
- Evaluation Method
RECIST 1.0
- Response Assessment PR
n = 4 (17%)
- Response Assessment SD
n = 7 (38%)
- Response Assessment PD
n = 11 (45%)
- (Median) Duration Assessments PFS
9 weeks
- (Median) Duration Assessments TTP
63 days
- (Median) Duration Assessments OS
29 weeks
Assessment, Analysis, and Discussion
- Completion
Study terminated before completion
- Terminated Reason
Toxicity
- Investigator's Assessment
Active but too toxic as administered in this study
As single agents, both irinotecan and etoposide have documented activity against breast cancer among patients who have received multiple forms of prior chemotherapy [1], [2].
Combinations of Topo I and Topo II inhibitors have been suggested based on the observation that Topo II levels may be upregulated after administration of a Topo I inhibitor [3]. In addition, Topo II may be able to partially compensate for Topo I, as has been seen in Saccharomyces cerevisiae [5], [6], permitting maintenance of critical transcriptional functions. This concept has been difficult to realize in the clinic when topotecan and etoposide were administered sequentially [4]. One explanation may be the lapsed time between administration of the Topo I and Topo II inhibitors in the clinical trial, whereas the preclinical data showed maximal synergy when the Topo II inhibitor was administered immediately after the Topo I inhibitor [3].
In our trial, the majority of patients had refractory disease with an extensive prior treatment history (see Patient Characteristics for demographics). The combination of irinotecan and etoposide was found to have modest clinical activity, with a 55% response rate by RECIST criteria (Fig. 1) and median PFS of 9 weeks (range, 3–59). However, there were significant side effects, with >70% of patients experiencing grade 3 or 4 treatment‐related adverse events, primarily neutropenia. See attached table 1 for details on AEs. All patients on study received maximal symptomatic management, transfusions for cytopenias, growth colony‐stimulating factor when indicated, dose reductions, and drug holidays. Growth colony‐stimulating factor support was needed in 85% of patients who had grade 3 or 4 neutropenia requiring dose reduction. Transfusion support for anemia was needed in 13% of patients.
Figure 1.
Computed tomography chest showing decrease in left pleural nodule after three cycles of therapy.
Table 1. Treatment‐related adverse events.
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
The study protocol originally planned to accrue a total of 54 patients and specified early stopping if the response rate was 2 or fewer of the first 21 evaluable patients (9.5%) according to Simon's optimal design criteria. At the time of interim analysis, despite a promising response rate, the regimen was determined to be too toxic, and the study was terminated early by the data safety monitoring board and study principal investigator.
The current treatment armamentarium for MBC is expanding with newer targeted therapies that improve PFS and quality of life. As the tumor becomes refractory to more treatments, the current treatment landscape includes evaluating for mutations in driver pathways, assessing the microenvironment, and testing novel targeted therapies. As MBC tumor biology and pathways are better understood, allowing for exploitation with novel targeted therapies, the field is moving away from combination chemotherapy regimens. Although combination chemotherapy does have some role in MBC (e.g., in visceral crisis), it is not ideal for long‐term therapy. Based on our experience, we do not expect the combination of irinotecan and etoposide to be used routinely because of an unacceptable toxicity profile.
Footnotes
ClinicalTrials.gov Identifier: NCT00693719
Sponsor: University of Arizona Cancer Center
Principal Investigator: Robert B. Livingston
IRB Approved: Yes
Disclosures
Alison Stopeck: Novartis, AstrzZeneca, Biothera (C/A), Genomic Health, Amgen (H), Amgen, Eli Lilly & Co. (RF); Pavani Chalasani: Pfizer (RF). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
References
- 1.Martín M, Lluch A, Casado A et al. Clinical activity of chronic oral etoposide in previously treated metastatic breast cancer. J Clin Oncol 1994;12:986–991. [DOI] [PubMed] [Google Scholar]
- 2.Perez E, Hillman D, Mailliard J et al. Randomized phase II study of two irinotecan schedules for patients with metastatic breast cancer refractory to an anthracycline, a taxane, or both. J Clin Oncol 2004;22:2849–2855. [DOI] [PubMed] [Google Scholar]
- 3.Whitacre C, Zborowska E, Gordon NM et al. Topotecan increases topoisomerase II alpha levels and sensitivity to treatment with etoposide in schedule‐dependent process. Cancer Res 1997;57:1425–1428. [PubMed] [Google Scholar]
- 4.Hammond L, Eckhardt J, Ganapathi R et al. A phase I and translational study of sequential administration of the topoisomerase I and II inhibitors topotecan and etoposide. Clin Cancer Res 1998;4:1459–1467. [PubMed] [Google Scholar]
- 5.Goto T, Wang J. Cloning of yeast TOPI, the encoding DNA topoisomerase I, and construction of mutants defective in both DNA topoisomerase I and topoisomerase II. Proc Natl Acad Sci USA 1985;82:7178–7182. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Brill S, DeNardo S, Voelkel‐Meiman K et al. Need for topoisomerase activity as a swivel for DNA replication for transcription of ribosomal RNA. Nature 1987;326:414–416. [DOI] [PubMed] [Google Scholar]