Dose‐Dense Nonpegylated Liposomal Doxorubicin and Docetaxel Combination in Breast Cancer: Dose‐Finding Study. (19th January 2015)

• Record Type: Journal Article
• Authors: Ricevuto, Enrico; Cocciolone, Valentina; Mancini, Maria; Cannita, Katia; Romano, Silvio; Bruera, Gemma; Pelliccione, Michela; Adinolfi, Maria Ilaria; Ciccozzi, Antonietta; Bafile, Alberto; Penco, Maria; Ficorella, Corrado
• Is Part Of: Oncologist. Volume 20:Number 2(2015)
• Page Start: 109
• Page End: 110
• Publication Date: 2015-01-19
• Subjects: Oncology -- Periodicals; Tumors -- Periodicals; Cancérologie -- Périodiques; Tumeurs -- Périodiques; Oncology; Tumors; Neoplasms; Electronic journals; Periodicals; Periodicals; 616.994
• DOI: 10.1634/theoncologist.2014-0129
• Languages: English
• ISSNs: 1083-7159

Abstract

Abstract : Background: Anthracyclines and taxanes are effective drugs in breast cancer (BC), but their toxicity profiles limit their use in combination. A dose‐finding study was performed to determine maximum tolerated doses (MTDs) of nonpegylated liposomal doxorubicin (TLC‐D99) and docetaxel (DTX) as a dose‐dense schedule, to maintain dose intensity, and to limit toxicity, particularly cardiac. Methods: Twenty‐four patients were enrolled, 12 with metastatic BC, 5 with locally advanced BC, and 7 with early BC. An intra‐ and interpatient approach was planned in two sequential steps. In the first step, TLC‐D99 was administered at dose levels of 40, 45, and 50 mg/m 2 plus DTX at a fixed dose of 50 mg/m 2 . In the second step, TLC‐D99 was administered at the dose established in the first step plus DTX at dose levels of 55, 60, and 65 mg/m 2 . Every treatment cycle was delivered on day 1 every 14 days. Pegylated granulocyte colony‐stimulating factor was scheduled on day 2. Dose‐limiting toxicities (DLTs) were defined as G4 hematological; G3 nonhematological; ≥10% or ≥20% left ventricular ejection fraction (LVEF) reduction if the final value was <50% or ≥50%, respectively; severe arrhythmia; and symptomatic heart failure. LVEF was evaluated by echocardiography every two cycles, and precursor brain natriuretic peptide (pBNP) and cardiac troponin I (cTnI) were monitored on days 1 and 2. Results: Five DLTs occurred (20.8%). No cardiac event of congestive heart failure was reported; 2 events of grade 3 cardiac dysfunction (8.3%), including a ≥20% LVEF reduction in 1 patient and symptomatic arrhythmia in another; 2 incidences of G4 neutropenia (8.3%); and 1 occurrence of G3 asthenia (4.2%) were reported. MTDs were not reached. The recommended doses were established as TLC‐D99 50 mg/m 2 and DTX 65 mg/m 2 . Cumulatively, mild (G1–G2) cardiac dysfunction was observed in 58.4% of patients: G1 cardiac arrhythmia was noted in 50%, G1–G2 general cardiac toxicity occurred in 25%, and concomitant toxicity was present in 17%. cTnI never increased. pBNP was increased in 25% and was associated with limiting arrhythmia in 4% and cardiac dysfunction in 16%. Conclusion: Dose‐dense TLC‐D99 50 mg/m 2 and DTX 65 mg/m 2 can be safely administered in combination every 2 weeks for breast cancer, with the highest projected dose intensity for each drug at 25 and 32.5 mg/m 2 per week, respectively. Abstract : 摘要 背景： 蒽环类和紫杉烷类药物治疗乳腺癌（BC）有效，但两种药物的毒性谱使其联合用药受限。研究者开展了一项剂量探索研究，以确定密集化疗方案中非聚乙二醇脂质体多柔比星（TLC‐D99）和多西他赛（DTX）的最大耐受剂量（MTD），使其能够在维持剂量强度的基础上限制毒性，尤其是心脏毒性。 方法： 纳入 24 例患者，其中包括 12 例转移性 BC 患者、5 例局部晚期 BC 患者和 7 例早期 BC 患者。计划开展两个阶段的研究，评估患者内和患者间差异。在第一阶段，分别给予 40 mg/m 2 、45 mg/m 2 和 50 mg/m 2 三种剂量水平的 TLC‐D99，同时给予固定剂量 DTX（50 mg/m 2 ）。在第二阶段，TLC‐D99 采用在第一阶段中确定的剂量，分别给予 55 mg/m 2 、60 mg/m 2 和 65 mg/m 2 三种剂量水平的 DTX。以 14 天为一个治疗周期，第 1 天给药。化疗给药的第 2 天安排注射聚乙二醇粒细胞集落刺激因子。剂量限制性毒性反应（DLT）包括：4 级血液学毒性反应；3 级非血液学毒性反应；左心室射血分数（LVEF）降幅≥ 10%（最终值< 50%）或≥ 20%（最终值≥ 50%）；严重心律失常；有症状的心力衰竭。每两个治疗周期通过心脏超声测定 LVEF；在每个治疗周期的第 1 天和第 2 天监测脑利钠肽前体（pBNP）和心脏肌钙蛋白 I （cTnI）。 结果： 5 例患者发生 DLT（20.8%）。未观察到充血性心力衰竭；2 例患者出现 3 级心功能不全（8.3%），其中 1 例患者 LVEF 下降≥ 20%，另 1 例出现症状性心律失常；2 例患者出现 4 级中性粒细胞减少（8.3%）；1 例患者出现 3 级无力（4.2%）。未达到 MTD。TLC‐D99 的推荐剂量为 50 mg/m 2 ， DTX 的推荐剂量为 65 mg/m 2 。共有58.4% 的患者出现轻度（1 ∼ 2 级）心功能不全；50% 的患者出现 1 级心律失常，25% 的患者出现 1 ∼ 2 级一般心脏毒性反应，17% 的患者出现多种心脏毒性反应。所有患者中未观察到 cTnI 升高。25% 的患者出现 pBNP 升高，其中 4% 与心律失常相关，16% 与心功能不全相关。 结论： 对于乳腺癌患者，每 2 周一次剂量密集 TLC‐D99 50 mg/m 2 和 DTX 65 mg/m 2 联合治疗方案是安全的，预计两种药物的每周最高剂量强度分别为 25 mg/m 2 和 32.5 mg/m 2 。 The Oncologist 2015;20:109–110