A Pilot, Phase II, Randomized, Open‐Label Clinical Trial Comparing the Neurotoxicity of Three Dose Regimens of Nab‐Paclitaxel to That of Solvent‐Based Paclitaxel as the First‐Line Treatment for Patients with Human Epidermal Growth Factor Receptor Type 2‐Negative Metastatic Breast Cancer

• Published in: The oncologist (Dayton, Ohio) Vol. 24; no. 11; pp. e1024 - e1033
• Main Authors: Ciruelos, Eva, Apellániz‐Ruiz, María, Cantos, Blanca, Martinez‐Jáñez, Noelia, Bueno‐Muiño, Coralia, Echarri, Maria‐Jose, Enrech, Santos, Guerra, Juan‐Antonio, Manso, Luis, Pascual, Tomas, Dominguez, Cristina, Gonzalo, Juan‐Francisco, Sanz, Juan‐Luis, Rodriguez‐Antona, Cristina, Sepúlveda, Juan‐Manuel
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.11.2019
• Subjects: Breast Cancer; Metastatic breast cancer; Nab‐paclitaxel; Neurotoxicity; Paclitaxel; Polyneuropathy; Total neurotoxicity score; Metastatic breast cancer; Neurotoxicity; Nab‐paclitaxel; Polyneuropathy; Paclitaxel; Total neurotoxicity score
• ISSN: 1083-7159; 1549-490X
• DOI: 10.1634/theoncologist.2017-0664

Background This study aimed to characterize the neurotoxicity of three different regimens of nab‐paclitaxel compared with a standard regimen of solvent‐based (sb) paclitaxel for the first‐line treatment of HER2‐negative metastatic breast cancer based on the Total Neurotoxicity Score (TNS), a tool specifically developed to assess chemotherapy‐induced neurotoxicity. Materials and Methods This was a randomized, open‐label study testing 4‐week cycles of 80 mg/m2 sb‐paclitaxel (PACL80/w) on days 1, 8, and 15; 100 mg/m2 nab‐paclitaxel on days 1, 8, and 15 (NAB100/w); 150 mg/m2 nab‐paclitaxel on days 1, 8, and 15 (NAB150/w); and 150 mg/m2 nab‐paclitaxel on days 1 and 15 (NAB150/2w). In addition to the TNS, neuropathy was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI‐CTCAE). Tumor response and quality of life were also evaluated. Results Neurotoxicity, as evaluated by the TNS, did not significantly differ between the sb‐paclitaxel group and any of the nab‐paclitaxel groups. The frequency of (any grade) polyneuropathy, as measured by the NCI‐CTCAE, was lower in the PACL80/w (n = 7, 50%) and NAB150/2w (n = 10, 62.5%) groups than in the NAB100/w (n = 13, 81.3%) or NAB150/w (n = 11, 78.6%) group. Although the differences were not statistically significant, compared with the other groups, in the NAB150/w group, the time to occurrence of grade ≥2 polyneuropathy was shorter, and the median time to recovery from grade ≥2 polyneuropathy was longer. Dose delays and reductions due to neurotoxicity and impact of neurotoxicity on the patients’ experience of symptoms and functional limitations was greater with NAB150/w. Among the seven polymorphisms selected for genotyping, the variant alleles of EPHA5‐rs7349683, EPHA6‐rs301927, and EPHA8‐rs209709 were associated with an increased risk of paclitaxel‐induced neuropathy. Conclusion The results of this exploratory study showed that, regardless of the dose, nab‐paclitaxel did not differ from sb‐paclitaxel in terms of neurotoxicity as evaluated with the TNS. However, results from NCI‐CTCAE, dose delays and reductions, and functional tools consistently indicate that NAB150/w regimen is associated with a greater risk of chemotherapy‐induced neuropathy. Thus, our results question the superiority of the TNS over NCI‐CTCAE for evaluating chemotherapy‐induced neuropathy and guiding treatment decisions in this context. The selection of the nab‐paclitaxel regimen should be individualized based on the clinical context and potentially supported by pharmacogenetic analysis. Registry: EudraCT, 2012‐002361‐36; NCT01763710 Implications for Practice The results of this study call into question the superiority of the Total Neurotoxicity Score over the National Cancer Institute Common Terminology Criteria for Adverse Events for evaluating chemotherapy‐induced neuropathy and guiding treatment decisions in this context and suggest that a regimen of 150 mg/m2 nab‐paclitaxel administered on days 1, 8, and 15 is associated with a greater risk of chemotherapy‐induced neuropathy and hematological toxicity compared with other lower‐dose nab‐paclitaxel regimens or a standard regimen of solvent‐based paclitaxel. The selection of the nab‐paclitaxel regimen should be individualized based on the clinical context and could benefit from pharmacogenetics analysis. 摘要 背景。本研究的目的是采用总神经毒性评分 (TNS)(一种专门用于评估化疗诱发的神经毒性的工具)进行评分，对比三种不同剂量的白蛋白结合型紫杉醇与标准剂量的溶剂型 (sb) 紫杉醇在一线治疗 HER‐2 阴性转移性乳腺癌中的神经毒性。 材料和方法。本研究为随机、开放标签研究，治疗疗程为 4 周:一组采用sb紫杉醇 80 mg/m2，于第 1 天、第 8 天和第 15 天给药 (PACL80/w)；一组采用白蛋白结合型紫杉醇 100 mg/m2， 于第 1 天、第 8 天和第 15 天给药 (NAB100/w)；一组采用白蛋白结合型紫杉醇 150 mg/m2，于第 1 天、第 8 天和第 15 天服用 (NAB150/w)；一组采用白蛋白结合型紫杉醇 150 mg/m2，于第 1 天和第 15 天 给药 (NAB150/2w)。除 TNS 外，采用美国国家癌症研究所不良事件常用术语标准 (NCI‐CTCAE) 评估神经病变。同时，对肿瘤反应和生活质量进行评估。 结果。经 TNS 评估，sb紫杉醇组与白蛋白结合型紫杉醇组之间的神经毒性无显著差异。根据 NCI‐CTCAE 测定，PACL80/w 组 (n = 7,50%) 和 NAB150/2w 组 (n = 10,62.5%) 发生(任何等级)多发性神经病变的次数低于 NAB100/w 组(n = 13,81.3%) 与 NAB150/w 组 (n = 11,78.6%)。尽管差异无统计学意义，但与其他组相比，NAB150/w 组发生 ≥ 2级多发性神经病变的时间较短，且从 ≥ 2级多发性神经病变中康复的中位时间较长。由于神经毒性的产生及其对患者症状和功能限制的影响，NAB150/w 组的剂量延迟时间更长，减少量更大。在选定的 7 种基因分型多态性中，EPHA5‐rs7349683、EPHA6‐rs301927 和 EPHA8‐rs209709 的变异等位基因与紫杉醇引起的神经病变的风险增加有关。 结论。本项探索性研究的结果表明，无论剂量多少，白蛋白结合型紫杉醇与sb紫杉醇的神经毒性 TNS 评分并无差异。然而，NCI‐CTCAE、剂量延迟和减少量以及功能工具的结果一致表明，NAB150/w 方案与化疗引起的神经病变的风险增加有关。因此，研究结果质疑了在评估化疗引起的神经病变及其指导治疗决策中，TNS 相比 NCI‐CTCAE 的优势。白蛋白结合型紫杉醇方案应根据临床情况进行具体选择，而且可以经过药物遗传学分析获得证据。注册编号:EudraCT, 2012‐002361‐36; NCT01763710 实践意义:研究结果对神经毒性评分相比美国国家癌症研究所不良事件常用术语标准在评估化疗所致神经病变及其指导治疗决定问题中具有一定优势的结论提出了质疑；结果显示，采用白蛋白结合型紫杉醇 150 mg/m2第 1 天、第 8 天和第 15 天给药的治疗方案相比其他低剂量白蛋白结合型紫杉醇或基于溶剂型紫杉醇的标准治疗方案，发生化疗引起的神经病变和出现血液学毒性的风险更大。白蛋白结合型紫杉醇方案应根据临床情况进行具体选择，而且可以经过药物遗传学分析获得更好的效果。 The Total Neurotoxicity Score (TNS) is a tool for assessing chemotherapy‐induced neurotoxicity. This article reports results of a phase II study characterizing the neurotoxicity, based on TNS, of three different regimens of nab‐paclitaxel compared with a standard regimen of solvent‐based paclitaxel for the first‐line treatment of metastatic breast cancer.