Nokihara Hiroshi, Yamamoto Noboru, Ohe Yuichiro, Hiraoka Masaki, Tamura Tomohide
Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
Clin Ther. 2016 Feb;38(2):338-47. doi: 10.1016/j.clinthera.2015.12.009. Epub 2016 Jan 13.
Weekly paclitaxel combined with a platinum-based agent has been advocated as an alternative regimen for patients with advanced non-small cell lung cancer (NSCLC). Limited studies exist on the tolerability of weekly paclitaxel in Japanese patients with advanced NSCLC. Furthermore, the feasibility of dexamethasone taper in the premedication regimen for weekly paclitaxel has not been examined in these patients. To address this issue, we assessed the maximum tolerated dose, dose-limiting toxicity, and pharmacokinetics of weekly paclitaxel in Japanese patients with advanced NSCLC in a dose-escalation Phase I trial and examined the feasibility of dexamethasone taper in these patients.
Weekly 1-hour infusions of paclitaxel were administered at doses of 80 to 120 mg/m(2) (dose escalation of 20 mg/m(2)). The 7-week treatment cycle consisted of 6 infusions followed by a 2-week treatment interval. Pharmacokinetics were assessed during the first cycle. Dexamethasone was commenced at 16 mg and doses were successively halved if hypersensitivity reactions were absent.
A total of 15 patients with either Stage IIIB or IV NSCLC were enrolled. Although no dose-limiting toxicity was observed at 120 mg/m(2), 4 of 6 patients with peripheral neuropathy required discontinuation of treatment. The maximum accepted dose and the recommended dose were 120 and 100 mg/m(2), respectively. No grade ≥3 adverse events were observed at 100 mg/m(2). The maximum drug concentration and AUC correlated with dose escalation. The pharmacokinetic parameters after the first and sixth infusions were similar, indicating that repeated administration of paclitaxel did not result in drug accumulation or affect its pharmacokinetic profile. Partial response was observed in 3 of 15 patients. Plasma adrenocorticotropic hormone and cortisol levels decreased during treatment but approached baseline levels after a dexamethasone-free interval.
Weekly paclitaxel at 100 mg/m(2) given as a 1-hour infusion for 6 weeks followed by a 2-week treatment interval was well tolerated by Japanese patients with advanced NSCLC. Dexamethasone taper was feasible in these patients, and no clear trend in plasma adrenocorticotropic hormone or cortisol levels was observed.
每周一次的紫杉醇联合铂类药物已被推荐作为晚期非小细胞肺癌（NSCLC）患者的替代治疗方案。关于日本晚期NSCLC患者对每周一次紫杉醇的耐受性的研究有限。此外，在这些患者中，尚未研究在每周一次紫杉醇预处理方案中逐渐减少地塞米松剂量的可行性。为了解决这个问题，我们在一项剂量递增的I期试验中评估了日本晚期NSCLC患者每周一次紫杉醇的最大耐受剂量、剂量限制性毒性和药代动力学，并研究了这些患者中逐渐减少地塞米松剂量的可行性。
每周1小时输注紫杉醇，剂量为80至120mg/m²（剂量递增20mg/m²）。7周的治疗周期包括6次输注，随后是2周的治疗间隔。在第一个周期评估药代动力学。地塞米松起始剂量为16mg，如果没有过敏反应，剂量依次减半。
共纳入15例IIIB期或IV期NSCLC患者。虽然在120mg/m²时未观察到剂量限制性毒性，但6例周围神经病变患者中有4例需要停止治疗。最大可接受剂量和推荐剂量分别为120和100mg/m²。在100mg/m²时未观察到≥3级不良事件。最大药物浓度和AUC与剂量递增相关。第一次和第六次输注后的药代动力学参数相似，表明重复给药紫杉醇不会导致药物蓄积或影响其药代动力学特征。15例患者中有3例观察到部分缓解。治疗期间血浆促肾上腺皮质激素和皮质醇水平下降，但在无地塞米松间隔后接近基线水平。
日本晚期NSCLC患者对每周一次100mg/m²的紫杉醇进行1小时输注，共6周，随后间隔2周的治疗耐受性良好。在这些患者中逐渐减少地塞米松剂量是可行的，并且未观察到血浆促肾上腺皮质激素或皮质醇水平有明显趋势。
