Frasci G, Comella P, Scoppa G, Guida C, Gravina A, Fiore F, Casaretti R, Daponte A, Parziale A, Comella G
Department of Radiology and Radiation Therapy, National Tumor Institute of Naples, Italy.
J Clin Oncol. 1997 Apr;15(4):1409-17. doi: 10.1200/JCO.1997.15.4.1409.
Both cisplatin (CDDP) and paclitaxel have shown good antitumor activity in non-small-cell lung cancer (NSCLC) patients and are able to potentiate the antitumor effects of radiation therapy (RT). This study aimed to determine the maximum-tolerated doses (MTDs) of CDDP and paclitaxel (escalated alternately) when given concurrently with RT and to define the nature of the dose-limiting toxicity (DLT).
Chemotherapy-naive patients with locally advanced NSCLC received six weekly administrations of a CDDP-paclitaxel combination with concurrent local RT. The starting doses of CDDP and paclitaxel were 30 mg/m2/wk and 35 mg/m2/wk, respectively. RT was initially given at the dose of 1.2 Gy twice daily for 5 days per week for 5 weeks (total dose, 60 Gy) and at a single daily dose of 2 Gy for 5 days per week for 6 weeks in the last two cohorts of patients. The drug doses were escalated alternately until DLT occurred in more than one third of the patients in a given cohort.
Overall, 25 patients were recruited through five different cohorts. All were assessable for toxicity. Esophagitis was the main toxicity and occurred in 16 of 25 patients (64%) and was grade 3 or 4 in five of them. At step 3 (CDDP 35 mg/m2/wk and paclitaxel 45 mg/m2/wk), two of five patients had to discontinue treatment because of severe esophagitis and one of these died of complications related to grade 4 esophagitis. However, keeping the same doses of chemotherapy and replacing hyperfractionation with a standard single-day fraction, weekly doses of CDDP and paclitaxel of 35 mg/m2 and 45 mg/m2 could be safely administered. Neutropenia was by far the most relevant hematologic toxicity and occurred in 33 of 141 weekly delivered courses, but it was of grade 4 in only four courses. Substantial pulmonary or neurologic toxicity was not observed in this study. Two complete responses (CRs) and 13 partial responses (PRs) were observed, for a 60% overall response rate (95% confidence interval [CI], 39% to 79%). The median survival time was 16 months, with a 66% 1-year survival probability.
CDDP 35 mg/m2/wk and paclitaxel 45 mg/m2/wk can be safely administered with concurrent standard RT. The use of hyperfractionation is associated with a more frequent occurrence of severe esophagitis and requires a reduction of the CDDP dose to 30 mg/m2/ wk. Only future randomized trials will elucidate which of these two approaches (standard or hyperfractionated RT) is the better option to improve the outcome of patients with locally advanced NSCLC.
顺铂（CDDP）和紫杉醇在非小细胞肺癌（NSCLC）患者中均显示出良好的抗肿瘤活性，并且能够增强放射治疗（RT）的抗肿瘤效果。本研究旨在确定CDDP和紫杉醇（交替递增）与RT同时使用时的最大耐受剂量（MTD），并明确剂量限制毒性（DLT）的性质。
未经化疗的局部晚期NSCLC患者接受每周一次的CDDP-紫杉醇联合治疗，并同时进行局部RT，共6周。CDDP和紫杉醇的起始剂量分别为30mg/m²/周和35mg/m²/周。RT最初剂量为每日1.2Gy，每周5天，共5周（总剂量60Gy），在最后两组患者中为每日单次剂量2Gy，每周5天，共6周。药物剂量交替递增，直到给定队列中超过三分之一的患者出现DLT。
总体而言，通过五个不同队列招募了25名患者。所有患者均进行了毒性评估。食管炎是主要毒性，25名患者中有16名（64%）出现，其中5名患者为3级或4级。在第3步（CDDP 35mg/m²/周和紫杉醇45mg/m²/周）时，5名患者中有2名因严重食管炎不得不停止治疗，其中1名死于与4级食管炎相关的并发症。然而，保持相同的化疗剂量并将超分割放疗改为标准单日分割放疗后，CDDP和紫杉醇每周剂量35mg/m²和45mg/m²可以安全给药。中性粒细胞减少是迄今为止最主要的血液学毒性，在141个每周给药疗程中有过33次，但只有4个疗程为4级。本研究未观察到明显的肺部或神经毒性。观察到2例完全缓解（CR）和13例部分缓解（PR），总缓解率为60%（95%置信区间[CI]，39%至79%）。中位生存时间为16个月，1年生存概率为66%。
CDDP 35mg/m²/周和紫杉醇45mg/m²/周与标准RT同时使用时可以安全给药。超分割放疗的使用与严重食管炎更频繁发生相关，需要将CDDP剂量降至30mg/m²/周。只有未来的随机试验才能阐明这两种方法（标准放疗或超分割放疗）中哪一种是改善局部晚期NSCLC患者预后的更好选择。
