Langer Corey J, Somer Robert, Litwin Samuel, Feigenberg Steven, Movsas Benjamin, Maiale Christine, Sherman Eric, Millenson Michael, Nicoloau Nicos, Huang Chao, Treat Joseph
Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
J Thorac Oncol. 2007 Mar;2(3):203-9. doi: 10.1097/JTO.0b013e318031cd3c.
Irinotecan and cisplatin individually are active in non-small cell lung carcinoma (NSCLC). Each is synergistic with radiation. Dosages of 65 mg/m2 of irinotecan and 30 mg/m2 of cisplatin Q weekly times four every 6 weeks yielded a 36% response rate and median survival of 11.6 months in advanced NSCLC (Jagasia et al.; Clinical Cancer Research 7: 68, 2001). A weekly schedule for each agent (versus less frequent doses) limits toxicity and increases the opportunity for radiosensitization.
We initiated a phase I study of weekly irinotecan and cisplatin during radical thoracic radiation (TRT). Cisplatin was fixed at 25 mg/m2 Q weekly times seven. Irinotecan was dosed initially at 30 mg/m2 per week for 7 weeks and was increased by 10 mg/m2 per week in three- to six-patient cohorts. TRT was administered in 34 single daily fractions to 63 Gy. Eligibility stipulated locally advanced NSCLC; Eastern Cooperative Oncology Group performance status 0 to 1; < or = 10% unintended weight loss; and adequate physiologic indices.
Fifteen patients were accrued: nine were stage IIIB, five were stage IIIA, and one had isolated mediastinal node recurrence after prior surgery. Median age was 65 years (range, 47-77). Seven patients received irinotecan at a dose of 30 mg/m2 per week; (dose level 1). Seven other patients received irinotecan at a dose of 40 mg/m2 per week; (dose level 2). The one other patient received irinotecan in doses of 50 mg/m2 per week; (dose level 3). Neutropenic fever occurred in one patient each at dose levels 1 and 2. Grade 4 neutropenia occurred in three patients at each dose level. Transient grade 3 diarrhea occurred in one patient at dose level 1. Esophagitis of grade 3 or higher occurred in one patient each at dose levels 2 and 3. There was one late grade 3 pneumonitis at dose level 2. Delivered irinotecan dose intensity for dose level 1 was 27 mg/m2 per week; for dose level 2, it was 31.4 mg/m2 per week. Nine of 13 evaluable patients (69%) responded. At median potential follow-up of 5 years, 14 have progressed, and 11 have died. Projected median survival is 28 months; one patient who was treated for mediastinal node recurrence remains free from progression at 6 years.
Weekly irinotecan and cisplatin combined with radical TRT (63 Gy) is active and fairly well tolerated in locally advanced NSCLC. In combination with fixed-dose cisplatin (25 mg/m2 per week), the maximum-tolerated dose of irinotecan is 30 mg/m2 per week.
伊立替康和顺铂单药对非小细胞肺癌（NSCLC）均有活性。二者与放疗均具有协同作用。在晚期NSCLC中，伊立替康剂量为65mg/m²、顺铂剂量为30mg/m²，每6周每周1次，共4次，有效率为36%，中位生存期为11.6个月（贾加西亚等人；《临床癌症研究》7: 68, 2001）。每种药物采用每周给药方案（相对于给药频率较低的方案）可限制毒性并增加放射增敏的机会。
我们启动了一项在根治性胸部放疗（TRT）期间每周使用伊立替康和顺铂的I期研究。顺铂固定剂量为25mg/m²，每周1次，共7次。伊立替康最初剂量为每周30mg/m²，共7周，随后在每组3至6例患者中每周增加10mg/m²。TRT分34次每日单次给予，剂量为63Gy。入选标准为局部晚期NSCLC；东部肿瘤协作组体能状态为0至1；体重意外减轻≤10%；以及生理指标良好。
共纳入15例患者：9例为IIIB期，5例为IIIA期，1例为既往手术后孤立纵隔淋巴结复发。中位年龄为65岁（范围47 - 77岁）。7例患者接受每周30mg/m²的伊立替康治疗（剂量水平1）。另外7例患者接受每周40mg/m²的伊立替康治疗（剂量水平2）。另1例患者接受每周50mg/m²的伊立替康治疗（剂量水平3）。剂量水平1和2各有1例患者发生中性粒细胞减少性发热。每个剂量水平均有3例患者发生4级中性粒细胞减少。剂量水平1有1例患者发生短暂3级腹泻。剂量水平2和3各有1例患者发生3级或更高等级的食管炎。剂量水平2有1例晚期3级肺炎。剂量水平1的伊立替康给药剂量强度为每周27mg/m²；剂量水平2为每周31.4mg/m²。13例可评估患者中有9例（69%）有反应。中位潜在随访5年时，14例病情进展，11例死亡。预计中位生存期为28个月；1例接受纵隔淋巴结复发治疗的患者6年无病情进展。
每周使用伊立替康和顺铂联合根治性TRT（63Gy）对局部晚期NSCLC有活性且耐受性较好。与固定剂量顺铂（每周25mg/m²）联合使用时，伊立替康的最大耐受剂量为每周30mg/m²。
