Johnson Faye M, Kurie Jonathan M, Peeples Beverly O, Lee J Jack, Feng Lei, Pisters Katherine M, Fossella Frank V, Papadimitrakopoulou Vassiliki A, Blumenschein George R, Komaki Ritsuko, Glisson Bonnie S
Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, USA.
Clin Lung Cancer. 2003 Jul;5(1):40-5. doi: 10.3816/CLC.2003.n.020.
The combination of IP (irinotecan/cisplatin) has been shown to confer a survival benefit compared with EP (etoposide/cisplatin) in patients with extensive-stage small-cell lung cancer (SCLC). Based on this and potential synergy from sequential inhibition of topoisomerases I and II, we conducted a phase I study to assess the feasibility of weekly therapy alternating IP and EP. The doses of EP were fixed (etoposide 60 mg/m2 on days 1-3 and cisplatin 20 mg/m2 on day 1). The dose of irinotecan was escalated in serial cohorts at 3 dose levels: 80, 90, and 100 mg/m2 on day 1. Granulocyte colony-stimulating factor was given on days 2-5 and days 4-7 after IP and EP, respectively. Patients with limited-stage SCLC received chemoradiation during weeks 4-6 with etoposide 120 mg/m2 on days 1-3, cisplatin 60 mg/m2 on day 1, and thoracic radiation 1.5 Gy twice daily in 30 fractions. Patients received 12 weeks of therapy. To evaluate dose escalation in subsequent cohorts, dose-limiting toxicity (DLT) was initially assessed during weeks 1-3 of treatment. Characteristics of the 18 patients accrued are as follows: performance status 0/1, n = 9; female sex, n = 9; extended-stage SCLC, n = 16; and median age, 53 years. Four patients treated at irinotecan dose level 1 (80 mg/m2), 6 patients at dose level 2 (90 mg/m2), and 6 patients at dose level 3 (100 mg/m2) did not experience DLT in weeks 1-4 and completed therapy without major incident. The only 2 patients to experience DLT during weeks 1-4 were treated at dose level 2. Both were hospitalized during week 4 and subsequently died. However, patients had already been accrued at dose level 3 and tolerated therapy well. Therefore, the trial design was modified to assess DLT during weeks 1-4, and additional patients were cautiously added to the dose level 2 and 3 cohorts. Analysis of summary toxicity data resulted in a recommendation that dose level 3 be used in phase II based on the probability of DLT of 16% (95% CI, 3%-29%). Responses in 16 evaluable patients include complete response in 1 patient, partial response in 14 patients, and minor response in 1 patient. With the exception of the 2 deaths, the therapy was well tolerated and active. Phase II evaluation of the regimen in patients with extensive-stage SCLC is ongoing.
与依托泊苷/顺铂（EP）方案相比，伊立替康/顺铂（IP）方案已被证明可使广泛期小细胞肺癌（SCLC）患者生存获益。基于此以及拓扑异构酶I和II序贯抑制的潜在协同作用，我们开展了一项I期研究，以评估IP和EP交替的每周疗法的可行性。EP的剂量固定（第1 - 3天，依托泊苷60 mg/m²；第1天，顺铂20 mg/m²）。伊立替康的剂量在3个剂量水平的连续队列中逐步递增：第1天分别为80、90和100 mg/m²。分别在IP和EP治疗后的第2 - 5天和第4 - 7天给予粒细胞集落刺激因子。局限期SCLC患者在第4 - 6周接受同步放化疗，第1 - 3天给予依托泊苷120 mg/m²，第1天给予顺铂60 mg/m²，胸部放疗每日2次，每次1.5 Gy，共30次分割。患者接受12周治疗。为评估后续队列中的剂量递增情况，在治疗的第1 - 3周初步评估剂量限制性毒性（DLT）。纳入的18例患者的特征如下：体能状态0/1，9例；女性，9例；广泛期SCLC，16例；中位年龄53岁。在伊立替康剂量水平1（80 mg/m²）治疗的4例患者、剂量水平2（90 mg/m²）治疗的6例患者和剂量水平3（100 mg/m²）治疗的6例患者在第1 - 4周均未发生DLT，并顺利完成治疗，无重大事件。在第1 - 4周仅有的2例发生DLT的患者接受的是剂量水平2的治疗。两人均在第4周住院，随后死亡。然而，剂量水平3队列中已有患者入组且对治疗耐受性良好。因此，试验设计修改为在第1 - 4周评估DLT，并谨慎地向剂量水平2和3队列中增加额外患者。汇总毒性数据分析结果表明，基于DLT概率为16%（95%CI，3% - 29%），建议在II期使用剂量水平3。16例可评估患者的疗效包括1例完全缓解、14例部分缓解和1例轻微缓解。除2例死亡外，该疗法耐受性良好且有活性。针对广泛期SCLC患者的该方案的II期评估正在进行。
