Pujol J L, Lafontaine T, Quantin X, Reme-Saumon M, Cupissol D, Khial F, Michel F B
Department of Respiratory Diseases, Hôpital Arnaud de Villeneuve, Montpellier, France.
Chest. 1999 Jan;115(1):144-50. doi: 10.1378/chest.115.1.144.
To determine the applicability and safety of an ifosfamide, cisplatin, and etoposide (VIP) regimen as a neoadjuvant chemotherapy to a concomitant thoracic radiotherapy and cisplatin continuous infusion in locally advanced non-small cell lung cancer (NSCLC).
Forty-four patients (stage IIIb in 43 and stage IIIa in 1) entered a study of VIP, followed by concomitant thoracic radiotherapy and cisplatin continuous infusion. Chemotherapy consisted of three courses of cisplatin 25 mg/m2, ifosfamide 1.5 g/m2 (with uroprotection), and etoposide 100 mg/m2 given on days 1 to 4 of a 21-day cycle with hematopoietic support using recombinant human methionyl granulocyte colony stimulating factor. Patients who achieved a response or a stabilization were planned to receive a split-course normofractionated thoracic radiotherapy (first course: 30 Gy/10; 4-week rest period; second course: 25 Gy/10). A continuous cisplatin infusion of 6 mg/m2 daily was administered using an autonomous chemotherapy delivery device. Total plasma platinum titration was performed daily during the two courses in five of the patients. Analyses were done on an intent-to-treat basis.
Thirty-nine of the 44 patients received the three-cycle chemotherapy program. Received dose intensity was 82%. Thirty-eight patients received the radiotherapy and, among them, 35 received the complete concomitant continuous cisplatin infusion. Objective (complete) response rates were 48% (7%) at the end of chemotherapy and increased up to 61% (16%) by the end of radiotherapy. At the end of the first radiotherapy cycle, the mean total plasma platinum concentration was twice as high as that of the residual postinduction chemotherapy concentration. During induction chemotherapy, myelosuppression was the limiting toxicity requiring hospital readmission in 23 patients. During radiotherapy, the main toxicity was acute esophagitis. A relatively high rate of pulmonary fibrosis was observed using the subjective objective management analytic--late effects of normal tissue score without life-threatening pulmonary function impairment. None of the patients died from toxic reactions. Probability of survival at 1, 2, and 3 years was 49%, 19%, and 5%, respectively. Primary cause of failure was a local relapse in 63% of the patients, brain metastases in 24%, and hematogeneous metastases to other sites in 13%.
Neoadjuvant VIP followed by concomitant radiotherapy-chemotherapy is feasible, but the split-course radiotherapy did not prevent a high rate of local recurrences. The high rate of toxic reactions requiring hospital readmission limits further development of such an aggressive regimen in NSCLC.
确定异环磷酰胺、顺铂和依托泊苷（VIP）方案作为新辅助化疗联合胸部放疗和顺铂持续输注用于局部晚期非小细胞肺癌（NSCLC）的适用性和安全性。
44例患者（43例为Ⅲb期，1例为Ⅲa期）进入VIP方案研究，随后接受胸部放疗联合顺铂持续输注。化疗包括3个疗程，顺铂25mg/m²、异环磷酰胺1.5g/m²（给予尿路保护）、依托泊苷100mg/m²，在21天周期的第1至4天给药，使用重组人甲硫氨酰粒细胞集落刺激因子进行造血支持。达到缓解或病情稳定者计划接受分程常规分割胸部放疗（第一疗程：30Gy/10次；休息4周；第二疗程：25Gy/10次）。使用自动化疗给药装置每日持续输注顺铂6mg/m²。5例患者在两个疗程期间每日进行总血浆铂滴定。分析基于意向性治疗原则。
44例患者中有39例接受了3周期化疗方案。接受的剂量强度为82%。38例患者接受了放疗，其中35例接受了完整的同步顺铂持续输注。化疗结束时客观（完全）缓解率为48%（7%）；放疗结束时升至61%（16%）。在第一个放疗周期结束时，平均总血浆铂浓度是诱导化疗后残留浓度的两倍。诱导化疗期间，骨髓抑制是限制毒性，23例患者因此需要再次住院。放疗期间，主要毒性为急性食管炎。使用主观客观管理分析——正常组织晚期效应评分观察到较高的肺纤维化发生率，但无危及生命的肺功能损害。无患者死于毒性反应。1年、2年和3年生存率分别为49%、19%和5%。失败的主要原因是63%的患者局部复发，24%发生脑转移，13%发生血行转移至其他部位。
新辅助VIP方案联合放疗化疗是可行的，但分程放疗未能预防高比例的局部复发。需要再次住院的高毒性反应发生率限制了这种积极方案在NSCLC中的进一步发展。
