Elias A D, Skarin A T, Leong T, Mentzer S, Strauss G, Lynch T, Shulman L, Jacobs C, Abner A, Baldini E H, Frei E, Sugarbaker D J
Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, MA 02115, USA.
Lung Cancer. 1997 May;17(1):147-61. doi: 10.1016/s0169-5002(97)00658-2.
Neoadjuvant therapy in patients with Stage IIIA NSCLC is associated with a 50-70% resection rate and a 3-5 year survival of 20-32%, but few trials have required meticulous staging of the mediastinum to ensure homogeneity of the study population. Continuous infusion cisplatin 25 mg/m2/day 1-5, 5-fluorouracil 800 mg/m2/day 2-5, and high-dose leukovorin 500 mg/m2/day 1-5 (PFL) given every 4 weeks achieved a 41% response rate in metastatic NSCLC (Lynch TJ, Kalish LA, Kass F, Strauss G, Elias A, Skarin A, Shulman L, Sugarbaker D, Frei E. Continuous infusion cisplatin, 5-fluorouracil, and leukovorin for advanced non-small cell lung cancer. Cancer 1994; 73: 1171-1176). The regimen was therefore evaluated in 34 patients with pathologic Stage IIIA N2 disease between 3/91 and 10/92.
Staging consisted of chest, liver, brain computerized tomography and bone scan, bronchoscopy and surgical mediastinal node mapping. Patients received PFL for 3 cycles, followed by thoracotomy and thoracic radiotherapy (TRT) to 54-60 Gy.
Median age was 57 (42-68) years. Demographic factors included: male 56%; adenocarcinoma 59%, squamous cell carcinoma 24%; Stage T3N2 26%, T2N2 56%, and T1N2 18%. No treatment related deaths occurred. Radiographically defined response to PFL was 65% (6% complete). Thoracotomy was performed in 28 patients (82%) (6 had no attempt due to disease progression). Complete resection was achieved in 21 (75%) and seven were unresectable. Pathologic complete response was observed in five patients (15%) and an additional unresectable patient had fibrosis-only documented at thoracotomy for an overall clinicopathologic response rate of 76% (18% pathologic CR). Another ten patients had residual primary with or without hilar disease with resolution of previously documented mediastinal involvement. Six (18%) patients remain alive and disease-free with a median follow-up of 46 (33-50) months, four of whom had achieved pathologic complete response at time of surgery.
Long-term event-free survival was associated with complete surgical resection which in turn was associated with clinical response to chemotherapy. There was a possible trend associating pathologic downstaging (absent residual disease in mediastinal nodes), particularly pathologic complete response observed in patients with non-bulky mediastinal disease, with improved event-free survival. Pathologic downstaging might therefore be a useful surrogate endpoint in trials evaluating the preoperative activity of new chemotherapy regimens. While radiographic response generally correlated with findings at surgery, response as determined by histologic examination of resected tissue was generally more extensive and may more accurately reflect the systemic impact of the chemotherapy regimen.
IIIA期非小细胞肺癌（NSCLC）患者的新辅助治疗与50%-70%的切除率以及20%-32%的3-5年生存率相关，但很少有试验要求对纵隔进行细致分期以确保研究人群的同质性。持续输注顺铂25mg/m²/天，第1-5天使用；5-氟尿嘧啶800mg/m²/天，第2-5天使用；高剂量亚叶酸钙500mg/m²/天，第1-5天使用（PFL），每4周给药一次，在转移性NSCLC中实现了41%的缓解率（Lynch TJ、Kalish LA、Kass F、Strauss G、Elias A、Skarin A、Shulman L、Sugarbaker D、Frei E。持续输注顺铂、5-氟尿嘧啶和亚叶酸钙治疗晚期非小细胞肺癌。《癌症》1994年；73:1171-1176）。因此，在1991年3月至1992年10月期间，对34例病理IIIA期N2疾病患者评估了该方案。
分期包括胸部、肝脏、脑部计算机断层扫描和骨扫描、支气管镜检查以及手术纵隔淋巴结图谱绘制。患者接受3个周期的PFL治疗，随后进行开胸手术和54-60Gy的胸部放疗（TRT）。
中位年龄为57（42-68）岁。人口统计学因素包括：男性56%；腺癌59%，鳞状细胞癌24%；T3N2期26%，T2N2期56%，T1N2期18%。未发生与治疗相关的死亡。PFL的影像学缓解率为65%（6%完全缓解）。28例患者（82%）进行了开胸手术（6例因疾病进展未尝试）。21例（75%）实现了完全切除，7例无法切除。5例患者（15%）观察到病理完全缓解，另有1例无法切除的患者在开胸手术时仅记录有纤维化，总体临床病理缓解率为76%（18%病理CR）。另外10例患者有残留原发灶，伴或不伴有肺门疾病，之前记录的纵隔受累情况得到缓解。6例（18%）患者存活且无疾病，中位随访时间为46（33-50）个月，其中4例在手术时实现了病理完全缓解。
长期无事件生存与完全手术切除相关联，而完全手术切除又与化疗的临床缓解相关。存在一种可能的趋势，即病理降期（纵隔淋巴结无残留疾病），特别是在非肿大纵隔疾病患者中观察到的病理完全缓解，与改善的无事件生存相关。因此，在评估新化疗方案术前活性的试验中，病理降期可能是一个有用的替代终点。虽然影像学缓解通常与手术结果相关，但通过对切除组织的组织学检查确定的缓解通常更广泛，可能更准确地反映化疗方案的全身影响。
