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INT 0139 放化疗在可手术IIIA(N2)NSCLC中的作用(Intergroup 0139（RTOG 9309）
Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial
入组了429 例ⅢA （pN2）期 NSCLC，所有患者接受了EP方案的同步放化疗（45Gy/25 次）后，随机分配进入手术组或根治性放疗组，两组患者后续都进行 2 个周期的巩固化疗。结果显示两组的 OS 相仿（23.6 个月 vs22.2 个月，P=0.24）；手术组具有一定的 PFS 优势（12.8 个月 vs 10.5 个月，P=0.017）；亚组分析显示新辅助同步放化疗后接受肺叶切除的患者可能具有一定的 OS 优势（33.6 个月 vs21.7 个月，P=0.002）。
Background: Results from phase II studies in patients with stage IIIA non-small-cell lung cancer with ipsilateral mediastinal nodal metastases (N2) have shown the feasibility of resection after concurrent chemotherapy and radiotherapy with promising rates of survival. We therefore did this phase III trial to compare concurrent chemotherapy and radiotherapy followed by resection with standard concurrent chemotherapy and definitive radiotherapy without resection. Methods: Patients with stage T1-3pN2M0 non-small-cell lung cancer were randomly assigned in a 1:1 ratio to concurrent induction chemotherapy (two cycles of cisplatin [50 mg/m(2) on days 1, 8, 29, and 36] and etoposide [50 mg/m(2) on days 1-5 and 29-33]) plus radiotherapy (45 Gy) in multiple academic and community hospitals. If no progression, patients in group 1 underwent resection and those in group 2 continued radiotherapy uninterrupted up to 61 Gy. Two additional cycles of cisplatin and etoposide were given in both groups. The primary endpoint was overall survival (OS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00002550. Findings: 202 patients (median age 59 years, range 31-77) were assigned to group 1 and 194 (61 years, 32-78) to group 2. Median OS was 23.6 months (IQR 9.0-not reached) in group 1 versus 22.2 months (9.4-52.7) in group 2 (hazard ratio [HR] 0.87 [0.70-1.10]; p=0.24). Number of patients alive at 5 years was 37 (point estimate 27%) in group 1 and 24 (point estimate 20%) in group 2 (odds ratio 0.63 [0.36-1.10]; p=0.10). With N0 status at thoracotomy, the median OS was 34.4 months (IQR 15.7-not reached; 19 [point estimate 41%] patients alive at 5 years). Progression-free survival (PFS) was better in group 1 than in group 2, median 12.8 months (5.3-42.2) vs 10.5 months (4.8-20.6), HR 0.77 [0.62-0.96]; p=0.017); the number of patients without disease progression at 5 years was 32 (point estimate 22%) versus 13 (point estimate 11%), respectively. Neutropenia and oesophagitis were the main grade 3 or 4 toxicities associated with chemotherapy plus radiotherapy in group 1 (77 [38%] and 20 [10%], respectively) and group 2 (80 [41%] and 44 [23%], respectively). In group 1, 16 (8%) deaths were treatment related versus four (2%) in group 2. In an exploratory analysis, OS was improved for patients who underwent lobectomy, but not pneumonectomy, versus chemotherapy plus radiotherapy. Interpretation: Chemotherapy plus radiotherapy with or without resection (preferably lobectomy) are options for patients with stage IIIA(N2) non-small-cell lung cancer. Intergroup 0139（RTOG 9309）的研究结果，1994年3月至2001年11月入组病人429例。可分析病例396例，治疗相关死亡（Treatment-related deaths）A组10例（5%），B组4例（2.1%）。手术类型与治疗相关死亡的关系，简单全肺切除（simple）治疗相关死亡为 5/23(22%), 复杂全肺切除(complex pneumonectomies)为 9/31(29%),肺叶切除(lobectomy)为1/98（1%）。手术组术后病理结果：T0N0 29例（18%），全部N0病例76例（46%）。手术组无疾病进展生存时间（PFS）高于非手术组，5年PFS分别为22% vs 11%；中位PFS分别为12.8个月和10.5个月， P=0.008。而A组非肿瘤死亡高于B组， P=0.021。两组中位生存期无明显差别（23.6个月 vs 22.2个月, P=0.24, HR 0.87(0.70, 1.10）。5年生存率分别为，27.2% vs 20.3%， 5年生存的风险比（Odd Ratio）为0.63(0.36, 1.10,p=0.10)。女性和体重减轻是独立的预后因素。在A组中，5年生存率与术后病理的关系, 术后病理pN0, 41%, pN1-3, 24%; 未手术的病例,8%。该研究的结论是：1)对IIIA（N2）病例，手术组PFS优于非手术组，但总生存率无差别。2） 三联治疗(trimodality therapy)有提高5年生存率的趋势。3）手术后病理p
N0 的病例预后好，4）对合适的病例可选择CT/RT+手术的治疗方式，5）对需要做全肺切除的病例，这种三联治疗方式可能不是最佳的选择。因此，IIIA（N2）病例仍然是综合治疗临床研究的热点。
IIIA-N2期非小细胞肺癌患者诱导化疗后的最佳局部治疗手段是选择手术还是选择放射治疗尚未明确。2003年引起轰动的北美0139（RTOG9309）研究，今年更新数据报道了5年的随访结果[4]。5年无复发生存率手术组为22.4%，放疗组为11.1%，比值比0.77（0.62~0.96，P=0.017），但总的5年生存率27.2% 对20.3%，比值比0.63 (0.36~1.10，P=0.10)。结果再次强调，化放疗后手术相对于化放疗，能提高IIIA-N2期非小细胞肺癌患者的无复发生存率，有提高总生存率的趋向，但这一治疗模式不适于需要全肺切除的患者。
EORTC 08941的研究与0139有所不同，它的入选病例为组织学或细胞学证实的 IIIA-N2期非小细胞肺癌，方案为先给予3周期的含铂方案诱导化疗，有效者随机分为手术组和放射治疗组。手术组行完全性切除+淋巴结清扫术，酌情术后放射治疗（PORT）；胸部放射治疗组剂量为纵隔至少40Gy/2Gy/d加累及野至少60Gy。结果：572例登记的患者诱导化疗的平均有效率为61.5%（95%CI 57.6-65.5），有效的333例患者随机分为手术组167例，放疗组166例。结果见表4。EORTC08941的结论认为，对于经过选择的IIIA-N2期非小细胞肺癌患者，诱导化疗后手术和诱导化疗后放射治疗比较，既不能改善无进展时间也不能提高总生存率。因此，对于IIIA-N2期非小细胞肺癌，应选择非手术的治疗为好。
Table 1: Baseline characteristics of eligible patients
Albain KS, Swann RS, Rusch VW, Turrisi AT 3rd, Shepherd FA, Smith C, Chen Y, Livingston RB, Feins RH, Gandara DR, Fry WA, Darling G, Johnson DH, Green MR, Miller RC, Ley J, Sause WT, Cox JD. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet. 2009 Aug 1;374(9687):379-86. doi: 10.1016/S0140-6736(09)60737-6. Epub 2009 Jul 24. PMID: 19632716; PMCID: PMC4407808.
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