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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。
表1 EORTC08941诱导化疗后手术与放射治疗比较的随机对照研究结果
| 手术组 | 放射治疗组 |
| 无进展生存时间
中位生存时间（月）2年生存率（%） | 9.0
27 | 11.4
24 | P=0.6 | 总生存生存时间
中位生存时间（月）
2年生存率（%）
5年生存率（%） | 16.4
35
16 | 17.5
41
13 | HR=0.95(0.75-1.19) |
Meerbeeck等[8]报道了另一个涉及手术的随机研究——EORTC 08941，其入选病例为组织学或细胞学证实的手术困难的ⅢA-N2期NSCLC，先给予3个周期的含铂方案诱导化疗，将有效者随机分为手术组和放疗组。手术组患者接受根治性肺癌切除术＋纵隔淋巴结清扫，放疗组剂量为60 Gy。结果显示，572例患者诱导化疗的平均有效率为61.5%。将有效的333例随机分为手术组167例，放疗组166例，放疗组的中位生存期略高于手术组，分别为17.5个月(95%CI为15.8～23.2个月)和16.4个月(95%CI为13.3～19.0个月)，但无明显差异。2006年Meerbeeck等[9]进一步分析发现，诱导化疗后肿瘤分期未降低，患者放疗组5年生存率显著高于手术组，分别为15%和8%(P＝0.035)，肿瘤分期降低的患者手术后5年生存率仅略高于放疗患者，分别为31%和19%(P＝0.16)。学者认为，对于手术困难的ⅢA-N2期NSCLC患者，诱导化疗后手术与诱导化疗后放疗相比，既不能改善无进展时间，也不能提高总生存率，此类患者的标准治疗应当是化放综合治疗，全肺切除的术式应当废弃。
选择非小细胞肺癌ⅢAN2病例，先给予3周期顺铂为基础的方案诱导化疗（platinum-based induction chemotherapy）。对化疗有效的病例进行随机分组为：根治性手术（radical surgery） 或胸部放疗（thoracic radiotherapy TRT）。登记入组进行诱导化疗的病例572例，诱导化疗有效率为61.5%，333例进入随机分组，手术组167例，放射治疗组166例。154例接受了手术治疗，其中探查手术14%，根治性切除术51%，病理降期(pathological downstaging) 42%，手术死亡4%；39%的病例接受了手术后放疗。随机进入放疗组的病人，155例接受了放疗，纵隔照射剂量40Gy，局部补量20Gy。放疗组3/4级毒性发生率3.9%。中位随诊72个月，S和TRT组中位生存时间分别为16.4个月和 17.5个月；2年、5年生存率为35% vs. 41%; 16% vs. 13%。中位PFS为9.0个月vs. 11.4个月； 2年PFS为27% vs. 24%, p=0.6。研究结论认为，对诱导化疗有效的 ⅢAN2病例，手术与放射治疗比较既不能改善生存率也不能改善无病生存率。
新辅助治疗≠ 新辅助化疗
2008年和2009年发表的两项研究[欧洲癌症研究与治疗组织（EORTC）08941和组间（Intergrop）0139研究]引发了人们对肺癌新辅助治疗的新思考——对N2期NSCLC新辅助化疗后手术和放疗的选择问题。
EORTC 08941研究显示，铂类为基础新辅助化疗后手术组和放疗组的中位总生存（OS）无显著差异。因此，有研究者认为，手术对于ⅢA-N2期患者的意义不大。但是，Intergrop 0139研究却再次证实了手术的价值：联合放化疗后手术组或放疗组的OS并无显著差异，但手术在无进展生存（PFS）方面优于放疗。因此相关评论指出，“外科又回来了”。
这两项研究的重要意义在于明确了一个事实：能使N2患者获益的是新辅助放化疗而非一贯所采用的新辅助化疗。其中0139研究还提示可进一步选择能从不同手术方式获益的患者：与放疗相比，接受肺叶切除术而非全肺切除术者的OS得到显著改善，但接受全肺切除者的OS显著差于放疗。
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，5年生存率手术组16%，放射治疗组13%。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。
Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer Jan P van Meerbeeck 1, Gijs W P M Kramer, Paul E Y Van Schil, Catherine Legrand, Egbert F Smit, Franz Schramel, Vivianne C Tjan-Heijnen, Bonne Biesma, Channa Debruyne, Nico van Zandwijk, Ted A W Splinter, Giuseppe Giaccone; European Organisation for Research and Treatment of Cancer-Lung Cancer Group
Background: Induction chemotherapy before surgical resection increases survival compared with surgical resection alone in patients with stage IIIA-N2 non-small-cell lung cancer (NSCLC). We hypothesized that, following a response to induction chemotherapy, surgical resection would be superior to thoracic radiotherapy as locoregional therapy. Methods: Selected patients with histologic or cytologic proven stage IIIA-N2 NSCLC were given three cycles of platinum-based induction chemotherapy. Responding patients were subsequently randomly assigned to surgical resection or radiotherapy. Survival curves were estimated using Kaplan-Meier analyses from time of randomization. Results: Induction chemotherapy resulted in a response rate of 61% (95% confidence interval [CI] = 57% to 65%) among the 579 eligible patients. A total of 167 patients were allocated to resection and 165 to radiotherapy. Of the 154 (92%) patients who underwent surgery, 14% had an exploratory thoracotomy, 50% a radical resection, 42% a pathologic downstaging, and 5% a pathologic complete response; 4% died after surgery. Postoperative radiotherapy was administered to 62 (40%) of patients in the surgery arm. Among the 154 (93%) irradiated patients, overall compliance to the radiotherapy prescription was 55%, and grade 3/4 acute and late esophageal and pulmonary toxic effects occurred in 4% and 7%; one patient died of radiation pneumonitis. Median and 5-year overall survival for patients randomly assigned to resection versus radiotherapy were 16.4 versus 17.5 months and 15.7% versus 14%, respectively (hazard ratio = 1.06, 95% CI = 0.84 to 1.35). Rates of progression-free survival were also similar in both groups. Conclusion: In selected patients with pathologically proven stage IIIA-N2 NSCLC and a response to induction chemotherapy, surgical resection did not improve overall or progression-free survival compared with radiotherapy. In view of its low morbidity and mortality, radiotherapy should be considered the preferred locoregional treatment for these patients.
Morbidity and mortality in the surgery arm of EORTC 08941 trial P Van Schil 1, J Van Meerbeeck, G Kramer, T Splinter, C Legrand, G Giaccone, C Manegold, N van Zandwijk
Controversial results of surgical treatment after induction chemotherapy, especially in relation to the extent of resection, have previously been reported. Mortality and morbidity were studied in the surgical arm of the European Organisation for Research and Treatment of Cancer (EORTC) 08941 trial. EORTC 08941 is a multicentre, prospective, randomised, phase-III trial of surgical resection versus radiotherapy in patients with proven stage IIIA-N2 nonsmall cell lung cancer after an objective response to platinum-based induction chemotherapy. Operative results in the 167 patients randomised in the surgical arm are presented within this study. Among these patients, one switched to the radiotherapy arm and 17 patients did not get any protocol treatment or information is not yet available. Radical resection with negative surgical margins was obtained in 74 patients (49.7%). In 61 patients (40.9%), a pathological down-staging to N0 or N1 was present. Operative 30-day mortality was 4.0%. Post-operative complications were mainly pneumonia, respiratory insufficiency, arrhythmias, air leak, cardiac decompensation, empyema and bronchopleural fistula. In total, 12 (8.1%) patients underwent re-operation due to positive margins, haemothorax, empyema and bronchopleural fistula. In conclusion, surgical resection after induction chemotherapy in the multicentre European Organisation for Research and Treatment of Cancer trial has yielded acceptable rates of morbidity and mortality.
Quality assurance of thoracic radiotherapy in EORTC 08941: a randomised trial of surgery versus thoracic radiotherapy in patients with stage IIIA non-small-cell lung cancer (NSCLC) after response to induction chemotherapy Gijsbert W P M Kramer 1, Catherine L Legrand, Paul van Schil, Lon Uitterhoeve, Egbert F Smit, Franz Schramel, Bonne Biesma, Vivianne Tjan-Heijnen, Nico van Zandwijk, Ted Splinter, Giuseppe Giaccone, Jan P van Meerbeeck; EORTC-Lung Cancer Group
The aim of this study was to investigate the improvement of quality of radiotherapy and compliance to the protocol amendment of EORTC study 08941. The radiotherapy-specific data were analysed from 154 patients with stage IIIA-N2 Non-Small-Cell Lung Cancer who were actually irradiated after response to 3 cycles of platinum-based induction chemotherapy. The parameters of quality, assessed in 93 patients before and in 61 after protocol amendment, included: time interval between last chemotherapy course and start of thoracic radiotherapy, the use of a 3-D planning CT, dose and fractionation scheme to the primary tumour, the involved and uninvolved mediastinum, duration of radiotherapy and toxicity. A significant improvement of all quality parameters was noted, except for the overall treatment time, which decreased slightly. Protocol amendment resulted in an improvement of the quality and the compliance of most observed parameters, at the cost of some increase in overall treatment time. The latter reflects logistical problems rather than poor compliance.
参考文献： van Meerbeeck JP, Kramer GW, Van Schil PE, Legrand C, Smit EF, Schramel F, Tjan-Heijnen VC, Biesma B, Debruyne C, van Zandwijk N, Splinter TA, Giaccone G; European Organisation for Research and Treatment of Cancer-Lung Cancer Group. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst. 2007 Mar 21;99(6):442-50. doi: 10.1093/jnci/djk093. PMID: 17374834.
Van Schil P, Van Meerbeeck J, Kramer G, Splinter T, Legrand C, Giaccone G, Manegold C, van Zandwijk N. Morbidity and mortality in the surgery arm of EORTC 08941 trial. Eur Respir J. 2005 Aug;26(2):192-7. doi: 10.1183/09031936.05.00127204. PMID: 16055865.
Kramer GW, Legrand CL, van Schil P, Uitterhoeve L, Smit EF, Schramel F, Biesma B, Tjan-Heijnen V, van Zandwijk N, Splinter T, Giaccone G, van Meerbeeck JP; EORTC-Lung Cancer Group. Quality assurance of thoracic radiotherapy in EORTC 08941: a randomised trial of surgery versus thoracic radiotherapy in patients with stage IIIA non-small-cell lung cancer (NSCLC) after response to induction chemotherapy. Eur J Cancer. 2006 Jul;42(10):1391-8. doi: 10.1016/j.ejca.2006.01.052. PMID: 16785054.
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