Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study.
Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study.
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DOI：
10.1016/s1470-2045(14)71207-0
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发表时间：
2015-02
期刊：
影响因子：
51.1
通讯作者：
Choy, Hak
中科院分区：
文献类型：
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作者：
Bradley, Jeffrey D.;Paulus, Rebecca;Komaki, Ritsuko;Masters, Gregory;Blumenschein, George;Schild, Steven;Bogart, Jeffrey;Hu, Chen;Forster, Kenneth;Magliocco, Anthony;Kavadi, Vivek;Garces, Yolanda I.;Narayan, Samir;Iyengar, Puneeth;Robinson, Cliff;Wynn, Raymond B.;Koprowski, Christopher;Meng, Joanne;Beitler, Jonathan;Gaur, Rakesh;Curran, Walter, Jr.;Choy, Hak
我们的目的是比较标准剂量与高剂量适形放疗联合同步化疗以及在同步放化疗基础上加用西妥昔单抗治疗不能手术的III期非小细胞肺癌患者的总生存率。在这项在美国和加拿大185家机构进行的开放标签、随机、2 × 2析因III期研究中，我们入组了不可切除的III期非小细胞肺癌患者（年龄≥ 18岁），Zubrod体力状态为0-1，肺功能良好，无锁骨上或对侧肺门淋巴结肿大的证据。我们将患者随机分配（1：1：1：1）接受60戈伊（标准剂量）、74戈伊（高剂量）、60戈伊+西妥昔单抗或74戈伊+西妥昔单抗。所有患者同时接受紫杉醇45 mg/m2和卡铂每周1次（AUC 2）化疗;放化疗后2周，给予2个周期的巩固化疗，其中紫杉醇（200 mg/m2）和卡铂（AUC 6）间隔3周。采用排列区组随机化方法进行随机化，按放射治疗技术、Zubrod体能状态、分期期间PET的使用和组织学分层;治疗组分配未设盲。根据计划靶区规定放射剂量，采用调强放射治疗或三维适形放射治疗，每日分次给予2戈伊。鼓励使用四维CT和图像引导放射治疗，但不是必要的。对于分配接受西妥昔单抗治疗的患者，在第1天给予400 mg/m2西妥昔单抗，随后每周给予250 mg/m2，并持续接受巩固治疗。主要终点是总生存期。所有分析均通过改良的意向治疗进行，该研究在ClinicalTrials.gov注册，编号为NCT 00533949。在2007年11月27日至2011年11月22日期间，166例患者被随机分配接受标准剂量放化疗，121例接受高剂量放化疗，147例接受标准剂量放化疗和西妥昔单抗，110例接受高剂量放化疗和西妥昔单抗。放疗比较的中位随访时间为22.9个月（IQR 27.5 - 33.3）。接受标准剂量放疗的患者中位总生存期为28.7个月（95%CI 24.1 - 36.9），接受高剂量放疗的患者中位总生存期为20.3个月（17.7 - 25.0）（风险比[HR] 1.38，95%CI 1.09 - 1.76; p= 0.004）。西妥昔单抗比较的中位随访时间为21.3个月（IQR 23.5 - 29.8）。接受西妥昔单抗治疗的患者中位总生存期为25.0个月（95%CI 20.2 - 30.5），而未接受西妥昔单抗治疗的患者中位总生存期为24.0个月（19.8 - 28.6）（HR 1.07，95%CI 0.84 - 1.35; p= 0.29）。放射剂量和西妥昔单抗结果均超出方案规定的无效边界。我们没有记录到放射治疗组之间3级或更严重的毒性反应的统计学差异。相比之下，使用西妥昔单抗与3级或更严重毒性反应的发生率更高相关（237例患者中的205例[86%] vs 228例患者中的160例[70%]; p<0.0001）。高剂量放化疗组和西妥昔单抗组有更多的治疗相关死亡（放疗组比较：8例vs 3例;西妥昔单抗组比较：10例vs 5例）。治疗组间重度肺部事件无差异。重度食管炎在接受高剂量放化疗的患者中比接受标准剂量治疗的患者更常见（207例患者中43例[21%] vs 217例患者中16例[7%]; p<0.0001）。74戈伊放疗2次戈伊同步化疗对III期非小细胞肺癌患者的疗效不如60戈伊同步化疗，且可能存在潜在危害。在同步放化疗和巩固治疗的基础上加用西妥昔单抗对这些患者的总生存期没有益处。国家癌症研究所和百时美施贵宝。
We aimed to compare overall survival after standard-dose versus high-dose conformal radiotherapy with concurrent chemotherapy and the addition of cetuximab to concurrent chemoradiation for patients with inoperable stage III non-small-cell lung cancer. In this open-label randomised, two-by-two factorial phase 3 study in 185 institutions in the USA and Canada, we enrolled patients (aged ≥ 18 years) with unresectable stage III non-small-cell lung cancer, a Zubrod performance status of 0–1, adequate pulmonary function, and no evidence of supraclavicular or contralateral hilar adenopathy. We randomly assigned (1:1:1:1) patients to receive either 60 Gy (standard dose), 74 Gy (high dose), 60 Gy plus cetuximab, or 74 Gy plus cetuximab. All patients also received concurrent chemotherapy with 45 mg/m2 paclitaxel and carboplatin once a week (AUC 2); 2 weeks after chemoradiation, two cycles of consolidation chemotherapy separated by 3 weeks were given consisting of paclitaxel (200 mg/m2) and carboplatin (AUC 6). Randomisation was done with permuted block randomisation methods, stratified by radiotherapy technique, Zubrod performance status, use of PET during staging, and histology; treatment group assignments were not masked. Radiation dose was prescribed to the planning target volume and was given in 2 Gy daily fractions with either intensity-modulated radiation therapy or three-dimensional conformal radiation therapy. The use of four-dimensional CT and image-guided radiation therapy were encouraged but not necessary. For patients assigned to receive cetuximab, 400 mg/m2 cetuximab was given on day 1 followed by weekly doses of 250 mg/m2, and was continued through consolidation therapy. The primary endpoint was overall survival. All analyses were done by modified intention-to-treat. The study is registered with ClinicalTrials.gov, number NCT00533949. Between Nov 27, 2007, and Nov 22, 2011, 166 patients were randomly assigned to receive standard-dose chemoradiotherapy, 121 to high-dose chemoradiotherapy, 147 to standard-dose chemoradiotherapy and cetuximab, and 110 to high-dose chemoradiotherapy and cetuximab. Median follow-up for the radiotherapy comparison was 22·9 months (IQR 27·5–33·3). Median overall survival was 28·7 months (95% CI 24·1–36·9) for patients who received standard-dose radiotherapy and 20·3 months (17·7–25·0) for those who received high-dose radiotherapy (hazard ratio [HR] 1·38, 95% CI 1·09–1·76; p=0·004). Median follow-up for the cetuximab comparison was 21·3 months (IQR 23·5–29·8). Median overall survival in patients who received cetuximab was 25·0 months (95% CI 20·2–30·5) compared with 24·0 months (19·8–28·6) in those who did not (HR 1·07, 95% CI 0·84–1·35; p=0·29). Both the radiation-dose and cetuximab results crossed protocol-specified futility boundaries. We recorded no statistical differences in grade 3 or worse toxic effects between radiotherapy groups. By contrast, the use of cetuximab was associated with a higher rate of grade 3 or worse toxic effects (205 [86%] of 237 vs 160 [70%] of 228 patients; p<0·0001). There were more treatment-related deaths in the high-dose chemoradiotherapy and cetuximab groups (radiotherapy comparison: eight vs three patients; cetuximab comparison: ten vs five patients). There were no differences in severe pulmonary events between treatment groups. Severe oesophagitis was more common in patients who received high-dose chemoradiotherapy than in those who received standard-dose treatment (43 [21%] of 207 patients vs 16 [7%] of 217 patients; p<0·0001). 74 Gy radiation given in 2 Gy fractions with concurrent chemotherapy was not better than 60 Gy plus concurrent chemotherapy for patients with stage III non-small-cell lung cancer, and might be potentially harmful. Addition of cetuximab to concurrent chemoradiation and consolidation treatment provided no benefit in overall survival for these patients. National Cancer Institute and Bristol-Myers Squibb.