Effect of the Addition of Cetuximab to Paclitaxel, Cisplatin, and Radiation Therapy for Patients With Esophageal Cancer The NRG Oncology RTOG 0436 Phase 3 Randomized Clinical Trial
Effect of the Addition of Cetuximab to Paclitaxel, Cisplatin, and Radiation Therapy for Patients With Esophageal Cancer The NRG Oncology RTOG 0436 Phase 3 Randomized Clinical Trial
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DOI：
10.1001/jamaoncol.2017.1598
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发表时间：
2017-11-01
期刊：
影响因子：
28.4
通讯作者：
Crane, Christopher H.
中科院分区：
文献类型：
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作者：
Suntharalingam, Mohan;Winter, Kathryn;Crane, Christopher H.
重要性表皮生长因子受体（EGFR）抑制在食管癌患者非手术治疗中的放化疗策略中的作用尚不明确。目的评价西妥昔单抗加用同步放化疗对食管癌患者非手术治疗的益处。随机临床试验向活检证实的食道癌患者开放。该研究从2008年至2013年招募了344名患者。干预患者随机接受每周一次的顺铂治疗（50 mg/m2），紫杉醇（25毫克/米（2）），每日放疗50.4戈伊/1.8戈伊分次，每周给予或不给予西妥昔单抗（第1天400 mg/m2，然后每周250 mg/m2）。主要结果和测量总生存期（OS）是主要终点，研究设计检测2年OS从41%增加到53%; 80%的把握度和单侧a = 0.025。结果2008年6月30日至2013年2月8日，344例患者入组。该分析使用了截至2015年4月12日在NRG Oncology收到的所有数据。16例患者不合格，导致328例可评估患者，159例在实验组，169例在对照组。患者在患者和肿瘤特征方面在治疗组之间匹配良好：263例（80%）为T3或T4疾病，215例（66%）为N1，62例（19%）为腹腔淋巴结受累。在任何时间，试验组中3级、4级或5级治疗相关不良事件的发生率分别为71例（46%）、35例（23%）或6例（4%），对照组分别为83例（50%）、28例（17%）或2例（1%）。在实验组中观察到临床完全缓解（cCR）率为81（56%），对照组为92（58%）（Fisher精确检验，P = 0.66）。两个治疗组的cCR在组织学（腺癌或鳞状细胞）方面均无差异。所有患者的中位随访时间为18.6个月。试验组24个月和36个月局部失败率分别为47%（95% CI，38%-57%）和49%（95% CI，40%-59%），对照组分别为49%（95% CI，41%-58%）和49%（95% CI，41%-58%）（HR，0.92; 95% CI，0.66-1.28; P = 0.65）。实验组的24和36个月OS率为45%（95% CI，37%-53%）和34%（95% CI，26%-41%）vs 44%（95% CI，36%-51%）和28%对照组（95% CI，21%-35%）（HR，0.90; 95% CI，0.70-1.16;结论和相关性在同步放化疗中加入西妥昔单抗并不能改善OS。这些3期试验结果表明，目前的EGFR-1抑制剂对治疗没有什么益处。靶向药物在食管癌患者人群中的应用，并强调了在食管癌治疗中对预测性生物标志物的需求。
IMPORTANCE The role of epidermal growth factor receptor (EGFR) inhibition in chemoradiation strategies in the nonoperative treatment of patients with esophageal cancer remains uncertain.OBJECTIVE To evaluate the benefit of cetuximab added to concurrent chemoradiation therapy for patients undergoing nonoperative treatment of esophageal carcinoma.DESIGN, SETTING, AND PARTICIPANTS A National Cancer Institute (NCI) sponsored, multicenter, phase 3, randomized clinical trial open to patients with biopsy-proven carcinoma of the esophagus. The study accrued 344 patients from 2008 to 2013.INTERVENTIONS Patients were randomized to weekly concurrent cisplatin (50 mg/m(2)), paclitaxel (25 mg/m(2)), and daily radiation of 50.4 Gy/1.8 Gy fractions with or without weekly cetuximab (400 mg/m(2) on day 1 then 250 mg/m(2) weekly).MAIN OUTCOMES AND MEASURES Overall survival (OS) was the primary endpoint, with a study designed to detect an increase in 2-year OS from 41% to 53%; 80% power and 1-sided a = .025.RESULTS Between June 30, 2008, and February 8, 2013, 344 patients were enrolled. This analysis used all data received at NRG Oncology through April 12, 2015. Sixteen patients were ineligible, resulting in 328 evaluable patients, 159 in the experimental arm and 169 in the control arm. Patients were well matched between the treatment arms for patient and tumor characteristics: 263 (80%) with T3 or T4 disease, 215 (66%) N1, and 62 (19%) with celiac nodal involvement. Incidence of grade 3, 4, or 5 treatment-related adverse events at any time was 71 (46%), 35 (23%), or 6 (4%) in the experimental arm and 83 (50%), 28 (17%), or 2 (1%) in the control arm, respectively. A clinical complete response (cCR) rate of 81 (56%) was observed in the experimental arm vs 92 (58%) in the control arm (Fisher exact test, P = .66). No differences were seen in cCR between treatment arms for either histology (adenocarcinoma or squamous cell). Median follow-up for all patients was 18.6 months. The 24- and 36-month local failure for the experimental arm was 47%(95% CI, 38%-57%) and 49%(95% CI, 40%-59%) vs 49%(95% CI, 41%-58%) and 49%(95% CI, 41%-58%) for the control arm (HR, 0.92; 95% CI, 0.66-1.28; P = .65). The 24- and 36-month OS rates for the experimental arm were 45%(95% CI, 37%-53%) and 34%(95% CI, 26%-41%) vs 44%(95% CI, 36%-51%) and 28%(95% CI, 21%-35%) for the control arm (HR, 0.90; 95% CI, 0.70-1.16; P = .47).CONCLUSIONS AND RELEVANCE The addition of cetuximab to concurrent chemoradiation did not improve OS. These phase 3 trial results point to little benefit to current EGFR-targeted agents in an unselected patient population, and highlight the need for predictive biomarkers in the treatment of esophageal cancer.