美国韦恩州立大学Anthony F. Shields联合丹娜-法伯癌症研究所Jeffrey A. Meyerhardt团队，比较了塞来昔布与安慰剂联合标准辅助治疗对Ⅲ期结肠癌患者无病生存率的影响。2021年4月6日，《美国医学会杂志》发表了这一成果。

在观察性和随机研究中，阿司匹林和环氧合酶2（COX-2）抑制剂与结直肠息肉和癌症的风险降低有关。COX-2抑制剂塞来昔布治疗非转移性结肠癌的疗效尚不清楚。

为了探讨在辅助化疗中加入塞来昔布和氟尿嘧啶、亚叶酸和奥沙利铂（FOLFOX）是否能提高Ⅲ期结肠癌患者的无病生存率，研究组在美国和加拿大的654个社区和学术中心进行了一项2×2析因设计的临床3期试验，2010年6月至2015年11月，共招募了2526名III期结肠癌患者，并随访至2020年8月10日。

将患者随机分组，分别服用佐剂FOLFOX（每2周一次）3个月和6个月，其中1263名服用3年塞来昔布，1261名服用3年安慰剂。主要终点是无病生存率，从分组时间开始，直到记录的任何原因的复发或死亡。次要终点包括总生存率、不良事件和心血管特异性事件。

2526例患者的平均年龄为61.0岁，其中1134例为女性，占44.9%，共有2524例被纳入初步分析。方案治疗的依从性为接受塞来昔布或安慰剂治疗超过2.75年或持续治疗直到复发、死亡或不可接受的不良事件，塞来昔布组患者依从性为70.8%，安慰剂组为69.9%。塞来昔布组中共有337名患者出现疾病复发或死亡，安慰剂组中有363名；塞来昔布组患者的3年无病生存率为76.3%，安慰剂组为73.4%。

塞来昔布治疗对无病生存率的影响在指定的辅助化疗持续时间内没有显著差异。塞来昔布组5年总生存率为84.3%，安慰剂组为81.6%。塞来昔布组有14.6%的患者在使用FOLFOX治疗时发生高血压，安慰剂组有10.9%；塞来昔布组在FOLFOX治疗完成后有1.7%的患者发生肌酐水平2级及以上升高，安慰剂组有0.5%。

研究结果表明，对于III期结肠癌患者，与安慰剂相比，在标准辅助化疗中加入塞来昔布治疗3年并没有显著提高无病生存率。

附：英文原文

Title: Effect of Celecoxib vs Placebo Added to Standard Adjuvant Therapy on Disease-Free Survival Among Patients With Stage III Colon Cancer: The CALGB/SWOG 80702 (Alliance) Randomized Clinical Trial

Author: Jeffrey A. Meyerhardt, Qian Shi, Charles S. Fuchs, Jeffrey Meyer, Donna Niedzwiecki, Tyler Zemla, Priya Kumthekar, Katherine A. Guthrie, Felix Couture, Philip Kuebler, Johanna C. Bendell, Pankaj Kumar, Dequincy Lewis, Benjamin Tan, Monica Bertagnolli, Axel Grothey, Howard S. Hochster, Richard M. Goldberg, Alan Venook, Charles Blanke, Eileen M. O’Reilly, Anthony F. Shields

Issue&Volume: 2021/04/06

Abstract:

Importance  Aspirin and cyclooxygenase 2 (COX-2) inhibitors have been associated with a reduced risk of colorectal polyps and cancer in observational and randomized studies. The effect of celecoxib, a COX-2 inhibitor, as treatment for nonmetastatic colon cancer is unknown.

Objective  To determine if the addition of celecoxib to adjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) improves disease-free survival in patients with stage III colon cancer.

Design, Setting, and Participants  Cancer and Leukemia Group B (Alliance)/Southwest Oncology Group 80702 was a 2×2 factorial design, phase 3 trial conducted at 654 community and academic centers throughout the United States and Canada. A total of 2526 patients with stage III colon cancer were enrolled between June 2010 and November 2015 and were followed up through August 10, 2020.

Interventions  Patients were randomized to receive adjuvant FOLFOX (every 2 weeks) for 3 vs 6 months with or without 3 years of celecoxib (400 mg orally daily; n=1263) vs placebo (n=1261). This report focuses on the results of the celecoxib randomization.

Main Outcomes and Measures  The primary end point was disease-free survival, measured from the time of randomization until documented recurrence or death from any cause. Secondary end points included overall survival, adverse events, and cardiovascular-specific events.

Results  Of the 2526 patients who were randomized (mean [SD] age, 61.0 years [11 years]; 1134 women [44.9%]), 2524 were included in the primary analysis. Adherence with protocol treatment, defined as receiving celecoxib or placebo for more than 2.75 years or continuing treatment until recurrence, death, or unacceptable adverse events, was 70.8% for patients treated with celecoxib and 69.9% for patients treated with placebo. A total of 337 patients randomized to celecoxib and 363 to placebo experienced disease recurrence or died, and with 6 years’ median follow-up, the 3-year disease-free survival was 76.3% for celecoxib-treated patients vs 73.4% for placebo-treated patients (hazard ratio [HR] for disease recurrence or death, 0.89; 95% CI, 0.76-1.03; P=.12). The effect of celecoxib treatment on disease-free survival did not vary significantly according to assigned duration of adjuvant chemotherapy (P for interaction=.61). Five-year overall survival was 84.3% for celecoxib vs 81.6% for placebo (HR for death, 0.86; 95% CI, 0.72-1.04; P=.13). Hypertension (any grade) occurred while treated with FOLFOX in 14.6% of patients in the celecoxib group vs 10.9% of patients in the placebo group, and a grade 2 or higher increase in creatinine levels occurred after completion of FOLFOX in 1.7% vs 0.5% of patients, respectively.

Conclusions and Relevance  Among patients with stage III colon cancer, the addition of celecoxib for 3 years, compared with placebo, to standard adjuvant chemotherapy did not significantly improve disease-free survival.

DOI: 10.1001/jama.2021.2454

Source: https://jamanetwork.com/journals/jama/article-abstract/2778113