新辅助直肠评分作为 CAO/ARO/AIO-04 随机 III 期临床试验中直肠癌无病生存的个体水平替代指标。

Neoadjuvant rectal score as individual-level surrogate for disease-free survival in rectal cancer in the CAO/ARO/AIO-04 randomized phase III trial.

机构信息

Department of Radiotherapy and Oncology, University of Frankfurt, Frankfurt, Germany; German Cancer Research Center (DKFZ), Heidelberg; German Cancer Consortium (DKTK), Partner Site: Frankfurt, Germany.

Department of Radiation Therapy, University of Erlangen-Nürnberg, Erlangen, Germany.

出版信息

Ann Oncol. 2018 Jul 1;29(7):1521-1527. doi: 10.1093/annonc/mdy143.

DOI:10.1093/annonc/mdy143

PMID:29718095

Abstract

BACKGROUND

Surrogate end points in rectal cancer after preoperative chemoradiation are lacking as their statistical validation poses major challenges, including confirmation based on large phase III trials. We examined the prognostic role and individual-level surrogacy of neoadjuvant rectal (NAR) score that incorporates weighted cT, ypT and ypN categories for disease-free survival (DFS) in 1191 patients with rectal carcinoma treated within the CAO/ARO/AIO-04 phase III trial.

PATIENTS AND METHODS

Cox regression models adjusted for treatment arm, resection status, and NAR score were used in multivariable analysis. The four Prentice criteria (PC1-4) were used to assess individual-level surrogacy of NAR for DFS.

RESULTS

After a median follow-up of 50 months, the addition of oxaliplatin to fluorouracil-based chemoradiotherapy (CRT) significantly improved 3-year DFS [75.9% (95% confidence interval [CI] 72.30% to 79.50%) versus 71.3% (95% CI 67.60% to 74.90%); P = 0.034; PC 1) and resulted in a shift toward lower NAR groups (P = 0.034, PC 2) compared with fluorouracil-only CRT. The 3-year DFS was 91.7% (95% CI 88.2% to 95.2%), 81.8% (95% CI 78.4% to 85.1%), and 58.1% (95% CI 52.4% to 63.9%) for low, intermediate, and high NAR score, respectively (P < 0.001; PC 3). NAR score remained an independent prognostic factor for DFS [low versus high NAR: hazard ratio (HR) 4.670; 95% CI 3.106-7.020; P < 0.001; low versus intermediate NAR: HR 1.971; 95% CI 1.303-2.98; P = 0.001] in multivariable analysis. Notwithstanding the inherent methodological difficulty in interpretation of PC 4 to establish surrogacy, the treatment effect on DFS was captured by NAR, supporting satisfaction of individual-level PC 4.

CONCLUSION

Our study validates the prognostic role and individual-level surrogacy of NAR score for DFS within a large randomized phase III trial. NAR score could help oncologists to speed up response-adapted therapeutic decision, and further large phase III trial data sets should aim to confirm trial-level surrogacy.

摘要

背景

术前放化疗后直肠癌的替代终点缺乏统计学验证，因为这存在重大挑战，包括基于大型 III 期试验的确认。我们在 CAO/ARO/AIO-04 期 III 期试验中检查了新辅助直肠 (NAR) 评分在 1191 例直肠癌患者中的预后作用和疾病无进展生存 (DFS) 的个体水平替代关系，该评分纳入了加权 cT、ypT 和 ypN 类别。

患者和方法

使用多变量分析中的 Cox 回归模型调整治疗臂、切除状态和 NAR 评分。使用 Prentice 四项标准 (PC1-4) 评估 NAR 对 DFS 的个体水平替代关系。

结果

中位随访 50 个月后，与氟尿嘧啶为基础的放化疗相比，奥沙利铂联合氟尿嘧啶为基础的放化疗 (CRT) 显著提高了 3 年 DFS [75.9% (95%CI 72.30%至 79.50%)比 71.3% (95%CI 67.60%至 74.90%); P=0.034;PC1)，并导致 NAR 组向较低水平转移 (P=0.034，PC2)，与仅氟尿嘧啶 CRT 相比。低、中、高 NAR 评分的 3 年 DFS 分别为 91.7% (95%CI 88.2%至 95.2%)、81.8% (95%CI 78.4%至 85.1%)和 58.1% (95%CI 52.4%至 63.9%) (P<0.001;PC3)。NAR 评分仍然是 DFS 的独立预后因素 [低 NAR 与高 NAR：危险比 (HR) 4.670;95%CI 3.106-7.020;P<0.001;低 NAR 与中 NAR：HR 1.971;95%CI 1.303-2.98;P=0.001]，在多变量分析中。尽管解释 PC4 以确定替代关系的内在方法学困难，但 NAR 捕获了对 DFS 的治疗效果，支持满足个体水平 PC4。