Goethe-University Frankfurt, University Hospital, Department of Radiotherapy, Frankfurt, Germany.
Frankfurt Cancer Institute, Frankfurt, Germany.
JAMA Netw Open. 2024 Sep 3;7(9):e2432927. doi: 10.1001/jamanetworkopen.2024.32927.
Patients with locally advanced rectal cancer and persistent lymph node metastases (PLNM) after neoadjuvant treatment are at high risk of developing locoregional and distant metastasis, yet optimal postsurgical treatment of these patients is limited.
To analyze the association of PLNM with pretreatment clinical parameters, intensity of neoadjuvant treatment, and long-term oncological outcomes.
DESIGN, SETTING, AND PARTICIPANTS: This cohort study is a post-hoc analysis of 3 randomized clinical trials (Surgical Oncology Working Group of Germany [CAO], Radiological Oncology Working Group of Germany [ARO], and Working Group for Internal Oncology in the German Cancer Society [AIO]) conducted in Germany in 1994, 2004, and 2012 that included 1948 patients with locally advanced rectal cancer recruited between February 1995 and January 2018. Statistical analysis was conducted between September 2023 and February 2024.
Receiving preoperative fluorouracil-based chemoradiotherapy (CRT, comprising the preoperative group of CAO/ARO/AIO-94 and the control group of CAO/ARO/AIO-04), fluorouracil-based CRT plus oxaliplatin (experimental group of CAO/ARO/AIO-04), or total neoadjuvant treatment (TNT) with fluorouracil-based CRT plus oxaliplatin with induction or consolidation leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin chemotherapy within the CAO/ARO/AIO-12 trial.
The associations of PLNM with clinical parameters, intensity of neoadjuvant treatment, and cumulative incidences of LR, DM, and overall survival were assessed.
A total of 1888 patients (1333 male participants [70.6%]; median [range] age, 62 [19-84] years) with locally advanced rectal adenocarcinoma (clinical tumor stage 3 to 4 and/or clinically node-positive) treated within 3 consecutive clinical trials were analyzed. A total of 522 (29%) experienced PLNM; 378 had lymph node stage (ypN) 1 (20%) after neoadjuvant treatment (ypN) 1 (20%), and 174 had ypN2 (9%). Age, clinical T-stage, N-stage, grading, carcinoembryonic antigen levels, and time interval from completion of CRT to surgery were significantly associated with PLNM, whereas sex and tumor location were not. The percentage of patients with ypN2 stage was almost halved after TNT (18 of 293 patients [6%]) compared with patients treated with fluorouracil-based CRT (114 of 1009 patients [11.3%]; χ26 = 16.693; P = .01). After a median (IQR) follow-up of 54 (37-62) months, 5-year overall survival was 86.1% (95% CI, 83.9%-88.4%) for ypN0, 74.0% (95% CI, 83.9%-88.4%) for ypN1, and 43% for ypN2 (95% CI, 35.4%-52.2%) (P < .001). The 5-year cumulative incidences of locoregional and distant metastases were, respectively, 3% (95% CI, 2.1%-4.2%) and 20% (95% CI, 18%-23%) for ypN0, 6% (95% CI, 3.4%-8.8%) and 40% (95% CI, 34%-46%) for ypN1, and 19% (95% CI, 13%-26%) and 72% (95% CI, 63%-79%) for ypN2 (both P < .001).
In this cohort study, PLNM unmasked an unfavorable phenotype of rectal cancer at high risk for treatment failure. More aggressive adjuvant treatment might be considered; however, risk-adapted surveillance strategies and early recurrence-directed surgery, if feasible, are important strategies in this group of patients with CRT- and/or chemotherapy-resistant disease.
新辅助治疗后仍存在局部淋巴结转移 (PLNM) 的局部晚期直肠癌患者发生局部区域和远处转移的风险很高，但这些患者的最佳术后治疗方法有限。
分析 PLNM 与治疗前临床参数、新辅助治疗强度和长期肿瘤学结局的关系。
设计、地点和参与者：这是一项对德国外科肿瘤学工作组（CAO）、放射肿瘤学工作组（ARO）和德国癌症协会内部肿瘤学工作组（AIO）进行的 3 项随机临床试验（Surgical Oncology Working Group of Germany [CAO]、Radiological Oncology Working Group of Germany [ARO] 和 Working Group for Internal Oncology in the German Cancer Society [AIO]）的事后分析，这些试验于 1994 年、2004 年和 2012 年在德国进行，共纳入 1948 例局部晚期直肠腺癌患者，招募时间为 1995 年 2 月至 2018 年 1 月。统计分析于 2023 年 9 月至 2024 年 2 月进行。
接受术前氟尿嘧啶为基础的放化疗（包括 CAO/ARO/AIO-94 的术前组和 CAO/ARO/AIO-04 的对照组）、氟尿嘧啶为基础的 CRT 加奥沙利铂（CAO/ARO/AIO-04 的实验组）或 CAO/ARO/AIO-12 试验中氟尿嘧啶为基础的 CRT 加奥沙利铂联合诱导或巩固亚叶酸钙（叶酸）、氟尿嘧啶和奥沙利铂化疗的全新辅助治疗。
评估了 PLNM 与临床参数、新辅助治疗强度以及局部复发、远处转移和总生存的累积发生率之间的关系。
对 3 项连续临床试验中 1888 例局部晚期直肠腺癌（临床肿瘤分期 3 至 4 期和/或临床淋巴结阳性）患者进行了分析。522 例（29%）发生 PLNM；378 例在新辅助治疗后（ypN）1（20%）存在淋巴结分期（ypN）1（20%），174 例存在 ypN2（9%）。年龄、临床 T 分期、N 分期、分级、癌胚抗原水平以及 CRT 完成至手术的时间间隔与 PLNM 显著相关，而性别和肿瘤位置则无相关性。与接受氟尿嘧啶为基础的 CRT 治疗的患者（1009 例中的 114 例 [11.3%]）相比，接受全新辅助治疗的患者（293 例中的 18 例 [6%]）ypN2 分期的患者比例几乎减半（χ26=16.693；P=.01）。中位（IQR）随访 54（37-62）个月后，ypN0 患者的 5 年总生存率为 86.1%（95%CI，83.9%-88.4%），ypN1 患者为 74.0%（95%CI，83.9%-88.4%），ypN2 患者为 43%（95%CI，35.4%-52.2%）（P<0.001）。ypN0 患者的 5 年局部区域和远处转移累积发生率分别为 3%（95%CI，2.1%-4.2%）和 20%（95%CI，18%-23%），ypN1 患者分别为 6%（95%CI，3.4%-8.8%）和 40%（95%CI，34%-46%），ypN2 患者分别为 19%（95%CI，13%-26%）和 72%（95%CI，63%-79%）（均 P<0.001）。
在这项队列研究中，PLNM 揭示了局部晚期直肠癌的一种不良表型，这些患者发生治疗失败的风险较高。可能需要更积极的辅助治疗；然而，风险适应性监测策略和早期复发导向手术（如果可行）是这组 CRT 和/或化疗耐药疾病患者的重要策略。
