Chemotherapy for patients with circulating tumour DNA-positive, stage II colon cancer (CIRCULATE)-an AIO/ABCSG trial.

Post-operative circulating tumour DNA (ctDNA) has higher prognostic value than classical clinical markers, with ctDNA positivity indicating an unfavourable outcome.

术后循环肿瘤DNA（ctDNA）的预后价值高于经典临床标志物，ctDNA阳性表明预后不佳。

patients_and_methods

Patients with Union for International Cancer Control stage II, mismatch repair proficient/microsatellite stable colon cancer were tested for ctDNA using an academic, tumour-informed, next-generation sequencing-based test. ctDNA-positive patients were randomly assigned 2:1 to CHEMO (capecitabine ± oxaliplatin) or observation (OBS). ctDNA-negative patients were randomly assigned 1:4 to OBS or OFF-STUDY. ctDNA results were not disclosed in the OBS group.

使用学术性的肿瘤信息指导的下一代测序基础检测，对肿瘤分期为国际抗癌联盟II期、错配修复功能正常/微卫星稳定型结直肠癌患者进行循环肿瘤DNA（ctDNA）检测。ctDNA阳性患者按2:1比例随机分配至化疗组（卡培他滨±奥沙利铂）或观察组（OBS）。ctDNA阴性患者按1:4比例随机分配至OBS组或退出研究组。OBS组中未披露ctDNA检测结果。

The primary endpoint was disease-free survival (DFS) in ctDNA-positive patients.

主要终点是ctDNA阳性患者的无病生存期（DFS）。

All differences were tested using one-sided log-rank tests.

所有差异均使用单侧对数秩检验进行测试。

The trial ended early due to funding expiry.

由于资金耗尽，该试验提前结束。

Results

From June 2020 to July 2025, 2126 patients were screened in Germany and Austria.

从2020年6月到2025年7月，在德国和奥地利共有2126名患者接受了筛查。

Overall, 1396 patients (2.9% ctDNA-positive) were randomly assigned: 1083 to OFF-STUDY, 287 to OBS, and 26 to CHEMO, of whom 81% started therapy.

总体而言，1396名患者（其中2.9%的患者ctDNA阳性）被随机分配：1083名患者退出研究，287名患者接受观察（OBS），26名患者接受化疗（CHEMO），其中81%的患者开始了治疗。

DFS and overall survival(OS) were significantly worse in ctDNA-positive versus ctDNA-negative patients [3-year DFS 52% versus 87%, hazard ratio(HR) 4.28, 95% confidence interval(CI) 2.32-7.93, P < 0.001; 3-year OS 88% versus 98%, HR 5.48, 95% CI 1.64-18.28, P = 0.001].

无复发生存期（DFS）和总生存（OS）在 ctDNA 阳性患者中显著比 ctDNA 阴性患者差 [3年 DFS 为 52% 对比 87%，风险比（HR）为 4.28，95% 置信区间（CI）为 2.32-7.93，P < 0.001；3年 OS 为 88% 对比 98%，HR 为 5.48，95% CI 为 1.64-18.28，P = 0.001].

In the intention-to-treat(ITT) cohort, the between-arm differences were not significant (3-year recurrence 36% versus 62%, HR 0.48, 95% CI 0.17-1.33, P = 0.075; 3-year DFS 61% versus 38%, HR 0.55, 95% CI 0.21-1.48, P = 0.12).

在意向治疗（ITT）队列中，两组之间的差异不显著（3年复发率为 36% 对比 62%，HR 为 0.48，95% CI 为 0.17-1.33，P = 0.075；3年 DFS 为 61% 对比 38%，HR 为 0.55，95% CI 为 0.21-1.48，P = 0.12）

In the per-protocol analysis (excluding untreated CHEMO patients), time to recurrence and DFS were improved with CHEMO compared with OBS (3-year recurrence 19% versus 62%, HR 0.23, 95% CI 0.06-0.87, P = 0.009; 3-year DFS 77% versus 38%, HR 0.31, 95% CI 0.09-1.03, P = 0.021).

在按方案分析中（排除未接受化疗的CHEMO患者），与OBS相比，化疗组的复发时间和无病生存期得到改善（3年复发率为19%对比62%，风险比为0.23，95%置信区间为0.06-0.87，P = 0.009；3年无病生存率为77%对比38%，风险比为0.31，95%置信区间为0.09-1.03，P = 0.021）。

Conclusions

The primary ITT endpoint was not met, potentially related to the reduced power due to premature trial closure.

主要的意向性治疗（ITT）终点未达到，可能与由于提前终止试验导致的统计功效降低有关。

The per-protocol analysis suggests a benefit from adjuvant therapy in ctDNA-positive patients, supporting ctDNA testing for adjuvant decision making in the future.

意向性分析表明，在ctDNA阳性患者中，辅助治疗有益，支持未来在辅助决策中使用ctDNA检测。