编者按：2024年美国临床肿瘤学会胃肠道肿瘤研讨会（ASCO GI 2024）将于当地时间2024年1月18日-20日在美国旧金山举行。作为胃肠道肿瘤领域最高水平的世界级学术盛会之一，本次大会汇集了全球的肿瘤学家汇报胃肠道肿瘤领域的研究进展。北京时间2024年1月17日上午ASCO GI官网公布了除LBA摘要外其他全部摘要内容，本文对结直肠癌领域口头报告专场研究内容进行介绍，以飨读者。

循环肿瘤DNA作为II期结肠癌患者辅助化疗的预测性生物标志物的II期研究结果：NRG-GI005（COBRA）II/III期研究

背景

方法

结果

结论

本研究II期研究终点未达到，根据预先指定的研究停止规则，停止了进一步患者招募。对于IIA期 CC切除后检测到ctDNA的患者，化疗6个月后未观察到ctDNA清除率的改善。因此，未来研究如果打算应用ctDNA作为确定微小残留病变的整体生物标志物的必须考虑患者人群的检测特异性。

临床试验信息

在具有分子残留病灶的结直肠癌患者中ctDNA动态变化：来自CIRCULATE-JAPAN的GALAXY研究的最新结果

摘要号：6

背景

方法

结果

结论

基于ctDNA的MRD检测和ACT治疗有效的ctDNA动态变化检测是患者结局的最显著预后因素。CIRCULATE-Japan项目正在进行的VEGA和ALTAIR随机研究将确立ctDNA引导辅助治疗的临床效用。

03

直肠癌器官保留：临床完全缓解后等待观察有哪些风险？数据来自2个国际直肠癌注册中心

摘要号：7

背景

方法

结果

结论

WW后发生LR是DM的一个重要且独立的危险因素，最终病理缓解是后续DM的危险因素。无论最终的ypT和ypN状态如何，局部复发的患者比TME治疗再分期患者发生DM的风险更高。原发性不可检测的肿瘤发生局部复发后其预后更差。未来纳入器官保留策略的研究应关注最终发生局部复发的患者发生DM的风险，这是临床相关主要终点之一。

腹腔镜辅助手术与开腹手术对低位直肠癌患者3年无病生存率的影响：LASRE随机临床研究

摘要号：8

背景

方法

结果

结论

在低位直肠癌患者中，由经验丰富的外科医生实施的腹腔镜手术在3年无病生存期方面不劣于开腹手术，结果支持腹腔镜手术是治疗低位直肠癌的安全、微创方法。

摘要原文

（一）

Phase II results of circulating tumor DNA as a predictive biomarker in adjuvant chemotherapy in patients with stage II colon cancer：NRG-GI005 （COBRA） phase II/III study

Background：

For patients （pts） with colon cancer （CC）， the detection of circulating tumor DNA （ctDNA） is associated with persistent disease after resection and outperforms traditional clinical and pathological features in prognosticating recurrence risk. We hypothesized that for pts with low-risk stage II CC, a positive ctDNA status after resection may identify those who benefit from adjuvant chemotherapy.

Methods：

In this prospective phase II/III clinical trial, pts with resected stage II CC without traditional high risk features and whom the evaluating oncologist deems suitable for active surveillance （i.e., not needing adjuvant chemotherapy） were randomized 1：1 to two arms：standard-of-care/observation （Arm A）， or ctDNA assay directed therapy （Arm B）. Postoperative blood was analyzed for ctDNA with the Guardant LUNAR assay, covering CC-relevant mutations and CC-specific methylation profiling. Arm B pts with ctDNA detected were treated with 6 mos of adjuvant （CAPOX or FOLFOX） chemotherapy. Primary endpoint for the phase II study was clearance of ctDNA at the 6-mo timepoint. A 1-sided Fisher exact test was used to compare ctDNA clearance between Arm A and Arm B among the first 16 pts with ctDNA detected at baseline. If p>35, the study would be stopped for futility of ctDNA clearance but would otherwise continue to phase III if p≤.35. We present the results of the pre-planned phase II analysis.

Results：

635 pts were randomized （Arm A：318; Arm B：317）. One pt with ctDNA detected in Arm B declined protocol-directed chemotherapy but was included in the intention to treat analysis. Among the first 16 pts with ctDNA detected at baseline for the primary endpoint analysis, clearance of ctDNA after 6 mos was observed in 3/7 pts （43%, 95% CI 10-82%） in the control arm and in 1/9 pts （11%, 95% CI 0.3-48%） in the experimental arm after chemotherapy （p=.98）. There were no unanticipated toxicities in those treated with chemotherapy.

Conclusions：

The phase II endpoint was not met and further enrollment has been halted based upon pre-specified study stopping rules utilizing the original assay. No improvement in ctDNA clearance was observed after 6 mos of chemotherapy for pts with ctDNA detected following resection of stage IIA CC. Future trials evaluating ctDNA as an integral biomarker for minimal residual disease determination must account for assay specificity in this pt population. Support：U10CA180868, -180822; UG1CA189867; Guardant Health. Clinical trial information：NCT04068103.

（二）

Circulating tumor DNA （ctDNA） dynamics in patients with colorectal cancer （CRC） with molecular residual disease：Updated analysis from GALAXY study in the CIRCULATE-JAPAN.

Background：

Our previous analysis of data from the prospective, observational GALAXY study （UMIN000039205） reported post surgical detection of molecular residual disease （MRD） to be prognostic of patient （pt） outcomes and the most significant risk factor for recurrence regardless of?BRAF?V600E status. Here, we present an updated analysis and correlation of ctDNA dynamics with outcomes in pts with radically resected, stage II-IV CRC from the GALAXY study.

Methods：

A personalized, tumor-informed assay （Signatera, Natera, Inc.） was used for the detection and quantification of ctDNA in serial plasma samples collected at 1, 3, 6, 9, 12, 18, and 24 months post surgery until recurrence. CT scans of chest/abdomen/pelvis were conducted every 6 months. Post curative-intent surgery, pts underwent either treatment with adjuvant chemotherapy （ACT; N = 1,000） or observation （N = 1,518）. The primary endpoint was disease-free survival （DFS）， defined as the time between the date of surgery and date of detection of relapse/death due to any cause.

Results：

Of the 3,034 CRC pts enrolled between May 2020 and November 2022 in GALAXY study, 2,518 pts met the inclusion criteria and were analyzed in this substudy. The median follow-up was 16.3 months （range 0.1-37 mos）. During the post-op MRD window, ctDNA results were available for 2,093 pts, 309 （14.8%） of whom were ctDNA+ and 1,784 （85.2%） were ctDNA-. Pts who were ctDNA+ during the MRD window （MRD+） had a significantly inferior DFS compared to MRD- pts （HR：15.75, 95%CI：12.59-19.68, p < 0.0001）. Within the MRD+ group, a landmark analysis of ctDNA dynamics from MRD detection to 3-month time point revealed that pts who remained ctDNA+ were over 5-times more likely to recur compared to those who had ctDNA clearance （HR：5.4, 95%CI：3.58-7.67%, p < 0.0001）. Among the 309 MRD+ pts, 181 received adjuvant therapy, 72.9% （132/181） of whom had ctDNA clearance. Notably, for those pts with subsequent ctDNA time points available, 68/126 （54%） had sustained clearance vs. 58/126 （46%） pts eventually returned ctDNA+. Pts with sustained clearance had remarkably better outcomes compared to those with transient ctDNA clearance （HR：32.57, 95% CI：9.94-106.76, p < 0.0001）. Furthermore, we observed that among MRD+ pts treated with ACT, a 50% or greater decrease in ctDNA levels （mean tumor molecules/mL） at 6 months was associated with better DFS compared to pts with <50% decrease or increase in ctDNA levels （HR：2.39, 95% CI：1.32-4.34, p = 0.004）.

Conclusions：

ctDNA-based detection of MRD as well as ctDNA dynamics in response to ACT were highly prognostic of pt outcomes. Ongoing randomized VEGA and ALTAIR studies in the CIRCULATE-Japan will establish clinical utility of ctDNA-guided adjuvant treatment. Clinical trial information：UMIN000039205.

（三）

Organ-preservation in rectal cancer：What is at risk when offering watch and wait for a clinical complete response? Data from 2 international registries in rectal cancer.

Background：

Organ-preservation has become an attractive alternative to total mesorectal excision （TME） among patients with rectal cancer following neoadjuvant therapy. Patients who achieve a clinical complete response （cCR） are currently offered watch-and-wait （WW） without immediate resection. Nearly 30% of these patients will develop local regrowth usually within 3 years from initial decision to WW. While salvage resection is frequently feasible, keeping the primary tumor in situ （despite clinically undetectable） may contribute to the risk for development of subsequent distant metastases （DM）. The aim of the present study is to compare the risk of DM between patients with local regrowth （LR） after WW （undetectable residual disease） and patients with near-complete pathological response managed by TME at time of reassessment of response.

Methods：

Data from patients with rectal cancer following neoadjuvant therapy entered a prospective international database （IWWD） with cCR managed by WW and subsequent LR were compared to patients managed by TME from a prospectively maintained national registry （VIKINGO project）. Near-complete response was defined at the presence of ≤10% residual cancer cells in the resected specimen. Primary endpoint was DM-free survival at 3 years from decision to WW or TME. Cox-logistic regression was performed to search for predictors of DM development. Kaplan-Meier curves were used to compare DM-free survival between groups based on statistically significant features found at multivariate analysis （p≤0.05） using log-rank test.

Results：

508 patients with LR were compared to 893 patients with near-complete response after TME. Overall, DM rate was significantly higher among local regrowths （22.8% vs. 10.2%,; p≤0.001）. Independent risk factors for DM included LR （versus TME at reassessment; p=0.001）， ypT3-4 status （p=0.016） and ypN+ status （p=0.001） at the time of surgery. 3yr-DM-free survival was significantly worse for patients with local regrowth （75% vs. 87%; p=0.001）. When stratified for pathological stage, patients with local regrowth did significantly worse through all stages ypT1-2N0 （p<0.001）；ypT3-4N0 （p=0.009） and ypTanyN+ （p<0.001）.

Conclusions：

Development of LR following WW is a significant and independent risk factor for subsequent DM. Final pathological stage is also a risk factor for subsequent DM. Patients with local regrowth have a higher risk for subsequent DM development than patients managed by TME at restaging irrespective of final ypT and ypN status. Leaving the primary undetectable tumor in situ until development of local regrowth may result in worse oncological outcomes. Future studies incorporating organ-preservation strategies should focus on the subsequent risk of DM among patients who eventually develop local regrowth as one of clinically relevant primary endpoints.

（四）

Effect of laparoscopy-assisted vs open surgery on 3-year disease-free survival in patients with low rectal cancer：The LASRE randomized clinical trial.

Background：

Laparoscopic surgery has been increasingly used for low rectal cancer due to short-term benefits versus open surgery, but the long-term oncologic outcomes have not been fully established.

Methods：

This is a multicenter, noninferiority trial. Surgeons who had completed ≥100 laparoscopic TME surgeries from 22 high-volume centers in China participated in this trial. A total of 1070 patients scheduled for curative-intent resection of low rectal cancer （lower margin <5.0 cm dentate line） were randomized at a 2：1 ratio to undergo laparoscopic or open surgery from November 2013 to June 2018.The primary outcome was 3-year DFS; the noninferiority margin was 10% in the modified intent-to-treat population. Secondary outcomes included 3-year overall survival （OS） and locoregional recurrence.

Results：

The final analysis included 1039 patients （median age：57 years, 620 men; 685 and 354 in laparoscopic and open groups, respectively）. Clinical TNM stage was II/III in 659 patients, and I in the remaining 380 patients. The 3-year DFS rate was 81.4% in the laparoscopic group versus 79.8% in the open group （HR, 0.9 [95% CI, 0.7 to 1.2]; log-rank P = .558）. The absolute difference was 1.6% （1-sided 97.5% CI, -3.34% to ∞）， not exceeding the noninferiority . The 3-year OS rate was 91.7% in the laparoscopic group versus 93.7% in the open group （95% CI, -5.12% to1.54%, log-rank P = .243）. The 3-year locoregional recurrence rate was 3.8% and 2.4%, respectively （95% CI, -1.07% to 3.45%, log-rank P = .209）. Results of the per-protocol and as-treated analysis were consistent with the main analysis.

Conclusions：

Among patients with low rectal cancer, laparoscopic surgery performed by experienced surgeons is not inferior to open surgery concerning 3-year disease-free survival. These results support laparoscopic surgery as a safe, minimally invasive approach for low rectal cancer. Clinical trial information：NCT01899547.