PO.CT01.05 · 临床试验
MEDOCC-CrEATE试验更新：术后测量循环肿瘤DNA以指导II期结肠癌患者辅助化疗的可行性
MEDOCC-CrEATE trial update: Feasibility of measuring circulating tumor DNA post-surgery to guide adjuvant chemotherapy in stage II colon cancer patients
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言：根据荷兰指南，未被归类为高危的II期结肠癌（CC）患者不接受辅助化疗（ACT）。然而，15-20%的II期CC患者会出现疾病复发，凸显了识别可能从ACT中获益患者的未满足临床需求。观察性研究表明，术后循环肿瘤DNA（ctDNA）可提示微小残留病灶（MRD），是疾病复发的强预后生物标志物。
目的：MEDOCC-CrEATE试验旨在评估：1）术后ctDNA可检测且接受ACT的II期CC患者比例；2）ctDNA指导的ACT是否降低2年复发率（RR）。
方法：MEDOCC-CrEATE是一项遵循"队列内试验"设计的介入性试验。前瞻性荷兰结直肠癌队列中患有II期CC且无ACT指征、并被随机分配至干预组的参与者，接受使用PGDx elio® plasma resolve或Labcorp Plasma Detect®的术后肿瘤指导MRD检测。Labcorp Plasma Detect是一种高灵敏度ctDNA检测，整合了对福尔马林固定石蜡包埋肿瘤组织、种系和血浆游离DNA的全基因组测序（WGS）分析。ctDNA检测阳性的患者获得4个周期的辅助卡培他滨+奥沙利铂。干预组中ctDNA阴性的患者和对照组的患者接受标准治疗随访。所有患者每6个月采集一次血液，持续3年以监测疾病复发。主要终点是术后ctDNA可检测且愿意接受ACT的患者比例。次要终点包括2年RR、无病生存和总生存、生活质量以及ctDNA指导ACT的成本效益。研究将持续至干预组中有10例术后ctDNA可检测的患者接受ACT治疗。
结果：已在29家荷兰医院优化了及时多中心采集肿瘤组织和血液的流程。目前已随机入组525例患者。干预组263例患者中，212例（83%）同意立即进行术后ctDNA分析。在目前已有的197份结果中，16例（8.1%）ctDNA可检测，其中11例开始了ACT。从手术到采血的中位时间为15天（IQR 12-19），从手术到ctDNA结果的中位周转时间为46天（IQR 40-53）。
结论：多中心术后肿瘤指导ctDNA检测MRD在临床相关的8-12周ACT起始窗口内在操作上和技术上均可行。观察到的ctDNA检出率符合预期和研究设计。研究完成后，结果将用于卫生技术评估，以证明ctDNA指导ACT在II期CC中潜在的临床效用。
查看英文原文 English abstract
Introduction: Patients with stage II colon cancer (CC) not classified as high risk do not receive adjuvant chemotherapy (ACT) according to Dutch guidelines. However, 15-20% of patients with stage II CC experience disease recurrence, highlighting an unmet clinical need to identify patients who could benefit from ACT. Observational studies demonstrate that postoperative circulating tumor DNA (ctDNA) is indicative of minimal residual disease (MRD) and a strong prognostic biomarker for disease recurrence.
Aim: The MEDOCC-CrEATE trial aims to assess 1) the proportion of stage II CC patients with detectable postoperative ctDNA accepting ACT, and 2) whether ctDNA-guided ACT reduces 2-year recurrence rate (RR).
Methods: MEDOCC-CrEATE is an interventional trial following the ‘trial within cohorts' design. Participants of the Prospective Dutch Colorectal Cancer cohort with stage II CC and no indication for ACT, and randomized to the intervention arm undergo postoperative tumor-informed MRD testing using PGDx elio® plasma resolve or Labcorp Plasma Detect®. Labcorp Plasma Detect is a highly sensitive ctDNA assay integrating whole genome sequencing (WGS) analyses of formalin-fixed paraffin-embedded tumor tissue, germline, and plasma cell-free DNA. Patients who test ctDNA-positive are offered 4 cycles of adjuvant capecitabine + oxaliplatin. ctDNA-negative patients in the intervention arm and patients in the control arm receive standard of care followup. For all patients, blood is collected every 6 months for 3 years to monitor disease recurrence. The primary endpoint is the proportion of patients with detectable postoperative ctDNA willing to receive ACT. Secondary endpoints include 2-year RR, disease-free and overall survival, quality of life and cost-effectiveness of ctDNA-guided ACT. The study will continue until 10 patients with detectable postoperative ctDNA are treated with ACT in the intervention arm.
Results: Logistics for timely multicenter collection of tumor tissue and blood have been optimized across 29 Dutch hospitals. At present, 525 patients have been randomized. Of the 263 patients in the intervention arm, 212 provided consent for immediate postoperative ctDNA analysis (83%). Of the 197 currently available results, 16 (8,1%) had detectable ctDNA of which 11 started ACT. The median time from surgery to blood collection was 15 days (IQR 12-19), with a median turnaround time from surgery to ctDNA result of 46 days (IQR 40-53).
Conclusion: Multicenter postoperative tumor informed ctDNA testing for MRD is operationally and technically feasible within the clinically relevant 8-12 week window to start ACT. The observed ctDNA detection rate is in accordance with expectations and the study design. Upon study finalization, the results will be used for health technology assessment to demonstrate the putative clinical utility of ctDNA-guided ACT in stage II CC.
利益披露 Disclosure
I. A. Franken,
Labcorp ).
DoMore Diagnostics ).
S. J. Schraa, None.
S. L. C. Ketelaars,
Labcorp ).
C. Rubio-Alarcón,
Labcorp ).
T. Bisschop-Snetselaar, None..
B. Adriaans, None..
M. van Dongen, None..
L. J. W. Bosch, None..
M. Lanfermeijer, None.
S. Angiuoli,
Labcorp Employment.
A. E. Greer,
Labcorp Employment.
E. Verner,
Labcorp Employment.
J. B. Jackson,
Labcorp Employment.
R. A. Previs,
Labcorp Employment.
V. M. H. Coupe,
Labcorp ).
D. van den Broek,
Delfi Diagnostics ).
G. A. Meijer,
Labcorp ).
Delfi Diagnostics ).
CRC Bioscreen Other Business Ownership.
Exact Sciences ).
Sysmex ).
Sentinel Ch SpA ).
J. Phallen, None.
V. E. Velculescu,
Delfi Diagnostics Stock, Other Business Ownership, Patent.
Labcorp Stock, Other Business Ownership.
Qiagen Patent.
Sysmex Patent.
Agios Patent.
Genzyme Patent.
Esoterix Patent.
Ventana Patent.
Mana T Bio Patent.
Viron Therapeutics Other, advisor.
Epitope Other, Advisor.
A. J. S. van Tetering-Houben,
GSK ).
Incyte ).
Merck ).
Natera ).
Nordic ).
Labcorp ).
Pierre Fabre ).
Servier ).
J. M. L. Roodhart,
GSK ).
Servier ).
BMS ).
ABBVIE ).
Pierre Fabre ).
Incyte ).
Xilis ).
Cleara ).
Hub Organoids BV ).
DoMore Diagnostics ).
N. F. M. Kok,
Delfi Diagnostics ).
Natera ).
Labcorp ).
F. H. van der Baan,
Labcorp ).
M. Sausen,
Labcorp ).
BMS Employment.
M. Koopman,
Amgen ).
Bayer ).
BMS ), Other, Advisor.
Merck-Serono ).
Nordic Pharma ), Other, Advisor.
Roche ).
Servier ), Other, Advisor.
Sirtex ).
Labcorp ).
Pierre Fabre ).
Sanofi-Aventis ).
G. R. Vink,
Natera ).
BMS ).
Merck ).
Servier ).
Labcorp ).
Bayer ).
Sirtex ).
Nordic Pharma ).
Pierre Fabre ).
Lilly ).
Delfi Diagnostics ).
R. J. Fijneman,
Labcorp ).
Delfi Diagnostics ).
Natera ).
Solvias (Cergentis BV) ).