Circulating tumor DNA guided adjuvant chemotherapy in stage II colon cancer (MEDOCC-CrEATE): study protocol for a trial within a cohort study
Authors: Schraa S. J. , van Rooijen K. L. , van der Kruijssen D. E. W. , Rubio Alarcón C. , Phallen J. , Sausen M. , Simmons J. , Coupé V. M. H. , van Grevenstein W. M. U. , Elias S. , Verkooijen H. M. , Laclé M. M. , Bosch L. J. W. , van den Broek D. , Meijer G. A. , Velculescu V. E. , Fijneman R. J. A. , Vink G. R. , Koopman M. ,   And on behalf of the PLCRC-MEDOCC group, Dunker Mich S. , Lutke Holzik Martijn F. , Hoekstra Ronald , Sommeijer Dirkje W. , van der Bilt Jarmila D. W. , Consten Esther C. J. , Cirkel Geert A. , Burghgraef Thijs A. , van der Schans Emma M. , Nieboer Peter , Rietbroek Ron C. , Dekker Jan Willem T. , Verschoor Arjan J. , Talsma Koen A. K. , Brosens Rebecca P. M. , Helgason Helgi H. , Marinelli Andreas W. K. S. , de Hingh Ignace H. J. T. , Oldenhuis Corina N. , Jansen Jan , van Halteren Henk K. , Stockmann Hein B. A. C. , Beeker Aart , Bosscha Koop , Pruijt Hans F. M. , Spierings Leontine E. A. M. M. , Valkenburg-Van Iersel Liselot B. J. , Vles Wouter J. , de Jongh Felix E. , van Cruijsen Hester , Heikens Joost T. , Zimmerman David D. E. , van Alphen Robert J. , Schiphorst Anandi H. W. , van Leeuwen-Snoeks Lobke L. , Vogelaar Jeroen F. J. , Peters Natascha A. J. B. 
Published: August 2020

Abstract
Background
Accurate detection of patients with minimal residual disease (MRD) after surgery for stage II colon cancer (CC) remains an urgent unmet clinical need to improve selection of patients who might benefit form adjuvant chemotherapy (ACT). Presence of circulating tumor DNA (ctDNA) is indicative for MRD and has high predictive value for recurrent disease. The MEDOCC-CrEATE trial investigates how many stage II CC patients with detectable ctDNA after surgery will accept ACT and whether ACT reduces the risk of recurrence in these patients.

Methods/design
MEDOCC-CrEATE follows the ‘trial within cohorts’ (TwiCs) design. Patients with colorectal cancer (CRC) are included in the Prospective Dutch ColoRectal Cancer cohort (PLCRC) and give informed consent for collection of clinical data, tissue and blood samples, and consent for future randomization. MEDOCC-CrEATE is a subcohort within PLCRC consisting of 1320 stage II CC patients without indication for ACT according to current guidelines, who are randomized 1:1 into an experimental and a control arm.
In the experimental arm, post-surgery blood samples and tissue are analyzed for tissue-informed detection of plasma ctDNA, using the PGDx elio™ platform. Patients with detectable ctDNA will be offered ACT consisting of 8 cycles of capecitabine plus oxaliplatin while patients without detectable ctDNA and patients in the control group will standard follow-up according to guideline.
The primary endpoint is the proportion of patients receiving ACT when ctDNA is detectable after resection. The main secondary outcome is 2-year recurrence rate (RR), but also includes 5-year RR, disease free survival, overall survival, time to recurrence, quality of life and cost-effectiveness. Data will be analyzed by intention to treat.

Discussion
The MEDOCC-CrEATE trial will provide insight into the willingness of stage II CC patients to be treated with ACT guided by ctDNA biomarker testing and whether ACT will prevent recurrences in a high-risk population. Use of the TwiCs design provides the opportunity to randomize patients before ctDNA measurement, avoiding ethical dilemmas of ctDNA status disclosure in the control group.

Trial registration
Netherlands Trial Register: NL6281/NTR6455. Registered 18 May 2017, https://www.trialregister.nl/trial/6281