ctDNA as a Assisted Diagnosis, Early Intervention and Prognostic Marker for Peritoneal Metastases From Colorectal Cancer

Circulating Tumor DNA (ctDNA) as a Assisted Diagnosis, Early Intervention and Prognostic Marker for Peritoneal Metastases From Colorectal Cancer: A Prospective, Open-label, Randomized Controlled Study

This is a prospective, open-label, randomized controlled clinical trial, by monitoring the serum ctDNA mutational profile using NGS, aiming to elucidate the correlation between the postoperative ctDNA status and the assisted diagnosis, early intervention and prognosis for colorectal cancer peritoneal metastases.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer; Peritoneal Metastases
• Intervention / Treatment: Diagnostic test: ctDNA monitoring; Diagnostic test: Imageology

• Study Type: Interventional
• Enrollment (Anticipated): 138
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Hui Wang, MD, PhD; Phone Number: 13926424886; Email: wang89@mail.sysu.edu.cn
• Study Contact Backup: Name: Tenghui Ma, MD, PhD; Phone Number: 13560232462; Email: austin_2004@163.com

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510655
      • Recruiting
      • Sixth Affiliated Hospital, Sun Yat-sen University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients must be a man or woman of at 18-75;
• Patients must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-21；
• Patients with primary colorectal cancer proven by pathology；
• Patients with high risk factors for peritoneal metastasis (simultaneous peritoneal metastasis, ovarian metastasis, PT4, CT4, tumor perforation, tumor-complete intestinal obstruction, mucinous adenocarcinoma/signet ring cell carcinoma of PT3, positive surgical margin, and tumor rupture and hemorrhage);
• 6-12 months after colorectal cancer radical surgery, patients who have two consecutive positive ctDNA tests within one month;
• Patients who have finished standard adjuvant therapy after surgery; (Choose 5-FU or 5-FU analog-based chemotherapy regimen, and the perioperative chemotherapy should not exceed 6 months)；
• Patients who are negative of recurrence or metastasis in conventional oncology examination (serology, endoscopy, imaging) ;
• Written informed consent must be obtained from patients and ability for patients to comply with the requirements of the study.

Exclusion Criteria:

• Patients who were diagnosed with other malignant tumors within 2 years before diagnosis of colorectal cancer;
• ASA class Ⅳ to Ⅴ;
• Patients who have other existence of distant metastasis outside the abdomen;
• Patients with serious mental illness;
• Patients with severe cardiovascular disease, uncontrollable infections, or other uncontrollable co-diseases;
• Patients who cannot be followed up as scheduled;
• Patients who participated in other clinical studies within 3 months prior to the trial;
• Pregnant or nursing women, men or women of childbearing potential who are unwilling to employ adequate contraception.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: ctDNA monitoring; ctDNA monitoring will be performed at protocol-specified intervals and requirement	Diagnostic test: ctDNA monitoring; Patients who undergoing radical surgery for colorectal cancer for 6~12 months and with 2 consecutive positive ctDNA testing results within 1 month will be enrolled, and diagnostic laparoscopy will be performed immediately after enrollment. Patients with positive peritoneal metastasis (PCI score <20) will be treated with CRS+HIPEC. Tumor markers, endoscopic and imaging examinations, and ctDNA monitoring will be performed every 3 months in patients with negative peritoneal metastasis. Laparoscopy will be performed when imaging suggested peritoneal metastasis (oligometastases). Re-diagnostic laparoscopy will be performed 24 months after radical surgery when there is no radiographic evidence of recurrence or metastasis. Follow-up time will up to 36 months after colorectal cancer surgery.
ACTIVE_COMPARATOR: Imageology (SOC); Imaging examination will be performed at protocol-specified intervals and requirement	Diagnostic test: Imageology; Patients who undergoing radical surgery for colorectal cancer for 6~12 months and with 2 consecutive positive ctDNA testing results within 1 month will be enrolled. and there will be no need to conduct endoscopic exploration immediately after enrollment. Tumor markers, endoscopic and imaging examinations, and ctDNA monitoring will be performed every 3 months until imaging suggested peritoneal metastasis (oligometastases). Patients with positive peritoneal metastasis (PCI score <20) will be treated with CRS+HIPEC. Re-diagnostic laparoscopy will be performed 24 months after radical surgery when there is no radiographic evidence of recurrence or metastasis. Follow-up time will up to 36 months after colorectal cancer surgery.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peritoneal Metastasis Free Survival (PMFS)	The survival rate without peritoneal metastasis (oligometastatic) at 24 months after radical resection of colorectal cancer.	Through study completion, up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Detection Rate (DR)	DR of ctDNA monitoring for predicting peritoneal metastasis with abdominal exploration as the reference. DR of imageological examination for predicting peritoneal metastasis with abdominal exploration as the reference. DR of combination of ctDNA monitoring and imageological examination for predicting peritoneal metastasis with abdominal exploration as the reference. Will be compared in both arms.	Interim analyses: After 69 patients have been enrolled, up to 1.5 years
Positive Percent Agreement (PPA)	PPA of ctDNA monitoring for predicting peritoneal metastasis with abdominal exploration as the reference. PPA of imageological examination for predicting peritoneal metastasis with abdominal exploration as the reference. PPA of combination of ctDNA monitoring and imageological examination for predicting peritoneal metastasis with abdominal exploration as the reference. Will be compared in both arms.	Interim analyses: After 69 patients have been enrolled, up to 1.5 years
Negative Percent Agreement (NPA)	NPA of ctDNA monitoring for predicting peritoneal metastasis with abdominal exploration as the reference. NPA of imageological examination for predicting peritoneal metastasis with abdominal exploration as the reference. NPA of combination of ctDNA monitoring and imageological examination for predicting peritoneal metastasis with abdominal exploration as the reference. Will be compared in both arms.	Interim analyses: After 69 patients have been enrolled, up to 1.5 years
The time of peritoneal metastasis diagnosed after radical surgery	Will be compared in both arms.	Interim analyses: After 69 patients have been enrolled, up to 1.5 years
Peritoneal Cancer Index (PCI) Score	This scale measures the extent of peritoneal cancer throughout the peritoneal cavity. The range of this scale is from 0 to 39. 0 = no disease within the peritoneal cavity 0-9 = minimal disease 10-29 = moderate disease 30-39 = extensive disease Lower values are considered a better outcome for the patient. Will be compared in both arms.	Interim analyses: After 69 patients have been enrolled, up to 1.5 years
Completeness of Cytoreduction (CC) Score	The degree to which the disease was able to be excised during the procedure. This scale ranges from CC0-CC3. CC0 = all disease has been cleared, with no visible peritoneal carcinomatosis after CRS CC1 = microscopic disease remains (Nodules persisting < 2.5 mm after CRS) CC2 = macroscopic disease remains (Nodules persisting between 2.5 mm and 2.5 cm) CC3 = Substantial Macroscopic disease remains (Nodules persisting > 2.5 cm) Lower values are considered a better outcome, with CC0/1 classed as favourable and CC2/3 indicating an incomplete clearance of disease. Will be compared in both arms.	Interim analyses: After 69 patients have been enrolled, up to 1.5 years
The ctDNA clearance rate before and after CRS+HIPEC treatment	Will be compared in both arms.	Interim analyses: After 69 patients have been enrolled, up to 1.5 years
The rate of Disease Free Survival (DFS) at 3 years after radical resection of colorectal cancer	Whether the patient is still alive and free of disease or not. Will be compared in both arms.	Through study completion, up to 3 years
The Overall Survival (OS) at 3 years after radical resection of colorectal cancer	Whether the patient is still alive or not. Will be compared in both arms.	Through study completion, up to 3 years

Collaborators and Investigators

• Sponsor: Sixth Affiliated Hospital, Sun Yat-sen University

Publications and helpful links

General Publications

• Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, Bartlett BR, Wang H, Luber B, Alani RM, Antonarakis ES, Azad NS, Bardelli A, Brem H, Cameron JL, Lee CC, Fecher LA, Gallia GL, Gibbs P, Le D, Giuntoli RL, Goggins M, Hogarty MD, Holdhoff M, Hong SM, Jiao Y, Juhl HH, Kim JJ, Siravegna G, Laheru DA, Lauricella C, Lim M, Lipson EJ, Marie SK, Netto GJ, Oliner KS, Olivi A, Olsson L, Riggins GJ, Sartore-Bianchi A, Schmidt K, Shih lM, Oba-Shinjo SM, Siena S, Theodorescu D, Tie J, Harkins TT, Veronese S, Wang TL, Weingart JD, Wolfgang CL, Wood LD, Xing D, Hruban RH, Wu J, Allen PJ, Schmidt CM, Choti MA, Velculescu VE, Kinzler KW, Vogelstein B, Papadopoulos N, Diaz LA Jr. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014 Feb 19;6(224):224ra24. doi: 10.1126/scitranslmed.3007094.
• Franko J, Shi Q, Goldman CD, Pockaj BA, Nelson GD, Goldberg RM, Pitot HC, Grothey A, Alberts SR, Sargent DJ. Treatment of colorectal peritoneal carcinomatosis with systemic chemotherapy: a pooled analysis of north central cancer treatment group phase III trials N9741 and N9841. J Clin Oncol. 2012 Jan 20;30(3):263-7. doi: 10.1200/JCO.2011.37.1039. Epub 2011 Dec 12.
• Elias D, Lefevre JH, Chevalier J, Brouquet A, Marchal F, Classe JM, Ferron G, Guilloit JM, Meeus P, Goere D, Bonastre J. Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin. J Clin Oncol. 2009 Feb 10;27(5):681-5. doi: 10.1200/JCO.2008.19.7160. Epub 2008 Dec 22.
• Yonemura Y, Bandou E, Kawamura T, Endou Y, Sasaki T. Quantitative prognostic indicators of peritoneal dissemination of gastric cancer. Eur J Surg Oncol. 2006 Aug;32(6):602-6. doi: 10.1016/j.ejso.2006.03.003. Epub 2006 Apr 17.
• Baratti D, Kusamura S, Deraco M. The Fifth International Workshop on Peritoneal Surface Malignancy (Milan, Italy, December 4-6, 2006): methodology of disease-specific consensus. J Surg Oncol. 2008 Sep 15;98(4):258-62. doi: 10.1002/jso.21056.
• Esquivel J, Chua TC, Stojadinovic A, Melero JT, Levine EA, Gutman M, Howard R, Piso P, Nissan A, Gomez-Portilla A, Gonzalez-Bayon L, Gonzalez-Moreno S, Shen P, Stewart JH, Sugarbaker PH, Barone RM, Hoefer R, Morris DL, Sardi A, Sticca RP. Accuracy and clinical relevance of computed tomography scan interpretation of peritoneal cancer index in colorectal cancer peritoneal carcinomatosis: a multi-institutional study. J Surg Oncol. 2010 Nov 1;102(6):565-70. doi: 10.1002/jso.21601.
• Dromain C, Leboulleux S, Auperin A, Goere D, Malka D, Lumbroso J, Schumberger M, Sigal R, Elias D. Staging of peritoneal carcinomatosis: enhanced CT vs. PET/CT. Abdom Imaging. 2008 Jan-Feb;33(1):87-93. doi: 10.1007/s00261-007-9211-7.
• Abbosh C, Birkbak NJ, Wilson GA, Jamal-Hanjani M, Constantin T, Salari R, Le Quesne J, Moore DA, Veeriah S, Rosenthal R, Marafioti T, Kirkizlar E, Watkins TBK, McGranahan N, Ward S, Martinson L, Riley J, Fraioli F, Al Bakir M, Gronroos E, Zambrana F, Endozo R, Bi WL, Fennessy FM, Sponer N, Johnson D, Laycock J, Shafi S, Czyzewska-Khan J, Rowan A, Chambers T, Matthews N, Turajlic S, Hiley C, Lee SM, Forster MD, Ahmad T, Falzon M, Borg E, Lawrence D, Hayward M, Kolvekar S, Panagiotopoulos N, Janes SM, Thakrar R, Ahmed A, Blackhall F, Summers Y, Hafez D, Naik A, Ganguly A, Kareht S, Shah R, Joseph L, Marie Quinn A, Crosbie PA, Naidu B, Middleton G, Langman G, Trotter S, Nicolson M, Remmen H, Kerr K, Chetty M, Gomersall L, Fennell DA, Nakas A, Rathinam S, Anand G, Khan S, Russell P, Ezhil V, Ismail B, Irvin-Sellers M, Prakash V, Lester JF, Kornaszewska M, Attanoos R, Adams H, Davies H, Oukrif D, Akarca AU, Hartley JA, Lowe HL, Lock S, Iles N, Bell H, Ngai Y, Elgar G, Szallasi Z, Schwarz RF, Herrero J, Stewart A, Quezada SA, Peggs KS, Van Loo P, Dive C, Lin CJ, Rabinowitz M, Aerts HJWL, Hackshaw A, Shaw JA, Zimmermann BG; TRACERx consortium; PEACE consortium; Swanton C. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature. 2017 Apr 26;545(7655):446-451. doi: 10.1038/nature22364. Erratum In: Nature. 2017 Dec 20;:
• Tie J, Wang Y, Tomasetti C, Li L, Springer S, Kinde I, Silliman N, Tacey M, Wong HL, Christie M, Kosmider S, Skinner I, Wong R, Steel M, Tran B, Desai J, Jones I, Haydon A, Hayes T, Price TJ, Strausberg RL, Diaz LA Jr, Papadopoulos N, Kinzler KW, Vogelstein B, Gibbs P. Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer. Sci Transl Med. 2016 Jul 6;8(346):346ra92. doi: 10.1126/scitranslmed.aaf6219.
• Saluja H, Karapetis CS, Pedersen SK, Young GP, Symonds EL. The Use of Circulating Tumor DNA for Prognosis of Gastrointestinal Cancers. Front Oncol. 2018 Jul 24;8:275. doi: 10.3389/fonc.2018.00275. eCollection 2018.
• Ossandon MR, Agrawal L, Bernhard EJ, Conley BA, Dey SM, Divi RL, Guan P, Lively TG, McKee TC, Sorg BS, Tricoli JV. Circulating Tumor DNA Assays in Clinical Cancer Research. J Natl Cancer Inst. 2018 Sep 1;110(9):929-934. doi: 10.1093/jnci/djy105.
• Yang QM, Bando E, Kawamura T, Tsukiyama G, Nemoto M, Yonemura Y, Furukawa H. The diagnostic value of PET-CT for peritoneal dissemination of abdominal malignancies. Gan To Kagaku Ryoho. 2006 Nov;33(12):1817-21.
• Yonemura Y, Elnemr A, Endou Y, Hirano M, Mizumoto A, Takao N, Ichinose M, Miura M, Li Y. Multidisciplinary therapy for treatment of patients with peritoneal carcinomatosis from gastric cancer. World J Gastrointest Oncol. 2010 Feb 15;2(2):85-97. doi: 10.4251/wjgo.v2.i2.85.
• Satoh Y, Ichikawa T, Motosugi U, Kimura K, Sou H, Sano K, Araki T. Diagnosis of peritoneal dissemination: comparison of 18F-FDG PET/CT, diffusion-weighted MRI, and contrast-enhanced MDCT. AJR Am J Roentgenol. 2011 Feb;196(2):447-53. doi: 10.2214/AJR.10.4687.
• Brucher BL, Piso P, Verwaal V, Esquivel J, Derraco M, Yonemura Y, Gonzalez-Moreno S, Pelz J, Konigsrainer A, Strohlein M, Levine EA, Morris D, Bartlett D, Glehen O, Garofalo A, Nissan A. Peritoneal carcinomatosis: cytoreductive surgery and HIPEC--overview and basics. Cancer Invest. 2012 Mar;30(3):209-24. doi: 10.3109/07357907.2012.654871.
• Koh JL, Yan TD, Glenn D, Morris DL. Evaluation of preoperative computed tomography in estimating peritoneal cancer index in colorectal peritoneal carcinomatosis. Ann Surg Oncol. 2009 Feb;16(2):327-33. doi: 10.1245/s10434-008-0234-2. Epub 2008 Dec 3.
• Rausei S, Ruspi L, Mangano A, Lianos GD, Galli F, Boni L, Roukos DH, Dionigi G. Advantages of staging laparoscopy in gastric cancer: they are so obvious that they are not evident. Future Oncol. 2015;11(3):369-72. doi: 10.2217/fon.14.283. No abstract available.
• Stroun M, Anker P, Maurice P, Lyautey J, Lederrey C, Beljanski M. Neoplastic characteristics of the DNA found in the plasma of cancer patients. Oncology. 1989;46(5):318-22. doi: 10.1159/000226740.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 24, 2020
• Primary Completion (ANTICIPATED): September 24, 2023
• Study Completion (ANTICIPATED): August 24, 2025

Study Registration Dates

• First Submitted: January 26, 2021
• First Submitted That Met QC Criteria: February 9, 2021
• First Posted (ACTUAL): February 12, 2021

Study Record Updates

• Last Update Posted (ACTUAL): February 12, 2021
• Last Update Submitted That Met QC Criteria: February 9, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: ctDNA
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplastic Processes; Colorectal Neoplasms; Neoplasm Metastasis
• Other Study ID Numbers: SixthSunYetSen-ctDNA

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No