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Oxaliplatin

Leucovorin

Fluorouracil

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Capecitabine

Cola

12 weeks of FOLFOXIRI neuoadjuvantly followed by surgery and adjuvant chemotherapy

surgery followed by 24 weeks of FOLFOX or CapeOX or Cape

mFOLFOXIRI (IV oxaliplatin given over 120 min at a dose of 85 mg/m2 on day 1 followed by IV leucovorin 400 mg/m2 over 2h, IV Irinotecan 150 mg/m2 and IV infusional 5-Fluorouracil 2400 mg/m2 over 48h every 14 days) for 6 cycles followed by colectomy (3 to 6 weeks after) . If PD was observed after 3 cycles, direct colectomy was performed.

neoadjuvant chemotherapyI

Colectomy

mFOLFOX6 (IV oxaliplatin given over 120 min at a dose of 85 mg/m2 on day 1 followed by IV leucovorin 400 mg/m2 over 2h, IV bolus 5-Fluorouracil 400 mg/m2 and IV infusional 5-Fluorouracil 2400 mg/m2 over 46h every 14 days) . CAPOX (IV oxaliplatin given over 120 min at a dose of 130 mg/m2 on day 1, oral capecitabine 1000 mg/m2 twice daily on days 1 through 14 every 21 days) . Oral capecitabine 1000 mg/m2 twice daily on days 1 through 14 every 21 days. The plan and cycles are determined according to the surgical pathology and physical conditions.

adjuvant chemotherapy

Peirong Ding, Doctor

Yuan Li, Doctor

BACKGROUND:

In patients with high risk stage II and stage III colon cancer (CC), curative surgery followed by adjuvant chemotherapy with FOLFOX or CAPOX regimens has become a standard treatment. However, 20 to 30 % of these patients will develop distant metastasis, which ultimately result in death. Perioperative chemotherapy is a promising strategy with potential benefits that could be more effective at eradicating micrometastases. Moreover, shrinking tumor before surgery not only facilitate removal of all the tumor by the surgeon but also reduce tumor cell spreading during the procedure. With recent advances in radiology, preoperative computed tomography allows a good prediction of tumor stage (wall penetration and nodal involvement) prior to surgery. The investigators conducted the present randomized study to explore whether perioperative chemotherapy with FOLFOXIRI regimen compared with postoperative chemotherapy could improve disease-free survival in patients with radiologically staged, High-risk, but resectable Stage II or III colon cancer.

OBJECTIVE:

The primary objective of this study is to evaluate the efficacy of perioperative chemotherapy with FOLFOXIRI regimen compared to postoperative chemotherapy in patients with High-risk Resectable Stage II and III colon cancer. Secondary objectives are efficacy in terms of R0 resection rate, overall survival (OS), relapse-free survival (RFS), down-staging of primary tumors, and tolerability of perioperative therapy and postoperative complications.

This trial is a a two-arm, multicenter, open labelled, prospective, randomized phase III studies. Eligible patients with High-risk Resectable Stage II and III (T4 or T3 with extramural depth≧5 mm) colon cancer patients will be randomly assigned, in a 2:1 ratio, to receive either perioperative or postoperative chemotherapy.

Neoadjuvant FOLFOXIRI Versus Immediate Surgery for Stage II and III Colon Cancers

Phase III Study of Neoadjuvant FOLFOXIRI Chemotherapy Versus Immediate Surgery for High-risk Resectable Stage II and III Colon Cancers

Defined as the time from randomization to relapse or death, whichever occurred first

Defined as the time from randomization to death from any cause

Down-staging of the resected tumour as measured by histopathological tumour diameter and stage according to the TNM staging system of AJCC (7th version)

The grade of toxicity will be assessed using the NCI common toxicity criteria, version 4.0

CT evaluation of the thickness of tumor walls or tumor diameter or tumor length. Efficacy evaluation will be assessed using the RECIST criteria, version 1.1.

Sun Yat-sen University

Professor

All patients with operable colon cancer who will undergo laparoscopic conventional colectomy

All patients with operable colon cancer who will undergo laparoscopic complete mesocolic excision

Laparoscopic colectomy with only lymph node dissection up to level 2 lymph nodes D2.

laparoscopic conventional colectomy

Laparoscopic colectomy with lymphovascular dissection from level 3 lymph nodes or more D3.

laparoscopic complete mesocolic excision

Ahmed E Ahmed, Professor

Mena Z Helmy, Ass prof.

Mostafa F Mohammed, Ass lecturer

The investigators will assess and compare Surgical, pathological and oncological outcomes between two laparoscopic procedures conventional colectomy versus complete mesocolic excision for operable colon cancer cases in Upper Egypt

Colon cancer is considered a huge clinical surgical burden accounting for 10% of cancer cases and deaths all over the world with consideration that surgery and adjuvant chemotherapy(if indicated) are the main lines of treatment .

When Werner Hohenberger and colleagues described complete mesocolic excision (CME) in 2009; resection along the embryological and lymphovascular planes with appropriate resection margins, they did it for years before describing it with suggestion of improved disease outcomes and overall survival compared to the conventional colectomy (CC).

The principles of CME were described after the significant improvement of rectal adenocarcinoma surgical outcomes with establishment of total mesorectal excision (TME) in which tumor resection is associated with dissection of mesorectal fascial embryologic and lymphovascular planes.

CME includes the same principles of the CC with maximizing lymph node dissection level into (D3 extended lymphadenectomy instead of D1 and D2 in conventional colectomy) and central vascular ligation (CVL) of the main feeding vessel(s) at their origin, with suggested improved disease-free and overall survival with suggested superior pathological and oncological results in the specimen.

Some surgeons consider that CME; with D3 extended lymphadenectomy and CVL is the optimal or standard surgical method in primary cancer colon based on suggested reduced local recurrence and improved disease-free and overall survival.

Although CME has a theoretical advantages and promising early results, it is not widely adopted as the standard in some areas. CME is technically more demanding than CC and suggested to be associated with more intraoperative visceral injuries and non-surgical complications and many doubts persist about safety and efficacy of the procedure.

The questions of interest and research, should CME be regarded as the optimal procedure for colon cancer cases? And also another question; is conventional colectomy suboptimal?

Comparison Between Results of 2 Laparoscopic Surgical Procedures in Operable Colon Cancer Cases in Upper Egypt

Surgical, Pathological and Oncological Outcomes of Laparoscopic Conventional Colectomy Versus Complete Mesocolic Excision for Operable Colon Cancer Cases in Upper Egypt

It is not yet known if there will be a plan to make IPD available.

Histopathological examination of the resected colon with lymph node status and number

Amount in cubic cm and nature of it with its management

Yes/No with Reporting the postoperative complications; according to the Clavien-Dindo Grading System

Reporting operative time with measurements in minutes

Yes/No with measurement in Cubic Cm and how managed

According to primary tumor, regional nodes, metastasis (TNM) staging system

Reporting Yes/No with amount in cm3 and management

Carcinoembryonic antigen (CEA) level by ng/mL

Type of anastomosis (intra- or extracorporeal)

cecum, appendix, ascending colon, hepatic flexure or at splenic flexure, transverse and descending colon and sigmoid colon

Yes/No Cardiopulmonary complications type and how managed

Sohag University

assistant lecturer of general surgery

Carcinoma

Hematinics

Vitamins

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Antidotes

Protective Agents

Folic Acid

Vitamin B Complex

Trace Elements

Folate

Vitamin B9

Raimund Jakesz, MD

This clinical investigation examined the influence of cytostatic chemotherapy with 5-fluorouracil, modulated by biologically active leucovorin, on patients' survival time following surgery for colon carcinoma Stage II.

Randomized Trial on Adjuvant Chemotherapy in Colon Carcinoma Dukes B

A Prospectively Randomized Study on Adjuvant Chemotherapy in Patients With Operated Colon Carcinoma Dukes B (Stage II; T3-4, N0, M0).

Austrian Breast & Colorectal Cancer Study Group

Andrea Laghi, MD

The goal of this clinical trial is to develop an artificial intelligence-based model to assess radiogenomics signature of colon tumor in patients with stage II-III colon cancer. The main question it aims to answer is:

• Can artificial intelligence-based algorithm of radiomics features combined with clinical factors, biochemical biomarkers, and genomic data recognise tumor behaviour, aggressiveness, and prognosis, identifying a radiogenomics signature of the tumor?

Participants will

* undergo a preoperative contrast-enhanced CT examination;
* undergo surgical excision of colon cancer
* undergo adjuvant therapy if deemed necessary based on current guidelines

The ATTRACT trial consist of a retrospective and a prospective part. In the retrospective part of the trial, radiology, pathology, and genomics data of 300 patients with stage II-III colon cancer will be used to identify the genetic and radiomics features of colon tumors and the clinical endpoints as the outcomes of the predictive model.

Tumors will be manually segmented on CT images and used for the AI (artificial intelligence)-model generation. Pathological annotations will be associated to the corresponding anonymised profiles. Immunohistochemistry will be used to classify the samples in the 4 molecular subtypes according.RNA-seq profiles will be also generated from tissue samples through targeted transcriptomics using custom NGS (next-generation sequencing) panels specifically designed to evaluate gene expression and assess Tumor Mutational Burden (TMB). Raw data will be processed and modelled using Topological Pathway Analysis to stratify patients according to the relevant molecular features and define molecular annotations that will be used to train the model for the identification of specific clinically relevant groups. Raw data together with radiological data will be used to generate and train the AI-models for the automated segmentation and the extraction of the radiogenomics signature.

Radiomics features will be extracted from manually segmented tumors. Standard PyRadiomics tools as well custom-made tools will be used. Feature robustness will be guaranteed by selecting only those with high inter-observer statistical correlation. Two families of AI models will be generated, one family dedicated to segmentation, and the other dedicated to radiogenomics-based phenotyping according to the clinical, molecular biology and pathological data available. The two families will be fused for the creation of the ATTRACT AI-model. For the generation of these models, specific convolutional neural network (CNN) architectures based on deep learning (DL) and Artificial Intelligence like UNet and MaskNet will be applied. The training will be performed using the manual ROI (region of interest) segmentations as ground truth. For the generation of radiogenomics analysis models, radiomics and genomic features will be combined using different multivariate algorithms. The classificatory will be trained to recognise the cancer subtypes and clinical endpoints.

In the prospective part of the trial, patients with stage II-III colon cancer will be recruited and will undergo a preoperative contrast-enhanced CT examination. The recruitment rate will be 70 patients per year, for a total of 210 patients. After pre-operative CT, surgery will be performed according to international standard protocols. Eventually adjuvant therapy will be considered following current guidelines. Pathological sample of the prospective enrollment will be analyzed. First, with RNA-seq data, TMB (of coding genes) and clinical data, patients will be clustered by making use of two different techniques Markov Cluster algorithm (MCL) and t-SNE (t-distributed stochastic neighbor embedding), Multi-Layer Network clustering. Patients will be represented as node of a network, edges between nodes will be weighted and thresholded according to the Jaccard Similarity. The similarity will be computed on top of Gene Expression, TMB, and perturbation information coming from Topological Pathway Analysis. Results of clustering will be matched with those coming from Immunohistochemistry. Clinical follow-up data (i.e. outcome of the therapy etc...) will be, once available, also plugged into the workflow to enforce the learning. Extracted knowledge will be used to annotate the dataset used to train and validate the radiomics classification. Gross specimen will be analyzed in order to extract different transcriptomics molecular subtypes (CMS1, CMS2, CMS3, CMS4) in accordance to the Colorectal Cancer (CRC) Subtyping Consortium (CRCSC) assessing the presence or absence of core subtype patterns among existing gene expression-based CRC subtyping algorithms. The accordance between pathological molecular profile and ctDNA analysis during protocol will be related to radiomics classification in order to provide a new whole-diagnostic model of approach in CRC treatment and surveillance.

Prospective data will be used to validate the AI models. For the segmentation models, the Dice Coefficient will be used as an indicator to measure the degree of overlap between the automated and the expert segmentation. For the radiogenomics model, performances will be evaluated using accuracy, integral under the receiver operator curve (ROC-AUC) and clinical decision curve. The investigators will also take into consideration, in order to select the best AI models, the response to the variation of the input characteristics and will produce saliency maps where the features of the input image that mostly contributed to the classification are highlighted.

Clinical evaluation with will be performed every 6 months for 2 years, including regular serum CEA (carcinoembryonic antigen) tests and Whole-Body CT every 6-12 months in patients who are at higher risk of recurrence in the first 3 years following ESMO (European Society for Medical Oncology) guidelines .Disease-free survival (DFS) and relapse-free survival (RFS) will be calculated.

ArTificial inTelligence-based RAdiogenomics in Colon Tumors

ATTRACT - ArTificial inTelligence-based RAdiogenomics in Colon Tumors

Associazione Italiana per la Ricerca sul Cancro

University of Roma La Sapienza

Full Professor

Capecitabine mono or Capecitabine/Oxaliplatin as investigator choice:

Patients who are positive for postoperative ctDNA (ctDNApos) and not microsatellite instable are randomized (2:1) to adjuvant chemotherapy with capecitabine or to follow up.

Capecitabine 2 x 1250 mg/m\^2, oral (d1-14), repeated at day 22 (- 2 ... + 6 days). Patients with a GFR between 30 and 50 ml/min start with capecitabine dose of 2 x 1000 mg/m\^2. Treatment duration: 8 cycles (approx. 6 months)

Capecitabine, if combined with Oxaliplatin (investigator choice):

If the investigation decides to add oxaliplatin, the following schedule should be used:

\[Oxaliplatin 130 mg/m\^2 i.v. (2 hours on d1)\] Capecitabine 2 x 1000 mg/m\^2, oral (d1-14), repeated at day 22 (- 2 ... + 6 days) Treatment duration: 4 or 8 cycles (approx. 3 or 6 months)

Patients negative for postoperative ctDNA (ctDNAneg) are randomized (1:4) to follow-up within CIRCULATE or to routine follow up outside the Trial protocol.

6 months capecitabine, in combination with oxaliplatin 3 to 6 months capecitabine

Gunnar Folprecht, Prof.

Gunnar Folprecht, Dr.

The CIRCULATE study evaluates the adjuvant therapy in patients with colon cancer UICC stage II. The primary aim of the study is to compare the disease free survival in patients who are positive for postoperative circulating tumour DNA with vs. without capecitabine.

CIRCULATE is an investigator-initiated, multicentre, prospective, randomised, controlled trial.

Screening phase:

Patients with colon cancer (or rectal cancer, if a radiation is not indicated i.e. due to the tumour localisation) are postoperatively screened for this trial.

For this purpose, they sign an informed consent for screening. The formalin fixed paraffin embedded (FFPE) tumour block is shipped to one of the central pathological laboratories and is analysed for microsatellite instability and by panel analysis for frequent mutations in the colorectal cancer. A plasma sample is sent in parallel to the central laboratory for ctDNA. The screening is preferably performed before the patient is discharged from the surgical department and at the latest 5 weeks after resection to allow sufficient time for the analysis.

The patient- specific tumour mutations known from the panel analysis are measure in the patients plasma by ultra deep sequencing. The results of the analysis - positive for circulating tumour DNA (ctDNApos) or negative for circulating tumour DNA (ctDNAneg) - is not communicated to the patient or the investigator.

Randomised phase:

Four to eight weeks after resection, the patient presents at an investigator that is experienced with chemotherapy (i.e. Medical Oncologist) and consent for the randomised part of the study with a second informed consent form. If this baseline visit confirms that there are not contraindications to chemotherapy and if no other exclusion criteria exist, the patient is randomised:

* ctDNApos patients are randomised (2:1) in "chemotherapy" (with capecitabine) or "follow-up",
* ctDNAneg patients are randomised (1:4) in "follow-up" or "off study" which means that the follow-up will be organised within the routine clinical practice.

The result of the ctDNA will not be communicated to the patients and investigators, so that patients in the arm "follow-up" remain blinded to the ctDNA result. Due to the randomisation ratio, the prognosis of these patients is similar to those in stage II without any ctDNA analysis and differs only slightly from patients not enrolled into a clinical trial.

Patients in the arm "chemotherapy" receive adjuvant therapy with 6 months capecitabine. The investigator can decide to add oxaliplatin and to shorten the adjuvant chemotherapy to 3 months if oxaliplatin is added.

Patients in the arms "chemotherapy" and "follow-up" are followed with the same methods and time point within the study.

Patients in the arm "off study" are recommended to be follow up according to the guidelines for stage II in the routine practice.

Circulating Tumour DNA Based Decision for Adjuvant Treatment in Colon Cancer Stage II Evaluation

Circulating Tumour DNA Based Decision for Adjuvant Treatment in Colon Cancer Stage II Evaluation (CIRCULATE) AIO-KRK-0217

Disease free survival of ctDNA positive patients randomised to "chemotherapy" vs. "follow-up", measured from randomisation to any recurrence, metastasis, second colorectal or non colorectal cancer and death from any cause. The primary endpoint will be tested in all randomised ctDNA positive patients and be evaluated by a stratified log rank test.

Interims analysis after 93 events (approx. 38 months after study start), final analysis for the primary endpoint after 154 events (approx. 60 months after study start).

Overall survival in ctDNApos patients with adjuvant therapy vs follow-up, measured from randomisation to death from any cause, in all randomised ctDNA positive patients and be evaluated by a stratified log rank test.

Disease free survival in ctDNAneg patients randomised to follow up (rate of patients disease free and alive 3 years after randomisation according to Kaplan-Meier estimation with 95% CI, intention-to-treat analysis). Any recurrence, metastasis, second colorectal or non-colorectal cancer and death from any cause is regarded as event (rate of patients disease free and alive 3 years after randomisation according to Kaplan-Meier estimation with 95% CI, intention-to-treat analysis). Any recurrence, metastasis, second colorectal or non- colorectal cancer and death from any cause is regarded as event

Overall survival in ctDNAneg patients randomised to "follow up" (rate of patients alive after 5 years after randomisation according to Kaplan-Meier estimation with 95% CI)

Disease free and overall survival of ctDNApos vs. ctDNAneg patients randomized to "follow-up" (measured from randomisation to the event in an intention-to-treat analysis by stratified log rank test). Any recurrence, metastasis, second colorectal or non-colorectal cancer and death from any cause are regarded as event for DFS. Death of any cause will be regarded as event for overall survival.

Site of metastases (lymph node vs. peritoneal/local recurrence vs other) in ctDNApos vs. ctDNAneg patients who have a recurrence / metastases

Frequency of adverse events from start of chemotherapy until 30 days after chemotherapy (descriptive analysis for patients randomised to "chemotherapy" who have received at least one dose of chemotherapy).

Technische Universität Dresden

Symptoms and General Pathology

Recurrence

Disease Attributes

Patients randomized to the ctDNA-based treatment group will have their post-surgery samples analysed directly after informed consent for MEDOCC-CrEATE. Results are reported to the treating physician and patients. All patients with detectable ctDNA are considered high risk stage 2 patients and will be offered adjuvant chemotherapy for 3 months (4 cycles CAPOX) according to routine clinical practice. Patients with undetectable ctDNA will receive routine follow-up at the surgical department.

The treating physician and patient are not informed about the ctDNA result and these patients will receive routine follow-up at the surgical department.

ctDNA analysis of post-surgery blood samples will be performed directly after informed consent for MEDOCC-CrEATE.

ctDNA analysis after surgery

Miriam Koopman, Prof. dr.

J.F.M. Pruijt

M.P. Hendriks

R. Hoekstra

J.D.W. van der Bilt

J.M. van Dodewaard

I. Werter

M. Streppel

A.J. Verschoor

F.J.F. Jeurissen

L.W. Kessels

M. Vidakovic

M. Verstappen

H.K. van Halteren

M.A. Davidis

H.B.A.C. Stockmann

A.P. Schouten van der Velden

L.B.J. Valkenburg

A.I. de Vos

M. Los

J. Janssen

S. Boudewijns

F.E. de Jongh

J. van Extel

L. van Leeuwen

Miriam Koopman

L.H.J Simkens

N.A.J.B. Peters

Patients in the Prospective Dutch ColoRectal Cancer cohort (PLCRC) with non-metastatic colon cancer that gave consent for additional blood withdrawals are enrolled in the observational PLCRC-MEDOCC substudy. In this study, blood is collected before surgery, after surgery and during follow-up. Within PLCRC-MEDOCC, patients with stage II colon cancer that are not considered to have an indication for adjuvant chemotherapy, can be included in the MEDOCC-CrEATE subcohort under the condition that they gave informed consent in PLCRC for biobanking of tissue and for future studies (Trial within Cohorts design).

Patients included in MEDOCC-CrEATE will be randomized 1:1 to the (A) ctDNA-based treatment group versus (B) the standard of care group. A total of 1320 patients will be randomized. Patients randomized to the ctDNA-based treatment group will have their post-surgery samples analysed directly after informed consent for MEDOCC-CrEATE. All patients with detectable ctDNA will be offered adjuvant chemotherapy (3 months CAPOX). Patients with undetectable ctDNA will receive routine follow-up at the surgical department. The aim of this Trial within Cohorts study is to investigate how many patients with detectable ctDNA after surgery start with adjuvant chemotherapy.

Circulating Tumor DNA Based Adjuvant Chemotherapy in Stage II Colon Cancer Patients: the MEDOCC-CrEATE Trial

Proportion of patients that will experience disease recurrence

Proportion of patients that are alive and free of disease

Quality of Life will be measured using questionnaires that are provided to patients who have given informed consent for the collection of questionnaires within PLCRC.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Neoadjuvant FOLFOXIRI Versus Immediate Surgery for Stage II and III Colon Cancers	NCT05194878	Colon Cancer St... Colon Cancer St...	neoadjuvant che... Colectomy adjuvant chemot...	18 Years - 75 Years	Sun Yat-sen University
Comparison Between Results of 2 Laparoscopic Surgical Procedures in Operable Colon Cancer Cases in Upper Egypt	NCT05421702	Colon Cancer St... Colon Cancer St...	laparoscopic co... laparoscopic co...	-	Sohag University
Randomized Trial on Adjuvant Chemotherapy in Colon Carcinoma Dukes B	NCT00309543	Colon Cancer St...	Fluorouracil Leucovorin	18 Years - 80 Years	Austrian Breast & Colorectal Cancer Study Group
ArTificial inTelligence-based RAdiogenomics in Colon Tumors	NCT06108310	Colon Cancer St... Colon Cancer St...		18 Years -	University of Roma La Sapienza
Circulating Tumour DNA Based Decision for Adjuvant Treatment in Colon Cancer Stage II Evaluation	NCT04089631	Colon Cancer St...	Capecitabine	18 Years -	Technische Universität Dresden
Randomized Trial on Adjuvant Chemotherapy in Colon Carcinoma Dukes B	NCT00309543	Colon Cancer St...	Fluorouracil Leucovorin	18 Years - 80 Years	Austrian Breast & Colorectal Cancer Study Group
Circulating Tumor DNA Based Adjuvant Chemotherapy in Stage II Colon Cancer Patients: the MEDOCC-CrEATE Trial	NCT06434896	Circulating Tum... Recurrence Colon Cancer St...	ctDNA analysis ...	18 Years -	UMC Utrecht
Circulating Tumor DNA Based Adjuvant Chemotherapy in Stage II Colon Cancer Patients: the MEDOCC-CrEATE Trial	NCT06434896	Circulating Tum... Recurrence Colon Cancer St...	ctDNA analysis ...	18 Years -	UMC Utrecht

Spots Global Cancer Trial Database for colon cancer stage ii