| Objective: |
2.1.1 Primary objective 1 (P1)
To confirm that patients with high risk of recurrence can be identified with ctDNA profiling performed immediately after treatment for CRC.
Specifically, we aim to determine in patients with localized colorectal cancer if the 3-year disease free survival (3y-DFS) is associated with detection of ctDNA in plasma immediately after:
• Curative intended surgery (P1A, stratified for UICC stage and adjuvant therapy)
• Adjuvant chemotherapy (P1B)
2.1.2 Primary objective 2 (P2)
To identify a cohort of stage I and stage II CRC patients without risk-factors currently qualifying for adjuvant chemotherapy but with ctDNA detected in post-operative plasma samples. Identification aims at inclusion in a phase II trial of adjuvant chemotherapy described in detail in IMPROVE INTERVENTIONAL ONCOLOGICAL TRIAL – IMPROVE IT.
2.2 Secondary objectives
2.2.1 Secondary objective 1 (S1)
To determine if the detection of ctDNA in post-operative plasma samples after intended curative resection for CRC correlates with pathological measures reflecting the quality of the primary surgery.
Specifically, we aim to determine the association between ctDNA detected in post-operative plasma samples and:
• The plane of surgery in the pathological specimen; muscular plane, intrameso-colic/rectal plan, or meso-colic/rectal plane, and
• The level of resection of the tumor feeding arteries as estimated by: 1) the length of the feeding artery in the resection specimen, and 2) the length of the artery residue remaining in the patient measured on the first follow-up CT-scan at month 12.
2.2.2 Secondary objective 2 (S2)
Furthermore, to ensure detection of ctDNA in post-operative samples reflects quality of surgery and not unrecognized metastasis, we aim to validate the quality of pre-operative staging CT-scan in patients with detection of ctDNA in plasma samples after curative resection compared to patients without ctDNA after curative resection.
2.2.3 Secondary objective 3 (S3)
To use ctDNA to evaluate quality improvement of colorectal surgery at an organizational level after implementation of an extensive 2-year focused post-graduate training program in colorectal surgery. Specifically, we aim:
• To compare the proportion of patients with ctDNA detected in post-operative plasma samples after curative resection for colorectal cancer before and after implementation of the training program at five Danish surgical centers.
• To compare the proportion of patients with ctDNA detected in post-operative plasma samples after CME surgery at the five surgical centers in the training program to a single Danish center (Hillerød) which is not in the training program, but has already documented a very high quality of CME surgery (reference center).
2.2.4 Secondary objective 4 (S4)
To investigate the effect of adjuvant chemotherapy on the level of ctDNA.
• Specifically, in patients ctDNA positive after surgery we will compare the ctDNA level in blood samples drawn before and after adjuvant chemotherapy and correlate the change in ctDNA level to oncological outcome (Time to clinical recurrence, disease free survival, and overall survival).
2.2.5 Secondary objective 5 (S5)
To investigate if time to Molecular recurrence using serial ctDNA analysis of longitudinally collect blood samples is shorter than time to Clinical recurrence using standard-of-care radiological imaging surveillance.
2.2.6 Secondary objective 6 (S6)
To investigate the correlation between ctDNA and CT-scanning findings. This analysis will be restricted to time points where the two analyses are made in parallel (12 and 36 months). The potential is that ctDNA analysis predicts the CT-scan result and can be used to guide when to perform CT-scan. Potentially, it also add evidence for the results of CT-scans perform subsequent to an uncertain CT-scan result.
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| Aim: |
The overall objective of these studies are to confirm that ctDNA detected in plasma after intended curative treatment for CRC can be applied in clinical practice as a marker of subclinical residual disease and risk of recurrence. |
| Methods: |
IMPROVE Part_I (Surgery): Observational study
IMPROVE Part_II (Surveillance): Observational study
IMPROVE_IT : Interventional study (https://clinicaltrials.gov/ct2/home NCT03748680) |
| Reason for International Trial: |
The results of the IMPROVE study are expected to be published in international scientific journals. Positive, negative and non-definable findings will be published as soon as at it is considered professionally sound. If results unexpectedly cannot be published in journals other means on publication will be sought such via the partners´ institutional websites.
This will contribute to better understanding and collaboration regarding the utility of ctDNA detected in plasma after CRC surgery, and that it can be applied in clinical practice as a marker of subclinical residual disease and risk of recurrence.
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