National clinical study

IMPROVE-IT2: Implementing non-invasive circulating tumor DNA analysis to optimize the operative and postoperative treatment for patients with colorectal cancer – Intervention Trial 2

The IMPROVE-IT2 study aims to investigate the potential benefit of postoperative surveillance guided by ctDNA for stage III CRC patients, compared to the current approach of one-size-fits-all CT-scan surveillance. In the experimental arm of the study, patients will undergo serial ctDNA analysis and be stratified into high- and low-risk recurrence groups. High-risk ctDNA-positive patients receive high-intensity radiological surveillance, while low-risk ctDNA-negative patients receive one end-of-study CT-scan.

ClinicalTrials.gov: NCT04084249

The project received funding in 2023

Abstract

Background:
After undergoing surgery and receiving adjuvant therapy, around one-third of patients with stage III CRC experience recurrence. Unfortunately, only approximately 15% of these recurrences are detected in time for curative-intent intervention, leaving the majority with limited palliative or best-supportive care options. The 5-year survival rate for patients who can receive curative-intent treatment is 40-60%, compared to less than 10% for those who cannot. Early detection of recurrence is key to improving patient outcomes, but there is currently no method in clinical use for identifying those at highest risk of recurrence.

Detection of ctDNA following adjuvant chemotherapy has been shown to effectively stratify stage III patients into high and low-recurrence risk groups (HR, 29.0; 95% CI, 6.4-130). Standard radiological surveillance typically detects recurrence within 8.7 months (range: 3-16.5 months) after ctDNA detection. Therefore, initiating intense radiological follow-up as soon as ctDNA is detected may result in earlier recurrence detection, increasing the fraction of patients eligible for curative intent intervention and ultimately improving survival rates.

Hypothesis:
Differentiated surveillance based on ctDNA stratification will result in earlier detection of recurrent disease, while tumor burden is low. The rationale behind this hypothesis is based on the principle that treating fewer and smaller lesions is more effective than treating multiple and larger lesions, which is a fundamental principle of oncology. The expected outcome is improved treatment and survival.

Objectives:
IMPROVE-IT2 is a national randomized controlled trial investigating the benefit of ctDNA-guided post-treatment surveillance compared to standard-of-care radiological surveillance in patients with CRC. The primary objective is to investigate if ctDNA-guided surveillance increases the fraction of relapsing patients receiving curative-intent resection or local treatment. Secondary objectives include investigation of the impact on survival, quality of life (QoL), fear of recurrence, and cost-effectiveness.

Study outline:
The study population is stage III and high-risk stage II CRC patients treated with resection and adjuvant chemotherapy. Patients will be randomized 1:1 into two groups: ctDNA-guided surveillance without routine CT scans (experimental arm), and standard-of-care surveillance with CT scans (control arm). In the experimental arm, ctDNA analysis is performed at months 4, 8, 12, 16, 20, and 24 postoperative. Upon ctDNA detection, patients are assessed with a whole-body PET/CT scan, followed by PET/CT scans every 3 months until relapse detection. Patients who test negative for ctDNA will not be scanned, except for an end-of-study CT scan at month 36. In the control arm, patients will undergo CT scans at 12 and 36 months in accordance with the Danish guidelines. QoL and fear of recurrence are assessed at months 12, 24, and 36 in both arms.

Perspectives:
This randomized trial is the first to investigate the clinical usefulness of ctDNA stratification for guiding the intensity of postoperative surveillance. If successful, it will represent a paradigm shift in the postoperative management of CRC by personalizing surveillance and redirecting resources towards those at greatest risk of recurrence. This shift is expected to result in the earlier detection of recurrences when tumor burden is low, leading to more effective treatment and improved survival. The study is being conducted on a national level within the Danish Colorectal Cancer Group, which will facilitate the implementation of its findings into national guidelines

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