National clinical study

CIRCPAC – Implementing non-invasive circulating tumor DNA and circular DNA analysis in patients with localized pancreatic cancer to optimize the pre-and postoperative treatment

In the present study, we will investigate if plasma circulating tumor DNA (ctDNA) and extrachromosomal circular DNA (eccDNA) measured before and after resection for pancreatic cancer can improve our ability to predict resectibility, early recurrence and prognosis (substudy I). Furthermore, we will investigate if plasma ctDNA combined with CT-scan and endoscopic ultrasound guided surveillance will increase the median overall survival compared with standard-of-care surveillance in patients resected for stage I-III pancreatic ductal adenocarcinoma (substudy II).

ClinicalTrials.gov: NCT05788744

The project received funding in 2020 

Abstract

Perspectives
Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with surgery being the only potentially curable treatment. However, even for the patients receiving surgery for PDAC about 80% have a recurrence in the first few years postsurgery.

In the present study, we will investigate if plasma circulating tumor DNA (ctDNA) and extrachromosomal circular DNA (eccDNA) measured before and after resection for pancreatic cancer can improve our ability to predict resectibility, early recurrence and prognosis (substudy I). Furthermore, we will investigate if plasma ctDNA combined with CT-scan and endoscopic ultrasound (EUS) guided surveillance increase the median overall survival compared with standard-of-care surveillance in patients resected for stage I-III PDAC (substudy II).

Background
In Denmark around 1,300 people are diagnosed with PDAC each year. Less than 20% are eligible for surgery since most patients are diagnosed with locally advanced or metastatic disease. Earlier detection of postoperative recurrence increases the number of treatment options and the likelihood of effective recurrence treatment. The guidelines in Denmark recommend CT scans at 6 and 12 months after surgery, and measurement of CA19-9 and hemoglobin (among other lab tests) and a history and clinical evaluation every 3 months the 1. year and every 6 months for 2 years. With this surveillance program the patients often have severe metastatic disease and performance status 1 or 2 at time of recurrence, which limits the treatment options.

Observational studies in patients with PDAC have shown that serial analyses of ctDNA detect postoperative residual molecular disease before clinical recurrence is detected by CT-scan. Intensified surveillance by CT-scan and EUS should also enable earlier clinical recurrence detection than standard-of-care surveillance.

Aim
The primary aim is to investigate if plasma ctDNA combined with CT-scan and EUS guided surveillance increases the median overall survival compared with standard-of-care surveillance of patients resected for stage IIII PDAC and treated with adjuvant chemotherapy. Secondary aims include survival benefit at 3- and 5 years, lead time between positive ctDNA analysis and recurrence detected on a CT-scan or EUS, cost effectiveness, and quality of life.

Methods
A total of 700 patients surgically resected for pancreatic cancer at four surgical departments in Denmark is planned for inclusion in substudy I. Substudy II is the randomized part, where 410 patients with PDAC and no recurrence 6 months post-surgery is randomized in a 1:1 manor. Patients will be randomized to either Arm A (experimental) or Arm B (control).

In Arm A patients will have blood drawn for ctDNA analyses alongside routine blood sampling every 3 months for 3 years or until disease recurrence. The plasma ctDNA analysis will be performed within 14 days after blood sampling and the patient will be informed about the result of ctDNA. If plasma ctDNA is positive at any time then a CT-scan and an EUS will be performed every 3 months until time of recurrence, or up to 3 years. If plasma ctDNA is negative then CT-scan and EUS will only be performed every 6 months until time of recurrence or up to 3 years.

In Arm B patients will follow the standard follow-up program according to local guidelines for up 3 years. The patients in arm B will only have a CT-scan if they have clinical symptoms of recurrence. The patients in Arm B will have blood samples drawn every 6 months for up to 3 years, or until disease recurrence. The plasma ctDNA analyses in arm B will first be performed at the end of the study.

Expected outcome
This study will demonstrate the feasibility and clinical benefit of plasma ctDNA-guided surveillance in patients resected for stage I-III PDAC.

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