Adjuvant Pancreatic Therapy Guided by MRD
brief summary
Pancreatic adenocarcinoma (PAAD) is a leading cause of cancer-related deaths worldwide. Although surgical resection can be curative, the 5-year overall survival (OS) rate after resection alone is approximately 20%. Adjuvant chemotherapy can improve survival outcomes in patients with resected PAAD. This study will explore the application of ctDNA MRD in guiding adjuvant therapy in these patients. This prospective, randomized, interventional trial will evaluate a ct-DNA MRD-guided adjuvant therapy strategy in PAAD patients who have undergone radical resection at our institution. Prior to adjuvant chemotherapy, patients will be randomized (1:1) to either the experimental arm (Arm A) or the control arm (Arm B). Arm A will receive ct-DNA MRD-guided therapy, while Arm B will receive non-ctDNA-driven standard of care post-operative adjuvant therapy. In Arm A, patients will receive a physician-selected, guideline-recommended adjuvant therapy regimen in 12-week cycles. ctDNA MRD will be assessed before the end of first cycle and at weeks 8 and 11. If two consecutive post-treatment MRD tests are negative, therapy will be "de-escalated" (discontinued) with regular follow-up as determined by the clinician. Otherwise, another treatment cycle will be administered, with the same MRD assessment. Following the second cycle, patients without two negative MRD results (only tested at week 8 and week 11 within each cycle) will "escalate" to a longer duration of chemotherapy (comparing to the 6-month standard of care) at the clinician's discretion. Treatment will continue until disease progression, intolerance, or study termination. Arm B will receive standard post-operative adjuvant therapy for a duration recommended by CSCO guidelines (typically 6 months), followed by regular follow-up every 8 weeks. The primary endpoint is to compare the prognosis, tolerability, and treatment completion rates between the two arms.
detailed description
In pancreatic cancer, circulating tumor DNA (ctDNA) carries tumor-specific mutations (e.g., KRAS, TP53), which can be tracked using next-generation sequencing (NGS) technology to detect minimal residual disease (MRD) after surgery. Previous observational studies suggest that ctDNA-positive patients have a significantly higher risk of postoperative recurrence. In the MRD window (2-12 weeks post-surgery), the median disease-free survival (DFS) for ctDNA-positive patients was only 6.37 months, compared to 33.31 months for ctDNA-negative patients (HR=5.45), indicating that ctDNA-positive patients may require intensified treatment. Furthermore, patients with persistent ctDNA positivity after completing adjuvant chemotherapy (e.g., gemcitabine) still have a high recurrence rate (70%-90%), suggesting the need for alternative treatment strategies.
In a previous study (NCT05479708) evaluating postoperative MRD detection using plasma ctDNA to assess survival benefits and optimize adjuvant chemotherapy strategies in resectable pancreatic cancer patients, we found that MRD-positive patients at 4-8 weeks post-surgery (Landmark MRD) had a higher risk of recurrence. Analysis from Landmark MRD to 36 weeks post-treatment showed that patients who converted from positive to negative MRD status (MRD clearance) had a significantly lower risk of recurrence compared to those who remained positive and those who converted from negative to positive, and MRD clearance was associated with significantly improved overall survival (OS).
Given the significant trauma of pancreatic surgery and the often poor postoperative physical condition of patients, the optimal adjuvant chemotherapy regimen (single-agent/combination, duration, initiation time, etc.) that balances patient recovery and recurrence control remains unclear. Serum biomarker CA 19-9 is commonly used to assess prognosis in pancreatic cancer but is not a reliable predictor of adjuvant therapy efficacy. Imaging methods such as CT/MRI are often used to assess residual tumor or recurrence risk, but their sensitivity and specificity are limited, making it difficult to accurately evaluate real-time tumor burden. Therefore, we designed a prospective, randomized, interventional clinical trial based on ctDNA MRD to guide adjuvant chemotherapy decisions in patients with radically resected pancreatic cancer. The aim is to evaluate whether a ctDNA-guided treatment approach can reduce the use of adjuvant chemotherapy in low-risk patients without increasing recurrence risk, while intensifying treatment in high-risk patients to improve prognosis.
A ctDNA MRD-guided adjuvant therapy approach can allow patients to receive individualized adjuvant treatment. When ctDNA MRD test results are negative, adjuvant chemotherapy can be stopped with active follow-up. This can ensure that clinical benefits are not compromised while avoiding unnecessary chemotherapy. In cases where ctDNA MRD remains positive, continuing treatment can provide patients with more intensive therapy and potentially lead to better prognoses.
official title
Assessing the Impact of Ct-DNA MRD-Guided Adjuvant Therapy on Outcomes in Resectable Pancreatic Cancer