Impact of Adjuvant Chemotherapy on Resected Intraductal Papillary Mucinous Neoplasm-Derived Pancreatic Cancer: Results from an International Multicenter Study

Academic Background

Intraductal Papillary Mucinous Neoplasm (IPMN) is the most common type of pancreatic cyst, and its incidence and prevalence have been increasing due to the widespread use and improved quality of cross-sectional imaging in modern medicine. It is estimated that approximately 15% of Pancreatic Ductal Adenocarcinoma (PDAC) originates from IPMN. Although IPMN-derived PDAC is biologically distinct from PanIN-derived PDAC, current adjuvant therapy strategies for IPMN-derived PDAC are largely based on clinical practices for PanIN-derived PDAC. Due to limited evidence, it remains unclear whether patients with IPMN-derived PDAC benefit from adjuvant chemotherapy. Therefore, this study aims to evaluate the role of adjuvant chemotherapy in IPMN-derived PDAC through an international multicenter retrospective cohort study.

Source of the Paper

This paper was co-authored by Joseph R. Habib, Benedict Kinny-Köster, and other scholars from multiple international research institutions, including New York University Grossman School of Medicine, Heidelberg University Hospital, Massachusetts General Hospital, and 15 other international centers. The study was published on September 10, 2024, in the Journal of Clinical Oncology (JCO), with the DOI: https://doi.org/10.1200/jco.23.02313.

Research Process

Study Design

This study is an international multicenter retrospective cohort study that included patients who underwent pancreatic resection and were diagnosed with IPMN-derived PDAC between 2005 and 2018 at 16 international centers. Patients with concomitant PanIN-derived PDAC, those who received neoadjuvant therapy, those with positive surgical margins (R2), or those who died within 90 days post-surgery due to non-cancer-related causes were excluded.

Pathological Assessment

All pathological diagnoses were reviewed by local pancreatic pathologists to ensure that all patients had invasive carcinoma arising from IPMN. The study used the American Joint Committee on Cancer (AJCC) 8th edition TNM staging system for staging and stratified patients based on lymph node status and preoperative serum carbohydrate antigen 19-9 (CA19-9) levels.

Statistical Analysis

The study used Cox regression models for risk-adjusted survival analysis, Kaplan-Meier curves, and Log-rank tests for survival analysis. Additionally, logistic regression was performed to identify factors influencing the administration of adjuvant chemotherapy, and a decision tree model was proposed to categorize patients into overtreatment, undertreatment, and optimal treatment groups.

Main Results

Patient Characteristics

A total of 1031 patients were included in the study, with a mean age of 67.9 years, and 54.8% were male. Preoperative CA19-9 levels were elevated in 54.9% of patients, with 52.4% having mildly elevated levels (≥37 to <200 m/ml) and 47.6% having significantly elevated levels (≥200 m/ml). Partial pancreatoduodenectomy was performed in 56.3% of patients, 29.7% had R1 margins, 68.2% had tubular subtype, and 63.1% had moderately differentiated disease.

Survival Analysis

The median follow-up was 33.3 months, and the median overall survival (OS) was 64.3 months. Multivariable analysis showed that increasing age, significantly elevated CA19-9 levels, perineural invasion (PNI), and lymph node metastasis were significantly associated with worse OS. Patients who received adjuvant chemotherapy had improved OS (HR, 0.66; 95% CI, 0.46-0.95).

Impact of Adjuvant Chemotherapy

In node-positive patients, those who received adjuvant chemotherapy had significantly longer median OS (20.1 months vs. 32.0 months, p=0.015). Specifically, in node-positive patients with elevated CA19-9 levels, adjuvant chemotherapy was associated with a 34.4-month improvement in median OS (p=0.047), while in those with significantly elevated CA19-9 levels, adjuvant chemotherapy was associated with a 12.6-month survival benefit (p<0.001). However, in node-negative patients, regardless of CA19-9 levels, adjuvant chemotherapy did not significantly improve OS.

Decision Tree Model

Based on the study results, a decision tree model was proposed, recommending adjuvant chemotherapy for node-positive patients with elevated CA19-9 levels, while not recommending it for node-negative patients or those with normal CA19-9 levels. According to this model, 18.1% of patients may have been undertreated, and 61.2% may have been overtreated.

Conclusion

This large international multicenter study revealed that current practices in adjuvant chemotherapy for IPMN-derived PDAC may involve overtreatment or undertreatment. The findings suggest that adjuvant chemotherapy does not provide a survival benefit for node-negative patients or those with normal CA19-9 levels, while it significantly improves survival in node-positive patients with elevated CA19-9 levels. The proposed decision tree model provides a basis for clinical decision-making regarding adjuvant chemotherapy and highlights the need for future randomized controlled trials to validate these findings.

Research Highlights

1. Large-Scale International Multicenter Study: This study is the largest international multicenter study to date on the efficacy of adjuvant chemotherapy in IPMN-derived PDAC, involving 1031 patients from 16 centers.
2. Decision Tree Model: The study proposed a decision tree model based on lymph node status and CA19-9 levels to assist clinicians in selecting patients for adjuvant chemotherapy.
3. Revelation of Overtreatment and Undertreatment: The study found that nearly half of the patients may have been overtreated or undertreated, indicating the need for optimization in current clinical practices.
4. Future Research Directions: The study emphasized the need for randomized controlled trials to validate the efficacy of adjuvant chemotherapy in patients with IPMN-derived PDAC and to inform the development of specific treatment guidelines.

Research Significance

This study provides important clinical evidence for the selection of adjuvant chemotherapy in patients with IPMN-derived PDAC, revealing issues in current treatment practices and proposing improvements. The findings not only have significant scientific value but also offer practical applications for clinical practice, helping to optimize patient treatment plans, reduce unnecessary treatment-related toxicity, and improve patient quality of life.