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Hepato-pancreato-biliary

E192: Re-evaluating the Role of Neoadjuvant Chemotherapy in Pancreatic Ductal Adenocarcinoma: Unveiling the Impact of Immortal Time Bias on Survival

Introduction: While the role of neoadjuvant chemotherapy (NAC) for potentially resectable pancreatic ductal adenocarcinoma (PDAC) is still evolving, previous studies have demonstrated possible advantages of NAC over upfront resection. However, most of these studies did not adjust for immortal time bias (ITB), which arises when there is a period of time in which the outcome of interest (e.g., death) cannot occur in the treatment group (e.g., patients who receive NAC). This leads to an exaggerated association between the treatment and the outcome. In this context, our aim was to examine the impact of NAC versus upfront surgery on overall survival (OS) after adjusting for ITB in patients with resectable PDAC.

Methods: Our cohort consisted of adult patients with resectable PDAC in the National Cancer Database between 2010 and 2017. Survival outcomes between patients who received NAC versus those who underwent upfront surgery were compared using Kaplan-Meier curves and multivariable Cox regression models, adjusting for factors such as age, sex, race, year of diagnosis, insurance status, Charlson-Deyo comorbidity score, clinical stage, hospital type, and the receipt of adjuvant chemotherapy and radiotherapy. To account for ITB, we utilized a multivariable time-varying Cox regression model, adjusting for the aforementioned variables.

Results: In a cohort of 14,256 patients with resectable PDAC, 11,619 patients underwent upfront surgery and 2,637 patients received NAC. The median age of the patients was 68 (IQR 61-75) and 50% were female. The majority of patients were white (87%), had insurance (98%), and were treated at an academic center (52%). Before adjusting for ITB, patients who received NAC had a median OS of 31.6 months compared to 25.8 months for those who underwent upfront surgery (Hazard Ratio [HR] 0.75, 95% CI 0.71-0.79, p< 0.001). However, after adjusting for ITB, there was no significant survival difference between patients who received NAC versus upfront surgery (HR 1.0, 95% CI 0.93-1.09, p >0.9).

Conclusions: While the initial multivariable analysis noted a survival benefit with NAC, NAC was no longer associated with improved overall survival for patients with resectable PDAC after accounting for ITB. This study highlights the importance of adjusting for ITB when evaluating treatment outcomes; otherwise, there is a risk of misinterpreting the true benefit of the treatment.

Learning Objectives:

  • Upon completion, participants will be able to explain the concept of immortal time bias (ITB), how it arises, and its implications on treatment outcome evaluations.
  • Upon completion, participants will be able to differentiate between the survival outcomes of PDAC patients who received NAC and those who underwent upfront surgery before and after adjusting for ITB.
  • Upon completion, participants will be able to distinguish between Kaplan-Meier curves, multivariable Cox regression models, and time-varying Cox regression models.