DEFINING EFFECTIVE NEOADJUVANT CHEMOTHERAPY (NAC) IN PDAC, IMPLICATIONS FROM SURVIVAL AND PATTERN OF FAILURE IN PATIENTS WHO RECEIVED NAC
Hao Liu*1, Mark D'Alesio1, Samer AlMasri1, Abdulrahman Y. Hammad1, Annissa deSilva1, Caroline Rieser1, Eishan Ashwat1, Erica D. Hampton1, Steven Lebowitz1, Hussein H. Khachfe1, Aatur Singhi1, Nathan Bahary2, Kenneth Lee1, Amer H. Zureikat1, Alessandro Paniccia1
1Surgery, UPMC, Pittsburgh, PA; 2Allegheny Health Network, Pittsburgh, PA
Introduction
Neoadjuvant chemotherapy (NAC) is gaining popularity over surgery-first (SF) approach in treating resectable and borderline resectable pancreatic ductal adenocarcinoma (PDAC). Although CA19-9 change during NAC predicts oncological outcomes among NAC patients, what constitutes effective neoadjuvant chemotherapy in resectable or borderline resectable PDAC patients is unknown.
Methods
We retrospectively analyzed resectable and borderline resectable PDAC patients who underwent pancreaticoduodenectomy (2010-2019) at a single institution. Optimal CA19-9 response was defined as normalization AND >50% reduction. Radiological evidence of metastasis development in the liver, lung, peritoneal cavity, and local recurrence was defined as disease progression. We utilized Kaplan-Meier and multivariable-adjusted Cox models, and competing risk subdistribution methods for statistical analysis. The propensity score of receiving neoadjuvant chemotherapy was calculated by age, gender, age-adjusted CCI, pre-treatment CA19-9, and administration of neoadjuvant radiation therapy. Overall survival (OS) was calculated from both diagnosis and surgery to account for the immortal time bias of receiving NAC.
Results
586 patients were included in this study. The multivariable-adjusted analysis demonstrated OS benefit in the NAC group only when OS was calculated from diagnosis (HR=0.77, p=0.021), but not from surgery (HR=0.89, p=0.312). However, in 59 patients who achieved optimal CA19-9 response, OS is significantly longer than the 134 patients with suboptimal CA19-9 response (39.3m vs. 21.5m, p=0.005) or the 117 SF patients (39.3m vs. 19.5m, p<0.001). Notably, a suboptimal CA19-9 response conferred no OS advantage compared to SF patients in both unadjusted and multivariable-adjusted models, even when calculating OS from diagnosis (HR=0.86, p=0.378).
Liver metastasis was significantly reduced in patients with optimal CA19-9 response to NAC (HR 0.41, p=0.02). However, lung metastasis was not affected, even with optimal CA19-9 response (HR 1.63, p=0.2). There is also no significant reduction in peritoneal metastatic progression or local recurrence reduction, even with optimal CA19-9 response.
Conclusions
We identified a CA19-9 response to NAC of "normalization AND >50% reduction" as the marker for effective NAC. Suboptimal CA19-9 NAC responses correlated with no survival benefit compared to the SF approach, even when accounting for the NAC immortal-time. However, optimal CA19-9 is associated with longer survival with a significant reduction in metastatic progression in the liver, but not other sites. This result should be verified in a multi-institutional study.
Abstract Figure 1
Unadjusted Kaplan-Meier Survival Analysis (KM) and Multivariable-adjusted Cox Proportional Hazards Model (CPH) on patients with and without neoadjuvant chemotherapy (NAC) (A and C) and on patients who had optimal and suboptimal CA19-9 response to NAC (B and D), counting from the time of diagnosis (A and B) and surgery (C and D).
Unadjusted Kaplan-Meier (KM) analysis on time to liver (E) and lung (F) metastatic progression from the time of diagnosis, as well as unadjusted KM and multivariate-adjusted Cox Proportional Hazards Ratio Model on time to liver (G) and lung (H) metastatic progression from the time of surgery.
*Covariates adjusted in multivariable CPH models include age, gender, Charlson Comorbidity Index (CCI), radiation therapy, vascular resection, tumor size, pre-treatment CA19-9, margin, lymph node ratio (LNR), lymphovascular invasion (LVI), perineural invasion (PNI), Grade, post-op complication, and adjuvant chemotherapy.
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