Changing paradigm in pancreatic cancer: from adjuvant to neoadjuvant chemoradiation

Historically, management of pancreatic cancer has been determined based on whether the tumor was amenable to resection and all patients deemed resectable received curative intent surgery followed by adjuvant therapy with chemotherapy (CT) ± RT. However, patients who undergo resection with microscopic (R1) positive margins have inferior rates of survival. The purpose of this study is to identify patients who have undergone pancreatectomy for pancreatic cancer, determine the surgical margins, types of adjuvant therapies given and patterns of failure. Our hypothesis was that in patients who have surgery without pre-operative therapy, there is a high rate of R1 resections and subsequent local recurrence, despite adjuvant therapy.

Seventy-one patients with curative resections for pancreatic cancer between 2003 and 2015 were reviewed. Tumor stage, margin status, distance to closest margin, receipt of adjuvant therapy and length of survival were collected. Patients were divided into two groups based on whether they received adjuvant CT + RT (n=37) or CT alone (n=37). Patients were further divided based on whether resection was R1 (n=29) or R0 (n=42). Wilcoxon survival tests and Cox proportional hazards regression models were performed to determine the effects of CT + RT vs. CT alone, stratified by surgical margin status.

Of the 29 patients (39%) who had R1, 15 received CT + RT and 14 received only CT. Patients who received CT + RT experienced a significantly longer period of PFS (13 vs. 7.5 mos, P=0.03) than patients who received CT alone. However, there was no significant difference found in time to death post cancer resection between CT + RT vs. CT alone (P=0.73). Of the 42 patients with R0, 21 received CT + RT and 21 received CT. There was a trend towards increase in PFS in patients treated with CT + RT (25 vs. 17 months, P=0.05), but there was no significant increase in time to death compared to patients treated with CT alone (P=0.53. Of the 36 patients with CT + RT, 21 had R0 and 15 had R1. Patients with R0 were more likely to have longer PFS (25 vs. 13 months, P=0.06), but there was no significant difference in time to death compared to patients with CT alone (P=0.68).

After curative resection, the addition of RT to CT improves PFS in both R0 and R1 settings. However, patients with R1 have significantly worse PFS and OS compared to patients with R0 and even aggressive adjuvant therapy does not make up for the difference. The paradigm has shifted and now for patients with resectable pancreatic cancers we recommend neoadjuvant CT + RT to improve RT targeting and treatment response assessment and most importantly, improve chances of obtaining R0.