Background: Neoadjuvant multi-agent chemotherapy and stereotactic body radiation therapy (SBRT) are utilized to increase margin negative (R0) resection rates in borderline resectable pancreatic cancer (BRPC) or locally advanced pancreatic cancer (LAPC) patients. Concerns persist that these neoadjuvant therapies may worsen perioperative morbidities and mortality.

Methods: Upfront resection patients (n=241) underwent resection without neoadjuvant treatment for resectable disease. They were compared to BRPC or LAPC patients (n=61) who underwent resection after chemotherapy and 5 fraction SBRT. Group comparisons were performed by Mann-Whitney U or Fisher’s exact test. Overall Survival (OS) was estimated by Kaplan-Meier and compared by log-rank methods.

Results: In the neoadjuvant therapy group, there was significantly higher T classification, N classification, and vascular resection/repair rate. Surgical positive margin rate was lower after neoadjuvant therapy (3.3% vs. 16.2%, P=0.006). Post-operative morbidities (39.3% vs. 31.1%, P=0.226) and 90-day mortality (2% vs. 4%, P=0.693) were similar between the groups. Median OS was 33.5 months in the neoadjuvant therapy group compared to 23.1 months in upfront resection patients who received adjuvant treatment (P=0.057).

Conclusions: Patients with BRPC or LAPC and sufficient response to neoadjuvant multi-agent chemotherapy and SBRT have similar or improved peri-operative and long-term survival outcomes compared to upfront resection patients.


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Keywords: Radiotherapy; neoadjuvant therapy; pancreatic neoplasms 


INTRODUCTION

Pancreatic cancer is currently the fourth most common cause of cancer death in the USA, and is projected to become the second most common by 2030 (1). Long-term survival is less than 2% in unresectable adenocarcinoma patients (2). However, approximately 15% of patients present with upfront resectable cancer, and 5-year survival as high as 31.4% is observed after standard of care pancreatectomy and adjuvant chemotherapy. Therefore, some efforts to improve survival in pancreatic cancer involve expanding the pool of patients who undergo complete tumor resection. This must be balanced with caution, as margin positive resection is associated with a poor prognosis (3). Thus, a subset of patients has been termed borderline resectable pancreatic cancer (BRPC), implying the possibility of margin negative resection after neoadjuvant therapy (4).

Numerous single institution studies have investigated neoadjuvant treatments for BRPC with no current standard of care (5). A 2011 meta-analysis of 14 prospective trials of neoadjuvant chemoradiotherapy with conventional radiation and assorted chemotherapies found that about one-third of tumors initially marginal for resection were ultimately resected (6). Given the lack of randomized trials, two groups have reported survival benefit for mixed populations of resectable and BRPC patients receiving neoadjuvant therapy compared to upfront resection (7,8). Others have reported equivalent survival (9-12).

An alternate neoadjuvant approach utilizes chemotherapy in sequential fashion with stereotactic body radiation therapy (SBRT)—a short course of high dose, precisely focused radiotherapy that might overcome the radioresistance of pancreatic adenocarcinoma. Single institutions have reported margin negative resection rates above 90% and minimal serious radiation associated toxicity (13,14).

There is continued apprehension about applying any type of radiotherapy before pancreatectomy. Analysis of the American College of Surgeons National Surgical Quality Improvement Program database revealed increased 30-day mortality after pancreaticoduodenectomy among patients who received preoperative radiation therapy (15). One case series demonstrated a 37.5% rate of portal vein (PV) stenosis after neoadjuvant chemoradiotherapy and pancreatectomy (16). Further, early studies of SBRT and single agent chemotherapy in locally advanced pancreatic cancer (LAPC) without pancreatectomy reported intolerably high acute and late toxicity rates not supported by more recent studies (17,18). To explore whether this intensified regimen worsened perioperative or long-term outcomes, we compared resectable patients who underwent upfront resection to patients resected after sufficient response following neoadjuvant treatment with SBRT and chemotherapy.