In general, pancreatic cancer has a poor prognosis and long-term survival remains limited, including for patients treated with tumor resection and adjuvant chemotherapy. Neoadjuvant chemotherapy, with or without radiation, is being investigated in several trials with the aim of improving resection rates and survival. Since meta-analyses of data from phase II and retrospective studies indicate survival benefit with neoadjuvant therapy, many centers recommend neoadjuvant therapy over upfront surgery for patients with resectable or borderline resectable disease. However, the role of neoadjuvant chemoradiotherapy (CRT) remains uncertain. Initial results from the Dutch randomized, phase III PREOPANC trial (N=246), which compared neoadjuvant CRT followed by surgery and adjuvant gemcitabine with upfront surgical resection and adjuvant gemcitabine, did not show a survival benefit. At a median follow-up of 27 months, the median overall survival (OS) was 16.0 months with neoadjuvant CRT and 14.3 months with upfront surgery (hazard ratio [HR], 0.78; P = 0.096).

A recent report published in the Journal of Clinical Oncology features long-term survival data from this trial. At a median follow-up of 59 months, OS was improved in the neoadjuvant CRT group compared with the upfront surgery group (15.7 vs. 14.3 months; HR, 0.73; P = 0.025) with a 5-year survival of 20.5% vs. 6.5%. The effect of neoadjuvant CRT on OS trended toward a survival benefit across all subgroups, although a significant benefit was seen only in the borderline resectable patients (HR, 0.67; P = 0.046). The secondary outcomes of disease-free survival, locoregional failure-free interval, and pathologic outcomes were also significantly better after neoadjuvant treatment. Regarding resection rates, fewer patients in the neoadjuvant CRT group underwent a resection following surgical exploration compared with those in the upfront surgery group (61% vs. 72%). The authors explained that the lower resection rate in the neoadjuvant CRT group is due to disease progression during neoadjuvant treatment: “We hypothesize that these patients would not have benefited from upfront resection because early progression reflects aggressive tumor biology rather than a missed opportunity for resection. This is reflected by the superior survival in the neoadjuvant CRT group, despite the lower resection rate.” Of interest, R0 resection was higher with neoadjuvant CRT than with upfront surgery (72% vs. 43%; P < 0.001). Furthermore, more patients received chemotherapy in the neoadjuvant CRT group compared with the upfront surgery group (77% vs. 51%; P < 0.001), and the cumulative dose was higher in the neoadjuvant group, suggesting better tolerability with neoadjuvant administration.

In their discussion, the authors highlighted that long-term follow-up is required to detect a clinically relevant survival difference. They also pointed out an important limitation of PREOPANC study, the use of adjuvant gemcitabine monotherapy, which has since been eclipsed by multiagent regimens such as FOLFIRINOX and gemcitabine plus capecitabine. However, this trial has paved the way for the PREOPANC-2 trial, which compares neoadjuvant gemcitabine-based CRT with neoadjuvant FOLFIRINOX and recently completed accrual in less than 3 years, with results expected in 2022. In addition, the role of neoadjuvant FOLFIRINOX in resectable pancreatic cancer is being investigated in four ongoing clinical trials: PREOPANC-3, NorPACT-1, PANACHE01-PRODIGE48, and ALLIANCE A021806.

Reference:
Versteijne E, et al. J Clin Oncol. 2022 Jan 27 [Online ahead of print].