Preoperative Chemoradiotherapy Versus Immediate Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Results of the Dutch Randomized Phase III PREOPANC Trial

Eva Versteijne, Mustafa Suker, Karin Groothuis, Janine M Akkermans-Vogelaar, Marc G Besselink, Bert A Bonsing, Jeroen Buijsen, Olivier R Busch, Geert-Jan M Creemers, Ronald M van Dam, Ferry A L M Eskens, Sebastiaan Festen, Jan Willem B de Groot, Bas Groot Koerkamp, Ignace H de Hingh, Marjolein Y V Homs, Jeanin E van Hooft, Emile D Kerver, Saskia A C Luelmo, Karen J Neelis, Joost Nuyttens, Gabriel M R M Paardekooper, Gijs A Patijn, Maurice J C van der Sangen, Judith de Vos-Geelen, Johanna W Wilmink, Aeilko H Zwinderman, Cornelis J Punt, Casper H van Eijck, Geertjan van Tienhoven, Dutch Pancreatic Cancer Group, Eva Versteijne, Mustafa Suker, Karin Groothuis, Janine M Akkermans-Vogelaar, Marc G Besselink, Bert A Bonsing, Jeroen Buijsen, Olivier R Busch, Geert-Jan M Creemers, Ronald M van Dam, Ferry A L M Eskens, Sebastiaan Festen, Jan Willem B de Groot, Bas Groot Koerkamp, Ignace H de Hingh, Marjolein Y V Homs, Jeanin E van Hooft, Emile D Kerver, Saskia A C Luelmo, Karen J Neelis, Joost Nuyttens, Gabriel M R M Paardekooper, Gijs A Patijn, Maurice J C van der Sangen, Judith de Vos-Geelen, Johanna W Wilmink, Aeilko H Zwinderman, Cornelis J Punt, Casper H van Eijck, Geertjan van Tienhoven, Dutch Pancreatic Cancer Group

Abstract

Purpose: Preoperative chemoradiotherapy may improve the radical resection rate for resectable or borderline resectable pancreatic cancer, but the overall benefit is unproven.

Patients and methods: In this randomized phase III trial in 16 centers, patients with resectable or borderline resectable pancreatic cancer were randomly assigned to receive preoperative chemoradiotherapy, which consisted of 3 courses of gemcitabine, the second combined with 15 × 2.4 Gy radiotherapy, followed by surgery and 4 courses of adjuvant gemcitabine or to immediate surgery and 6 courses of adjuvant gemcitabine. The primary end point was overall survival by intention to treat.

Results: Between April 2013 and July 2017, 246 eligible patients were randomly assigned; 119 were assigned to preoperative chemoradiotherapy and 127 to immediate surgery. Median overall survival by intention to treat was 16.0 months with preoperative chemoradiotherapy and 14.3 months with immediate surgery (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P = .096). The resection rate was 61% and 72% (P = .058). The R0 resection rate was 71% (51 of 72) in patients who received preoperative chemoradiotherapy and 40% (37 of 92) in patients assigned to immediate surgery (P < .001). Preoperative chemoradiotherapy was associated with significantly better disease-free survival and locoregional failure-free interval as well as with significantly lower rates of pathologic lymph nodes, perineural invasion, and venous invasion. Survival analysis of patients who underwent tumor resection and started adjuvant chemotherapy showed improved survival with preoperative chemoradiotherapy (35.2 v 19.8 months; P = .029). The proportion of patients who suffered serious adverse events was 52% versus 41% (P = .096).

Conclusion: Preoperative chemoradiotherapy for resectable or borderline resectable pancreatic cancer did not show a significant overall survival benefit. Although the outcomes of the secondary end points and predefined subgroup analyses suggest an advantage of the neoadjuvant approach, additional evidence is required.

Figures

FIG 1.
FIG 1.
CONSORT diagram. CRT, chemoradiotherapy; CT, computed tomography.
FIG 2.
FIG 2.
(A) Overall survival (OS), (B) disease-free survival (DFI), (C) locoregional failure–free interval (LFFI), and (D) distant metastasis–free interval (DMFI) in 246 patients randomly assigned to preoperative chemoradiotherapy (CRT; 119 patients) or immediate surgery (127 patients) according to intention-to-treat analysis. Tick marks indicate censored observations. HR, hazard ratio.
FIG 3.
FIG 3.
(A) Overall survival (OS), (B) disease-free survival (DFI), (C) locoregional failure–free interval (LFFI), and (D) distant metastasis–free interval (DMFI) in the 120 patients who had a resection of the tumor and started the postoperative chemotherapy and randomly assigned to preoperative chemoradiotherapy (CRT; 55 patients) or immediate surgery (65 patients). Tick marks indicate censored observations. HR, hazard ratio.

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