Sequential neoadjuvant chemoradiotherapy (CRT) followed by curative surgery vs. primary surgery alone for resectable, non-metastasized pancreatic adenocarcinoma: NEOPA- a randomized multicenter phase III study (NCT01900327, DRKS00003893, ISRCTN82191749)

Michael Tachezy, Florian Gebauer, Cordula Petersen, Dirk Arnold, Martin Trepel, Karl Wegscheider, Phillipe Schafhausen, Maximilian Bockhorn, Jakob Robert Izbicki, Emre Yekebas, Michael Tachezy, Florian Gebauer, Cordula Petersen, Dirk Arnold, Martin Trepel, Karl Wegscheider, Phillipe Schafhausen, Maximilian Bockhorn, Jakob Robert Izbicki, Emre Yekebas

Abstract

Background: Median OS after surgery in curative intent for non-metastasized pancreas cancer ranges under study conditions from 17.9 months to 23.6 months. Tumor recurrence occurs locally, at distant sites (liver, peritoneum, lungs), or both. Observational and autopsy series report local recurrence rates of up to 87% even after potentially "curative" R0 resection. To achieve better local control, neoadjuvant CRT has been suggested for preoperative tumour downsizing, to elevate the likelihood of curative, margin-negative R0 resection and to increase the OS rate. However, controlled, randomized trials addressing the impact of neoadjuvant CRT survival do not exist.

Methods/design: The underlying hypothesis of this randomized, two-armed, open-label, multicenter, phase III trial is that neoadjuvant CRT increases the three-year overall survival by 12% compared to patients undergoing upfront surgery for resectable pancreatic cancer. A rigorous, standardized technique of histopathologically handling Whipple specimens will be applied at all participating centers. Overall, 410 patients (n=205 in each study arm) will be enrolled in the trial, taking into regard an expected drop out rate of 7% and allocated either to receive neoadjuvant CRT prior to surgery or to undergo surgery alone. Circumferential resection margin status, i.e. R0 and R1 rates, respectively, surgical resectability rate, local and distant disease-free and global survival, and first site of tumor recurrence constitute further essential endpoints of the trial.

Discussion: For the first time, the NEOPA study investigates the impact of neoadjuvant CRT on survival of resectable pancreas head cancer in a prospectively randomized manner. The results of the study have the potential to change substantially the treatment regimen of pancreas cancer.

Trial registration: Clinical Trial gov: NCT01900327, DRKS00003893, ISRCTN82191749.

Figures

Figure 1
Figure 1
Trial flow. Patients are allocated either to intervention or control group after randomization. Patients in the intervention group undergo sequential neoadjuvant CRT (yellow bars) followed by curative surgery. Patients in the control group are subjected to upfront surgery. After completion of the study, subset analysis is performed stratifying patients with resectable vs. borderline resectable lesions. Both groups will receive adjuvant chemotherapy. No postoperative, adjuvant EBRT in patients undergoing upfront surgery (group 2) is performed.
Figure 2
Figure 2
Follow-up and study visits. Study visits will be performed in 3-months intervals within the first 18 months and in 6-months intervals thereafter. Total follow-up will be 24 months after end-of-recruitment or 36–72 months after randomization.

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