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      Preoperative radiochemotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer (PREOPANC trial): study protocol for a multicentre randomized controlled trial

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          Pancreatic cancer is the fourth largest cause of cancer death in the United States and Europe with over 100,000 deaths per year in Europe alone. The overall 5-year survival ranges from 2–7 % and has hardly improved over the last two decades. Approximately 15 % of all patients have resectable disease at diagnosis, and of those, only a subgroup has a resectable tumour at surgical exploration. Data from cohort studies have suggested that outcome can be improved by preoperative radiochemotherapy, but data from well-designed randomized studies are lacking. Our PREOPANC phase III trial aims to test the hypothesis that median overall survival of patients with resectable or borderline resectable pancreatic cancer can be improved with preoperative radiochemotherapy.

          Methods/design

          The PREOPANC trial is a randomized, controlled, multicentric superiority trial, initiated by the Dutch Pancreatic Cancer Group. Patients with (borderline) resectable pancreatic cancer are randomized to A: direct explorative laparotomy or B: after negative diagnostic laparoscopy, preoperative radiochemotherapy, followed by explorative laparotomy. A hypofractionated radiation scheme of 15 fractions of 2.4 gray (Gy) is combined with a course of gemcitabine, 1,000 mg/m 2/dose on days 1, 8 and 15, preceded and followed by a modified course of gemcitabine. The target volumes of radiation are delineated on a 4D CT scan, where at least 95 % of the prescribed dose of 36 Gy in 15 fractions should cover 98 % of the planning target volume. Standard adjuvant chemotherapy is administered in both treatment arms after resection (six cycles in arm A and four in arm B). In total, 244 patients will be randomized in 17 hospitals in the Netherlands. The primary endpoint is overall survival by intention to treat. Secondary endpoints are (R0) resection rate, disease-free survival, time to locoregional recurrence or distant metastases and perioperative complications. Secondary endpoints for the experimental arm are toxicity and radiologic and pathologic response.

          Discussion

          The PREOPANC trial is designed to investigate whether preoperative radiochemotherapy improves overall survival by means of increased (R0) resection rates in patients with resectable or borderline resectable pancreatic cancer.

          Trial registration

          Trial open for accrual: 3 April 2013

          The Netherlands National Trial Register – NTR3709 (8 November 2012)

          EU Clinical Trials Register – 2012-003181-40 (11 December 2012)

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          Most cited references 35

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          Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head.

          We conducted a phase II trial to assess the outcomes of patients who received preoperative gemcitabine-based chemoradiation and pancreaticoduodenectomy (PD) for stage I/II pancreatic adenocarcinoma. Eligible patients with pancreatic head/uncinate process adenocarcinoma and radiographically defined potentially resectable disease received chemoradiation with 7 weekly intravenous (IV) infusions of gemcitabine (400 mg/m(2) IV over 30 minutes) plus radiation therapy (30 Gy in 10 fractions over 2 weeks). Patients underwent restaging 4 to 6 weeks after completion of chemoradiation and, in the absence of disease progression, were taken to surgery. The study enrolled 86 patients. At the time of restaging, disease progression or a decline in performance status precluded 13 patients from surgery. Seventy-three (85%) of 86 patients were taken to surgery, extrapancreatic disease was found in nine, and 64 (74%) of 86 underwent a successful PD. Median overall survival (86 patients) was 22.7 months with a 27% 5-year survival. Median survival was 34 months for the 64 patients who underwent PD and 7 months for the 22 unresected patients (P < .001). The 5-year survival for those who did and did not undergo PD was 36% and 0%, respectively. Preoperative gemcitabine-based chemoradiation followed by restaging and evaluation for surgery separated the study population into two different subsets: patients likely to benefit from PD (n = 64) and those in whom surgery would be unlikely to provide clinical benefit (n = 22). Furthermore, the encouraging overall survival observed in this large trial supports the continued investigation of gemcitabine-based preoperative therapy in resectable pancreatic cancer.
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            Borderline resectable pancreatic cancer: the importance of this emerging stage of disease.

            Patients with borderline resectable pancreatic adenocarcinoma (PA) include those with localized disease who have tumor or patient characteristics that preclude immediate surgery. There is no optimal treatment schema for this distinct stage of disease, so the role of surgery is undefined. We defined patients with borderline resectable PA as fitting into one of three distinct groups. Group A comprised patients with tumor abutment of the visceral arteries or short-segment occlusion of the Superior Mesenteric Vein. In group B, patients had findings suggestive but not diagnostic of metastasis. Group C patients were of marginal performance status. Patients were treated initially with chemotherapy, chemoradiation, or both; those of sufficient performance status who completed preoperative therapy without disease progression were considered for surgery. Between October 1999 and August 2006, 160 (7%) of 2,454 patients with PA were classified as borderline resectable. Of these, 125 (78%) completed preoperative therapy and restaging, and 66 (41%) underwent pancreatectomy. Vascular resection was required in 18 (27%) of 66 patients, and 62 (94%) underwent a margin-negative pancreatectomy. A partial pathologic response to induction therapy (< 50% viable tumor) was seen in 37 (56%) of 66 patients. Median survival was 40 months for the 66 patients who completed all therapy and 13 months for the 94 patients who did not undergo pancreatectomy (p < 0.001). This is the first large report of borderline resectable PA and includes objective definitions for this stage of disease. Our neoadjuvant approach allowed for identification of the marked subset of patients that was most likely to benefit from surgery, as evidenced by the favorable median survival in this group.
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              Pancreatic cancer: a report of treatment and survival trends for 100,313 patients diagnosed from 1985-1995, using the National Cancer Database.

              The National Cancer Database is an electronic registry system sponsored jointly by the American College of Surgeons Commission on Cancer and the American Cancer Society. Patients diagnosed with pancreatic adenocarcinoma from 1985 to 1995 were analyzed for trends in stage of disease, treatment patterns, and outcomes. Seven annual requests for data were issued by the National Cancer Database from 1989 through 1995. Data on 100,313 patients were voluntarily submitted using a standardized reporting format. The anatomic site distribution was: head, 78%; body, 11%; and tail, 11%. The ratios of limited to advanced disease (Stage I/Stage IV) were 0.70 for tumors in the head, 0.24 for body tumors, and 0.10 for tail tumors. Of all patients, 83% did not have a surgical procedure and 58% did not have cancer-directed treatment. Resection was done for 9,044 (9%) patients, including 22% of those with Stage I disease. The overall 5-year survival rate was 23.4% for patients who had pancreatectomy, compared with 5.2% for those who had no cancer-directed treatment. Overall survival rates for pancreatic cancer have not changed in 2 decades. A small minority of patients presented with limited, resectable disease, but the best survival rates per stage were achieved after surgical resection. Five-year survival rates after resection reported herein corroborated the improved survival rates of more recent large, single institution studies.
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                Author and article information

                Contributors
                0031-205664231 , e.versteijne@amc.uva.nl
                c.vaneijck@erasmusmc.nl
                c.punt@amc.uva.nl
                m.suker@erasmusmc.nl
                a.h.zwinderman@amc.uva.nl
                miriam.dohmen@radboudumc.nl
                k.groothuis@iknl.nl
                o.r.busch@amc.uva.nl
                m.g.besselink@amc.uva.nl
                Ignace.d.Hingh@catharinaziekenhuis.nl
                AtenTije@amphia.nl
                g.a.patijn@isala.nl
                b.a.bonsing@lumc.nl
                Judith.de.vos@mumc.nl
                j.klaase@mst.nl
                S.Festen@olvg.nl
                d.boerma@antoniusziekenhuis.nl
                j.i.erdmann@umcg.nl
                i.q.molenaar@umcutrecht.nl
                HarstE@maasstadziekenhuis.nl
                marion.vanderkolk@radboudumc.nl
                c.r.rasch@amc.uva.nl
                g.vantienhoven@amc.uva.nl
                Journal
                Trials
                Trials
                Trials
                BioMed Central (London )
                1745-6215
                9 March 2016
                9 March 2016
                2016
                : 17
                Affiliations
                [ ]Department of Radiation Oncology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
                [ ]Department of Surgery, Erasmus Medical Center, Postbus 2040, 3000 CA Rotterdam, The Netherlands
                [ ]Department of Medical Oncology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
                [ ]Department of Clinical Epidemiologic Biostatics, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
                [ ]Clinical Research Department, Comprehensive Cancer Organisation the Netherlands (IKNL), Postbus 1281, 6501 BG Nijmegen, The Netherlands
                [ ]Department of Surgery, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
                [ ]Department of Surgery, Catharina Hospital, Postbus 1350, 5602 ZA Eindhoven, The Netherlands
                [ ]Department of Medical Oncology, Amphia Hospital, Postbus 90158, 4800 RK Breda, The Netherlands
                [ ]Department of Surgery, Isala Clinics, Postbus 10400, 8000 GK Zwolle, The Netherlands
                [ ]Department of Surgery, Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, The Netherlands
                [ ]Department of Medical Oncology, Maastricht University Medical Center, Postbus 3035, 6202 NA Maastricht, The Netherlands
                [ ]Department of Surgery, Medical Spectrum Twente, Postbus 50 000, 7500 KA Enschede, The Netherlands
                [ ]Department of Surgery, Onze Lieve Vrouwe Gasthuis, Postbus 95500, 1090 HM Amsterdam, The Netherlands
                [ ]Department of Surgery, Sint Antonius Hospital, Postbus 2500, 3430 EM Nieuwegein, The Netherlands
                [ ]Department of Surgery, University Medical Center Groningen, Postbus 30.001, 9700 RB Groningen, The Netherlands
                [ ]Department of Surgery, University Medical Center Utrecht, Postbus 85500, 3508 GA Utrecht, The Netherlands
                [ ]Department of Surgery, Maasstad Hospital, Maasstadweg 21, 3079 DZ Rotterdam, The Netherlands
                [ ]Department of Surgery, Radboud University Medical Center, Geert Grooteplein-Zuid 10, 6525 GA Nijmegen, The Netherlands
                Article
                1262
                10.1186/s13063-016-1262-z
                4784417
                26955809
                © Versteijne et al. 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004622, KWF Kankerbestrijding;
                Award ID: UVA 2012-5696
                Award Recipient :
                Categories
                Study Protocol
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                © The Author(s) 2016

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