PURPOSE: The benefit of neoadjuvant chemoradiotherapy in resectable and borderline resectable pancreatic cancer remains controversial. Initial results of the PREOPANC trial failed to demonstrate a statistically significant overall survival (OS) benefit. The long-term results are reported. METHODS: In this multicenter, phase III trial, patients with resectable and borderline resectable pancreatic cancer were randomly assigned (1:1) to neoadjuvant chemoradiotherapy or upfront surgery in 16 Dutch centers. Neoadjuvant chemoradiotherapy consisted of three cycles of gemcitabine combined with 36 Gy radiotherapy in 15 fractions during the second cycle. After restaging, patients underwent surgery followed by four cycles of adjuvant gemcitabine. Patients in the upfront surgery group underwent surgery followed by six cycles of adjuvant gemcitabine. The primary outcome was OS by intention-to-treat. No safety data were collected beyond the initial report of the trial. RESULTS: Between April 24, 2013, and July 25, 2017, 246 eligible patients were randomly assigned to neoadjuvant chemoradiotherapy (n = 119) and upfront surgery (n = 127). At a median follow-up of 59 months, the OS was better in the neoadjuvant chemoradiotherapy group than in the upfront surgery group (hazard ratio, 0.73; 95% CI, 0.56 to 0.96; P = .025). Although the difference in median survival was only 1.4 months (15.7 months v 14.3 months), the 5-year OS rate was 20.5% (95% CI, 14.2 to 29.8) with neoadjuvant chemoradiotherapy and 6.5% (95% CI, 3.1 to 13.7) with upfront surgery. The effect of neoadjuvant chemoradiotherapy was consistent across the prespecified subgroups, including resectable and borderline resectable pancreatic cancer. CONCLUSION: Neoadjuvant gemcitabine-based chemoradiotherapy followed by surgery and adjuvant gemcitabine improves OS compared with upfront surgery and adjuvant gemcitabine in resectable and borderline resectable pancreatic cancer.

In recent years, new treatment options have become available for pancreatic ductal adenocarcinoma (PDAC) including 5-fluorouracil, leucovorin, irinotecan and oxaliplatin. The impact hereof has not been assessed in nationwide cohort studies. This population-based study aimed to investigate nationwide trends in incidence, treatment and survival of PDAC. Patients with PDAC (1997-2016) were included from the Netherlands Cancer Registry. Results were categorised by treatment and by period of diagnosis (1997-2000, 2001-2004, 2005-2008, 2009-2012 and 2013-2016). Kaplan-Meier survival analysis was used to calculate overall survival. In a national cohort of 36,453 patients with PDAC, the incidence increased from 12.1 (1997-2000) to 15.3 (2013-2016) per 100,000 (p < 0.001), whereas median overall survival increased from 3.1 to 3.8 months (p < 0.001). Over time, the resection rate doubled (8.3%-16.6%, p-trend<0.001), more patients received adjuvant chemotherapy (3.0%-56.2%, p-trend<0.001) and 3-year overall survival following resection increased (16.9%-25.4%, p < 0.001). Over time, the proportion of patients with metastatic disease who received palliative chemotherapy increased from 5.3% to 16.1% (p-trend<0.001), whereas 1-year survival improved from 13.3% to 21.2% (p < 0.001). The proportion of patients who only received supportive care decreased from 84% to 61% (p-trend<0.001). The incidence of PDAC increased in the past two decades. Resection rates and use of adjuvant or palliative chemotherapy increased with improved survival in these patients. In all patients with PDAC, however, the survival benefit of 3 weeks is negligible because the majority of patients only received supportive care.

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. 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/m2/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. 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 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)

Pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA) are both deadly cancers and they share many biological features besides their close anatomical location. One of the main histological features is neurotropism, which results in frequent perineural invasion. The underlying mechanism of cancer cells favoring growth by and through the nerve fibers is not fully understood. In this review, we provide knowledge of these cancers with frequent perineural invasion. We discuss nerve fiber crosstalk with the main different components of the tumor microenvironment (TME), the immune cells, and the fibroblasts. Also, we discuss the crosstalk between the nerve fibers and the cancer. We highlight the shared signaling pathways of the mechanisms behind perineural invasion in PDAC and CCA. Hereby we have focussed on signaling neurotransmitters and neuropeptides which may be a target for future therapies. Furthermore, we have summarized retrospective results of the previous literature about nerve fibers in PDAC and CCA patients. We provide our point of view in the potential for nerve fibers to be used as powerful biomarker for prognosis, as a tool to stratify patients for therapy or as a target in a (combination) therapy. Taking the presence of nerves into account can potentially change the field of personalized care in these neurotropic cancers.

The aim of this systematic review is to provide an overview of the diagnosis, treatment options and treatment-related complications of cervical esophageal carcinoma (CEC) and to subsequently provide recommendations to improve quality of care. Studies were identified in PubMed, EMBASE and Web of Science. A total of 107 publications fulfilled the inclusion criteria and were included. CEC is uncommon, accounting for 2%–10% of all esophageal carcinomas. These tumors are often locally advanced at presentation and have a poor prognosis, with a 5-year overall survival of 30%. Tobacco and alcohol consumption seem to be the major risk factors for developing CEC. Surgery is usually not possible due to the very close relationship to other organs such as the larynx, trachea and thyroid gland. Therefore, the current standard of care is definitive chemoradiation (dCRT) with curative intent. Treatment regimens used to treat CEC are adapted by established regimens in lower esophageal squamous cell carcinoma and head and neck squamous cell carcinoma. However, dCRT may be accompanied by severe side-effects and complications. Several diagnostic and predictive markers have been studied, but currently, there is no other biomarker than clinical stage to determine patient management. Suggestions to improve patient outcomes are to determine the exact radiation dose needed for adequate locoregional control and to combine radiotherapy with optimal systemic therapy backbone. CEC remains unchartered territory for many practising physicians and patients with CEC have a poor prognosis. To improve the outcome for CEC patients, future studies should focus on the identification of new diagnostic biomarkers or targets for radiosensitizers, amelioration of radiation schedules, optimal combination of chemotherapeutic agents and/or new therapeutic targets.