The tumor microenvironment plays an important role in the initiation and progression of pancreatic adenocarcinoma (PDAC). In this systematic review, we provide an overview of clinical trials with stroma-targeting agents. We systematically searched MEDLINE/PubMed and the EMBASE database, using the PRISMA guidelines, for eligible clinical trials. In total, 2330 records were screened, from which we have included 106 articles. A meta-analysis could be performed on 51 articles which describe the targeting of the vascular endothelial growth factor (VEGF) pathway, and three articles which describe the targeting of hyaluronic acid. Anti-VEGF therapies did not show an increase in median overall survival (OS) with combined hazard ratios (HRs) of 1.01 (95% confidence interval (CI) 0.90–1.13). Treatment with hyaluronidase PEGPH20 showed promising results, but, thus far, only in combination with gemcitabine and nab-paclitaxel in selected patients with hyaluronic acid (HA)^high tumors: An increase in median progression free survival (PFS) of 2.9 months, as well as a HR of 0.51 (95% CI 0.26–1.00). In conclusion, we found that anti-angiogenic therapies did not show an increased benefit in median OS or PFS in contrast to promising results with anti-hyaluronic acid treatment in combination with gemcitabine and nab-paclitaxel. The PEGPH20 clinical trials used patient selection to determine eligibility based on tumor biology, which underlines the importance to personalize treatment for pancreatic cancer patients.

Definitive chemoradiation (dCRT) is considered curative intent treatment for patients with inoperable or irresectable esophageal cancer. Acute toxicity data focussing on dCRT are lacking.

Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with a poor prognosis. Resection is the only curative option and even then, reported 5-year survival rates are less than 10%. Most patients present with advanced disease and these rarely respond to chemotherapy. This lack of response is thought to be, at least in part, related to the abundant stromal tissue surrounding the tumor cells but tumor-restraining aspects have been attributed to the stroma as well. Pancreatic stellate cells (PSCs) are the main constituent of the PDAC stroma and are involved in remodelling the extracellular matrix. The crosstalk between tumor cells and PSCs has been studied extensively, but this has focused on PSC activation. Surprisingly, we now find that conditioned medium from mesenchymal but not from epithelial pancreatic tumor cell lines inactivates PSCs. This effect is stronger than that of known inhibitors such as retinoic acid and vitamin D, as determined by cell number and stromal activation marker expression. By differential filtration of the tumor cell conditioned medium, we find that the unknown protein should be between 30 and 50 kDa and using gene expression data a small selection of candidate proteins has been established. Validation experiments to identify the candidate protein are ongoing. Identification of this molecule can be used to devise novel therapeutics that act specifically on activated stroma and provide a more specific anticancer treatment.