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.