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Review
. 2019 Apr 26;11(5):588.
doi: 10.3390/cancers11050588.

Clinical Trials Targeting the Stroma in Pancreatic Cancer: A Systematic Review and Meta-Analysis

Madelaine G van Mackelenbergh  1   2 , Charlotte I Stroes  3 , René Spijker  4   5 , Casper H J van Eijck  6 , Johanna W Wilmink  7 , Maarten F Bijlsma  8 , Hanneke W M van Laarhoven  9
Affiliations
Review

Clinical Trials Targeting the Stroma in Pancreatic Cancer: A Systematic Review and Meta-Analysis

Madelaine G van Mackelenbergh et al. Cancers (Basel). .

Abstract

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.

Keywords: PDAC; clinical trial; stroma; systematic review; targeted therapy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic overview of pathways that are involved in desmoplasia in pancreatic cancer, including drugs and their targets. The vascular endothelial growth factor (VEGF) pathway is activated through ligand binding to any of the three receptors. Downstream of these receptors are both the phosphoinositide 3 kinase (PI3K) and the Ras/Mek pathway. Anti-angiogenic treatment works through ligand binding or receptor blocking. Hyaluronic acid is a component of the extracellular matrix and is involved in cell proliferation through the cluster of differentiation 44 (CD44) receptor. Hedgehog is secreted by the stroma and binds to the Patched (PTCH) receptor, which activates the smoothened receptor and, through Glioma-Associated Oncogene (GLI) cell proliferation and survival, is activated.
Figure 2
Figure 2
Flow chart of included articles according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [113].
Figure 3
Figure 3
Meta-analysis results of treatment with anti-angiogenic therapies for overall survival, (A) progression free survival (B) overall objective response rate (C) with random effects model. HR = hazard ratio, CI = confidence interval, IV = inverse-variance approach, M-H = Mantel-Haenszel test. Red: high risk of bias, Green: low risk of bias, Yellow: unclear risk of bias.
See this image and copyright information in PMC

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