Background: Desmoplasia is a central feature of the tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC). LDE225 is a pharmacological Hedgehog signaling pathway inhibitor and is thought to specifically target tumor stroma. We investigated the combined use of LDE225 and chemotherapy to treat PDAC patients. Methods: This was a multi-center, phase I/II study for patients with metastatic PDAC establishing the maximum tolerated dose of LDE225 co-administered with gemcitabine and nab-paclitaxel (phase I) and evaluating the efficacy and safety of the treatment combination after prior FOLFIRINOX treatment (phase II). Tumor microenvironment assessment was performed with quantitative MRI using intra-voxel incoherent motion diffusion weighted MRI (IVIM-DWI) and dynamic contrast-enhanced (DCE) MRI. Results: The MTD of LDE225 was 200 mg once daily co-administered with gemcitabine 1000 mg/m² and nab-paclitaxel 125 mg/m². In phase II, six therapy-related grade 4 adverse events (AE) and three grade 5 were observed. In 24 patients, the target lesion response was evaluable. Three patients had partial response (13%), 14 patients showed stable disease (58%), and 7 patients had progressive disease (29%). Median overall survival (OS) was 6 months (IQR 3.9–8.1). Blood plasma fraction (DCE) and diffusion coefficient (IVIM-DWI) significantly increased during treatment. Baseline perfusion fraction could predict OS (>222 days) with 80% sensitivity and 85% specificity. Conclusion: LDE225 in combination with gemcitabine and nab-paclitaxel was well-tolerated in patients with metastatic PDAC and has promising efficacy after prior treatment with FOLFIRINOX. Quantitative MRI suggested that LDE225 causes increased tumor diffusion and works particularly well in patients with poor baseline tumor perfusion.

Purpose: It is plausible that patients with pancreatic cancer experience fear of tumor recurrence or progression (FOP). The aim of this study was to compare FOP in patients with pancreatic cancer treated with surgical resection, palliative systemic treatment, or best supportive care (BSC) and analyze the association between quality of life (QoL) and FOP and the effect of FOP on overall survival (OS). Methods: This study included patients diagnosed with pancreatic cancer between 2015 and 2018, who participated in the Dutch Pancreatic Cancer Project (PACAP). The association between QoL and WOPS was assessed with logistic regression analyses. OS was evaluated using Kaplan–Meier curves with the log-rank tests and multivariable Cox proportional hazard analyses adjusted for clinical covariates and QoL. Results: Of 315 included patients, 111 patients underwent surgical resection, 138 received palliative systemic treatment, and 66 received BSC. Patients who underwent surgical resection had significantly lower WOPS scores (i.e., less FOP) at initial diagnosis compared to patients who received palliative systemic treatment or BSC only (P < 0.001). Better QoL was independently associated with the probability of having a low FOP in the BSC (OR 0.95, 95% CI 0.91–0.98) but not in the surgical resection (OR 0.97, 95% CI 0.94–1.01) and palliative systemic treatment groups (OR 0.97, 95% CI 0.94–1.00). The baseline WOPS score was not independently associated with OS in any of the subgroups. Conclusion: Given the distress that FOP evokes, FOP should be explicitly addressed by health care providers when guiding pancreatic cancer patients through their treatment trajectory, especially those receiving palliative treatment or BSC.