Impact of Arterial Input Function and Pharmacokinetic Models on DCE-MRI Biomarkers for Detection of Vascular Effect Induced by Stroma-Directed Drug in an Orthotopic Mouse Model of Pancreatic Cancer

Purpose: We demonstrated earlier in mouse models of pancreatic ductal adenocarcinoma (PDA) that K^trans derived from dynamic contrast-enhanced (DCE) MRI detected microvascular effect induced by PEGPH20, a hyaluronidase which removes stromal hyaluronan, leading to reduced interstitial fluid pressure in the tumor (Clinical Cancer Res (2019) 25: 2314-2322). How the choice of pharmacokinetic (PK) model and arterial input function (AIF) may impact DCE-derived markers for detecting such an effect is not known.

Procedures: Retrospective analyses of the DCE-MRI of the orthotopic PDA model are performed to examine the impact of individual versus group AIF combined with Tofts model (TM), extended-Tofts model (ETM), or shutter-speed model (SSM) on the ability to detect the microvascular changes induced by PEGPH20 treatment.

Results: Individual AIF exhibit a marked difference in peak gadolinium concentration. However, across all three PK models, k_ep values show a significant correlation between individual versus group-AIF (p < 0.01). Regardless individual or group AIF, when k_ep is obtained from fitting the DCE-MRI data using the SSM, k_ep shows a significant increase after PEGPH20 treatment (p < 0.05 compared to the baseline); %change of k_ep from baseline to post-treatment is also significantly different between PEGPH20 versus vehicle group (p < 0.05). In comparison, when k_ep is derived from the TM, only the use of individual AIF leads to a significant increase of k_ep after PEGPH20 treatment, whereas the %change of k_ep is not different between PEGPH20 versus vehicle group. Group AIF but not individual AIF allows detection of a significant increase of V_p (derived from the ETM) in PEGPH20 versus vehicle group (p < 0.05). Increase of V_p is consistent with a large increase of mean capillary lumen area estimated from immunostaining.

Conclusion: Our results suggest that k_ep derived from SSM and V_p from ETM, both using group AIF, are optimal for the detection of microvascular changes induced by stroma-directed drug PEGPH20. These analyses provide insights in the choice of PK model and AIF for optimal DCE protocol design in mouse pancreatic cancer models.