Transport properties of pancreatic cancer describe gemcitabine delivery and response
Eugene J. Koay, … , Mauro Ferrari, Jason B. Fleming
Eugene J. Koay, … , Mauro Ferrari, Jason B. Fleming
Published March 10, 2014
Citation Information: J Clin Invest. 2014;124(4):1525-1536. https://doi.org/10.1172/JCI73455.
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Clinical Research and Public Health

Transport properties of pancreatic cancer describe gemcitabine delivery and response

Abstract

Background. The therapeutic resistance of pancreatic ductal adenocarcinoma (PDAC) is partly ascribed to ineffective delivery of chemotherapy to cancer cells. We hypothesized that physical properties at vascular, extracellular, and cellular scales influence delivery of and response to gemcitabine-based therapy.

Methods. We developed a method to measure mass transport properties during routine contrast-enhanced CT scans of individual human PDAC tumors. Additionally, we evaluated gemcitabine infusion during PDAC resection in 12 patients, measuring gemcitabine incorporation into tumor DNA and correlating its uptake with human equilibrative nucleoside transporter (hENT1) levels, stromal reaction, and CT-derived mass transport properties. We also studied associations between CT-derived transport properties and clinical outcomes in patients who received preoperative gemcitabine-based chemoradiotherapy for resectable PDAC.

Results. Transport modeling of 176 CT scans illustrated striking differences in transport properties between normal pancreas and tumor, with a wide array of enhancement profiles. Reflecting the interpatient differences in contrast enhancement, resected tumors exhibited dramatic differences in gemcitabine DNA incorporation, despite similar intravascular pharmacokinetics. Gemcitabine incorporation into tumor DNA was inversely related to CT-derived transport parameters and PDAC stromal score, after accounting for hENT1 levels. Moreover, stromal score directly correlated with CT-derived parameters. Among 110 patients who received preoperative gemcitabine-based chemoradiotherapy, CT-derived parameters correlated with pathological response and survival.

Conclusion. Gemcitabine incorporation into tumor DNA is highly variable and correlates with multiscale transport properties that can be derived from routine CT scans. Furthermore, pretherapy CT-derived properties correlate with clinically relevant endpoints.

Trial registration. Clinicaltrials.gov NCT01276613.

Funding. Lustgarten Foundation (989161), Department of Defense (W81XWH-09-1-0212), NIH (U54CA151668, KCA088084).

Authors

Eugene J. Koay, Mark J. Truty, Vittorio Cristini, Ryan M. Thomas, Rong Chen, Deyali Chatterjee, Ya’an Kang, Priya R. Bhosale, Eric P. Tamm, Christopher H. Crane, Milind Javle, Matthew H. Katz, Vijaya N. Gottumukkala, Marc A. Rozner, Haifa Shen, Jeffery E. Lee, Huamin Wang, Yuling Chen, William Plunkett, James L. Abbruzzese, Robert A. Wolff, Gauri R. Varadhachary, Mauro Ferrari, Jason B. Fleming

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Figure 1

Deriving transport properties of pancreatic tumors from routine CT scans.

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Deriving transport properties of pancreatic tumors from routine CT scans...
(A) Measurement technique. The pancreatic protocol involved well-timed scans in relation to contrast injection: precontrast, arterial phase, and portal venous phase (dashed lines denote representative measurement area). Systematic measurements of the pancreatic tumor and normal pancreas were recorded, and a model was developed to derive transport properties from these measurements. The model function can be integrated with time to derive AUC, and a simple piecewise linear function can be used to estimate AUC. (B) Scans from 2 patients with different enhancement patterns in the normal pancreas and pancreatic tumor are shown. The density changed with time due to intravasation of contrast into the tissues. Modeled density changes are shown, demonstrating that the model provides transport parameters for each patient’s normal tissue (blue line) and cancer (red line). (C) AUC representing the time integral of enhancement in the tissue of interest. The model was validated by comparing tissue-derived parameters with the enhancement in the aorta at the level of the celiac axis, which should reflect enhancement in the tissues. The graph for all 176 patients with pancreatic protocol CTs in this study shows how normal pancreas closely reflected aortic enhancement, whereas pancreatic tumors had higher variability. (D) Distributions of the parameter AUC from CT scans of 176 patients, grouped by pancreatic tissue type. Significant differences in the distribution of transport parameters were evident between normal pancreas and pancreatic tumor, with tumors exhibiting worsened transport properties.