Abstract 641: Early therapy assessment of cetuximab and irinotecan in orthotopic pancreatic tumor xenografts by dynamic contrast-enhanced magnetic resonance imaging
Authors: Kim Hyunki , Folks Karri , Guo Lingling , Sellers Jeffery , Fineberg Naomi , Stockard Cecil , Grizzle William , Buchsbaum Donald , Morgan Desiree , George James , Zinn Kurt 
Published: February 2011

Purpose: To evaluate DCE-MRI as an early prognostic tool for effective anti-EGFR therapy with concurrent chemotherapy in a murine orthotopic pancreatic-cancer model, and to develop a novel timing-independent DCE-MRI biomarker for early therapy assessment.

Methods: Groups 1-4 (n=6/group) of SCID mice bearing orthotopic pancreatic adenocarcinoma (luciferase-positive MIA PaCa-2) were treated with PBS (control), cetuximab (1mg), irinotecan (25mg/kg), or cetuximab plus irinotecan respectively twice weekly for 3 weeks. DCE-MRI was performed on days 0, 1, 2, and 3 after therapy initiation, while anatomical MRI was performed once weekly for 3 weeks. Bioluminescence imaging was performed on days 0 and 21. At day 21, all tumors were collected for CD31 and Ki-67 staining. The averaged Ktrans values in the entire tumor region or within the 0.5-mm thick peripheral tumor region were calculated. The best-fitting 2nd-order polynomial curves for the Ktrans changes were retrieved, and the quadratic coefficient for each curve was proposed as the novel MRI biomarker.

Results: The change in Ktrans values of groups 1-4 for 3 days after therapy initiation in the entire tumor region were not statistically different among any of the groups. However, when analyzed in peripheral tumor region, change in Ktrans values were 102±16%, 42±21%, 15±6%, and −19±5% respectively, and the significant suppression of Ktrans increase was detected after irinotecan (p=0.008) or combination therapy (p&lt;0.001). During 21 days, the tumor-volume increase was significantly suppressed by either monotherapy or combined therapy (p&lt;0.050). The Ktrans changes observed for 3 days in the peripheral region were significantly correlated with tumor-volume changes (p&lt;0.001), bioluminescence-signal changes (p=0.050), microvessel densities (p=0.002) and proliferating-cell densities (p=0.001). The mean Ktrans changes of all 4 groups in peripheral tumor region followed second-order polynomial curves, and the quadratic coefficient of each curve was proposed as a novel DCE-MRI based biomarker; the mean value of novel biomarker of groups 1-4 were 0.050±0.026, −0.015±0.028, −0.071±0.021, and −0.082±0.013 respectively. The values of the novel biomarker were significantly correlated with tumor-volume changes (p&lt;0.001), bioluminescence-signal changes (p=0.019), microvessel densities (p=0.002), and proliferating-cell densities (p=0.001).

Conclusion: This study supports the clinical use of DCE-MRI to evaluate an anti-EGFR therapy combined with chemotherapy for pancreatic adenocarcinoma.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 641.