Early therapy evaluation of combined cetuximab and irinotecan in orthotopic pancreatic tumor xenografts by dynamic contrast-enhanced magnetic resonance imaging.

Pancreatic cancer has the highest fatality rate of all cancers and is the fourth leading cause of cancer death in the United States.1 The nonspecific and variable symptoms of pancreatic cancer often lead to late-stage disease at the time of diagnosis, and the majority of the newly diagnosed pancreatic cancers are unresectable.2 Gemcitabine is a standard drug for unresectable pancreatic cancer3; a small survival benefit of radiation therapy in combination with gemcitabine has been reported in patients with localized unresectable pancreatic cancer compared to gemcitabine monotherapy,4 whereas any of the conventional chemotherapeutic agents, such as 5-fluorouracil, cisplatin, irinotecan, and oxaliplatin, did not improve the survival of patients with advanced pancreatic cancer when added to gemcitabine.5–8 More recently, anti–epidermal growth factor receptor (EGFR) has been investigated as a targeted therapy for pancreatic cancer. EGFR regulates cell proliferation and differentiation and is expressed in a marked percentage of cases ranging from 45 to 95%.9,10 EGFR expression is associated with aggressive tumor growth and poor clinical prognosis.11 Erlotinib (a small molecule targeting EGFR) or cetuximab (anti-EGFR monoclonal antibody) combined with gemcitabine significantly improved the survival of patients with advanced pancreatic cancer over gemcitabine monotherapy.10,12 Combination therapy with erlotinib and gemcitabine is considered a newer standard for locally advanced, unresectable, or metastatic pancreatic cancer, recently approved by the Food and Drug Administration. However, there is a wide range of drug sensitivities among individuals with pancreatic cancer. Because the characteristics of an individual tumor vary among patients, it would be ideal to tailor the therapeutic strategy to each patient by detecting the early tumor response and in turn to increase the probability for a favorable outcome. Individualized optimal treatment, called personalized medicine, can be guided by molecular biomarkers obtained from biopsies or by the use of imaging biomarkers. Although minimally invasive biopsy techniques are available,13 they still involve pain, stress, and risk to patients. Biopsies can potentially stimulate neoangio-genesis by damaging tumor tissue and can also increase the risk of metastases by increasing circulating tumor cells. It has also been argued that data obtained from a small portion of the tumor mass may not be representative of the entire tumor response. This may be particularly important when the response to therapy is tumor necrosis. Therefore, noninvasive imaging might be an approach that addresses these problems for pancreatic cancer patients as it can minimize patient discomfort and the risk of inducing metastasis and can be used to evaluate the response of the entire tumor to therapy. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) noninvasively measures pharmacokinetic parameters in microvasculature by quantifying the transfer of a contrast agent from the vascular space to the extravascular-extracellular space over time.14 Effective cancer therapies disrupt tumor vascular angiogenesis, leading to a decrease in microvessel density, perfusion, and permeability. These features can be measured by DCE-MRI prior to a quantifiable tumor volume decrease or morphologic change. DCE-MRI has been clinically used for evaluating the early therapeutic efficacy of drugs for solid cancers such as glioblastoma,15 breast cancer,16,17 head and neck cancer,18 colorectal cancer,19 and renal cell cancer.20 The purpose of this study was to evaluate DCE-MRI as an early prognostic tool to identify and characterize effective anti-EGFR therapy with and without concurrent chemotherapy using cetuximab and irinotecan in an orthotopic murine pancreatic cancer model.