In the last several years, there has been a remarkable transformation in the field of cancer therapeutics, with a shift from traditional """"""""cytotoxic"""""""" agents to targeted therapies. There has also been a rapid increase in the number of potential compounds available for investigation. This trend has necessitated the development of innovative biomarkers that rapidly assess tumor response of a patient's tumor to a specific agent. Such biomarkers are urgently needed to personalize the treatment of tumors with effective agents. The overall purpose of this work is to develop new imaging strategies that measure early response to anti-angiogenic chemotherapeutic agents in liver tumors, using new magnetic resonance imaging (MRI) methods that measure blood flow to tumors (perfusion). Currently, the assessment of tumor response relies on the measurement of tumor size based on standard size criteria guidelines. This process requires months of treatment that may be ineffective or toxic and is often very expensive. Moreover, new """"""""anti- angiogenic"""""""" agents that interfere with the blood flow to growing tumors may provide clinical benefit while not actually resulting in a decrease in tumor size. For example, treatment with sorafenib (a new anti-angiogenic drug) results in a 3-month improvement in overall survival in advanced primary liver tumors (hepatocellular carcinoma (HCC)), while only 3% of tumors actually decreased in size. However, anti-angiogenic agents, such as sorafenib have a dramatic impact on the microscopic blood vessels of tumors within just hours or a few days. This underscores the concept that tumor size, measured with current cross-sectional imaging methods (CT or MRI), is a late indicator of tumor response, and does not reflect early changes from treatment at the cellular level. Therefore, we hypothesize that early changes of tumor blood flow are predictive of long-term tumor regression or stabilization in patients treated with anti-angiogenic chemotherapy. Our proposed studies could lead to more efficient evaluation of treatment options for tumors such as hepatocellular carcinoma (HCC) and metastatic liver tumors and may provide new measurements of tumor response in an effort to deliver more individualized cancer care in the future. This application addresses the broad Challenge Area (05): """"""""Comparative Effectiveness Research"""""""" and specific Challenge Topic, 05-EB-101 Comparative Effectiveness of Advanced Imaging Procedures. As described below, we propose to evaluate the clinical and cost effectiveness of advanced perfusion MRI methods to characterize blood flow to liver tumors before and immediately after initiation of systemic therapy.
We aim to determine the comparative effectiveness of advanced perfusion MRI with conventional cross- sectional imaging methods (CT) that measure tumor response based size, using tumor size criteria. By identifying tumors that will not respond to these drugs, their toxic side effects are avoided, and tremendous cost savings can be realized (eg. sorafenib costs ~$4000/month). Dynamic contrast enhanced perfusion imaging with MRI after the bolus injection of Gadolinium based contrast agents, is a safe, accurate and well-established method for characterizing blood flow (perfusion) in malignant tumors in various organs including the brain, breast, and prostate, among others. Unfortunately, perfusion imaging in the liver, the largest organ in the body, is challenging, and to date no methods have adequately provided the necessary combination of: 1) volumetric coverage, 2) high spatial resolution and 3) high temporal resolution, while maintaining 4) good signal to noise ratio (SNR), and 5) fidelity of Gadolinium contrast uptake curves in tissue. In this proposal we will use a novel perfusion MRI method based on a time resolved 3D """"""""radial"""""""" sampling methods developed at UW-Madison. Using a state of the art high-field (3.0T) clinical MRI scanner, we will combine this approach with a """"""""constrained reconstruction"""""""" algorithm to maximize the SNR performance and temporal resolution. Using the combination of 3D radial imaging and constrained reconstruction, we will acquire a time series of volumetric 3D images every 3 seconds, with very high spatial resolution (2.0x2.0x2.0mm3). Compared to the current state of the art, our approach increases temporal resolution by a factor of two and increases spatial resolution by a factor of five. To achieve these goals, we will 1) implement and test the new method on a state of the art 3.0T clinical scanner in volunteers, and in patients with hepatocellular carcinoma, and 2) Determine the impact of the optimized method on clinical outcome through a prospective longitudinal pilot study in HCC patients undergoing anti-angiogenic therapy. Successful validation of the proposed MRI measures of tumor response will provide a new image-based approach for clinical decision-making for chemotherapeutic regimens by transforming how MRI is used as a measure of tumor response. Treating physicians will be able to rapidly determine which chemotherapeutic agents are effective, while avoiding ineffective agents and their toxicities. Such methods would enable """"""""personalized"""""""" chemotherapy, rapidly determining the most effective agents for an individual's tumor(s).
This proposal describes a new, non-invasive method that uses magnetic resonance imaging (MRI) to measure blood flow in liver tumors, in order to determine whether drugs used to treat these tumors are effective. Currently, patients must undergo 2-3 months of treatment in order to see if the drug is effective against the tumor. Using the new perfusion MRI methods, the effectiveness of the drug will be ascertained in 2 days, and the prolonged use of ineffective, toxic and expensive drugs can be avoided and alternative therapies pursued.
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