Colorectal cancer patients are routinely treated with new highly-effective agents such as oxaliplatin and irinotecan which have been associated with changes in liver morphology. Because Magnetic Resonance Imaging and Spectroscopy provide non-invasive, repeatable assessments of tissue morphology and metabolism they are ideal techniques for studying the effects of chemotherapeutic agents on the liver. This is a pilot study to determine whether magnetic resonance (MR) techniques can detect chemotherapy-induced liver toxicity.
The first aim of this proposal is to determine whether non-invasive MR techniques can detect changes in normal liver morphology and metabolism caused by oxaliplatin-based chemotherapy.
The second aim i s to assess chemotherapy-induced liver abnormalities by histological techniques.
The third aim i s to test whether treatment-related MR parameter changes are correlated with histological measurements. There will be two patient cohorts. The first will include patients with colorectal liver metastases who will undergo neoadjuvant chemotherapy prior to resection of the tumor-bearing liver. The second cohort will include patients who have previously undergone resection of Stage II or III colorectal cancer and who will undergo adjuvant chemotherapy. MR studies will be performed prior to the start of chemotherapy, and at 6 and 12-24 weeks after the initiation of chemotherapy. The MR techniques to be employed are: a) proton-decoupled 31P Magnetic Resonance Spectroscopic Imaging to assess liver energetic status, pH, and cell membrane metabolism, and b) proton spectroscopy to measure fatty infiltration. Liver tissue will be obtained from cohort 1 patients for histological analysis which will include morphological analysis of fibrosis, steatosis, and proliferation as well as immunohistochemical assays of fibrogenesis (a-SMA) and proliferation (Ki-67). Statistical analyses will test for changes in MR parameters and histological markers with treatment, and determine whether they are related. In addition to subjecting patients to morbidity, chemotherapy-associated liver toxicity may limit further treatment options including surgery and chemotherapy. As of yet, no noninvasive technique has been shown to be useful in detecting this liver injury; yet such a technique would be extremely valuable for monitoring the hepatic side-effects of current therapy and planning future treatment. This project directly addresses the NIH mission to reduce the burdens of illness. Should this pilot study be successful, the ultimate goal, which would be the object of an expanded proposal, would be to determine whether MR markers of chemotherapy-induced liver damage can be used to predict perioperative morbidity after hepatic resection or toxicity to subsequent chemotherapy. ?

Public Health Relevance

All physicians seek to treat the patient's disease without causing unnecessary harmful side-effects. The proposed work will determine whether imaging techniques can monitor side-effects in the liver caused by certain drugs used to treat colorectal cancer. If successful, this work would provide a way for the doctor to make sure that the drug is not causing harm to the patient and therefore all patients undergoing this treatment for colorectal cancer would benefit. ? ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-SBIB-V (51))
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Farahani, Keyvan
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Sloan-Kettering Institute for Cancer Research
New York
United States
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Qi, Jing; Fong, Yuman; Saltz, Leonard et al. (2013) Serial measurement of hepatic lipids during chemotherapy in patients with colorectal cancer: a 1 H MRS study. NMR Biomed 26:204-12
Qi, Jing; Shukla-Dave, Amita; Fong, Yuman et al. (2011) 31P MR spectroscopic imaging detects regenerative changes in human liver stimulated by portal vein embolization. J Magn Reson Imaging 34:336-44