Approximately two thirds of patients with intrahepatic cancer present with unresectable disease. Our previous studies show that high dose conformal radiation combined with chemotherapy appears to prolong the survival of patients with unresectable intrahepatic cancers. However, attempts to increase radiation dose still further have been limited by the development of radiation-induced liver disease (RILD). The pathology of RILD is veno-occlusive disease, which is characterized by thrombosis within the central veins of the liver producing "post" hepatic congestion. In the past, efforts to develop models to estimate the likelihood of developing RILD have been based primarily on the planned radiation dose distribution for the normal liver. These analyses have demonstrated that increasing mean liver dose correlates with the likelihood of developing RILD. While these models have permitted the safe delivery of far higher doses of radiation than have previously been possible, they also suggest that there is a broad range of individual patient sensitivity that is not reflected by predictions made solely based on the physical dose distribution or general clinical features. As the basic pathophysiology of RILD is venous occlusion, we develop the hypothesis that early monitoring of portal venous perfusion and hepatobiliary function would have the potential to predict liver function after irradiation, thereby permitting to safely deliver the higher dose to the tumor without an increase of complications. Our preliminary data provide evidence to support this hypothesis. In this R01 application, we propose to develop a model to predict liver function after the completion of radiation therapy based upon the radiation treatment plan, and the values of portal venous perfusion and hepatobiliary function assessed by DCE MRI and SPECT prior to and during radiation therapy. Also, we assess individual and regional radiation sensitivity during radiation therapy using the liver dose response function that we have developed, for prediction of liver function after irradiation. Our proposed approach is highly innovative and represents a new paradigm to investigate radiation toxicity in the liver. It has potential to be a tool for individualized therapy.

Public Health Relevance

Our previous studies show that high dose conformal radiation combined with chemotherapy appears to prolong the survival of patients with unresectable intrahepatic cancers. However, attempts to increase radiation dose still further have been limited by radiation-induced liver injury. Our long term goal is to develop a new imaging approach for prediction of radiation-induced syptomatic liver injury. Therefore, higher dose of radiation can be safely delivered to tumor in patients who can be better tolerant to radiation, thereby improving survival.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA132834-03
Application #
8305731
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Vikram, Bhadrasain
Project Start
2010-08-01
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$340,730
Indirect Cost
$121,611
Name
University of Michigan Ann Arbor
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Tsien, Christina; Cao, Yue; Chenevert, Thomas (2014) Clinical applications for diffusion magnetic resonance imaging in radiotherapy. Semin Radiat Oncol 24:218-26
Stenmark, Matthew H; Cao, Yue; Wang, Hesheng et al. (2014) Estimating functional liver reserve following hepatic irradiation: adaptive normal tissue response models. Radiother Oncol 111:418-23
Wang, Hesheng; Farjam, Reza; Feng, Mary et al. (2014) Arterial perfusion imaging-defined subvolume of intrahepatic cancer. Int J Radiat Oncol Biol Phys 89:167-74
Wang, Hesheng; Feng, Mary; Frey, Kirk A et al. (2013) Predictive models for regional hepatic function based on 99mTc-IDA SPECT and local radiation dose for physiologic adaptive radiation therapy. Int J Radiat Oncol Biol Phys 86:1000-6
Cao, Yue; Wang, Hesheng; Johnson, Timothy D et al. (2013) Prediction of liver function by using magnetic resonance-based portal venous perfusion imaging. Int J Radiat Oncol Biol Phys 85:258-63
Wang, Hesheng; Cao, Yue (2013) Spatially resolved assessment of hepatic function using 99mTc-IDA SPECT. Med Phys 40:092501
Cao, Yue (2011) The promise of dynamic contrast-enhanced imaging in radiation therapy. Semin Radiat Oncol 21:147-56