Blood oxygen level dependent MRI detects changes in hepatocellular carcinoma induced by sorafenib treatment
Keith Michel1, Nina Munoz2, Kiersten Maldonado1, James Bankson1, Jia Sun3, Aliya Qayyum4, and Rony Avritscher2

1Department of Imaging Physics, UT MD Anderson Cancer Center, Houston, TX, United States, 2Department of Interventional Radiology, UT MD Anderson Cancer Center, Houston, TX, United States, 3Department of Biostatistics, UT MD Anderson Cancer Center, Houston, TX, United States, 4Department of Diagnostic Radiology, UT MD Anderson Cancer Center, Houston, TX, United States


Imaging biomarkers are needed for assessing treatment response in hepatocellular carcinoma (HCC). We evaluated BOLD MRI with hyperoxic challenge in an orthotopic rodent model of HCC for animals treated with the widely used kinase inhibitor sorafenib. A reduction in ΔT2* in tumor and background liver was exhibited for rats treated with sorafenib relative to untreated controls, while no significant change was observed in skeletal muscle. These results demonstrate that BOLD MRI could be a useful tool for detecting treatment effects in HCC.


Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver and represents a leading cause of cancer mortality worldwide. Despite a range of treatment options, the prognosis for patients with HCC remains poor, with a 5-year survival rate of less than 5%.1 The kinase inhibitor sorafenib is the main systemic therapy for patients with advanced HCC, but provides only modest improvements in overall survival by inhibiting proliferative and angiogenic signaling.2 Effectiveness of sorafenib treatment is currently assessed by monitoring tumor size and contrast enhancement in anatomical images, however this approach can be slow to demonstrate treatment failure.2 Functional imaging biomarkers of treatment response are therefore sorely needed to better asses the effects of sorafenib in individual patients. Blood oxygen level dependent (BOLD) MRI measures the effect of deoxygenated hemoglobin, which decreases the T2* relaxation time in tissue. This method has traditionally been utilized in functional imaging of the brain, but recent work has demonstrated it to provide sensitive and reproducible measures of blood oxygenation state in liver parenchyma and HCC tumors when combined with hyperoxic and hypercapnic challenges.3 In this work we evaluated BOLD MRI with hyperoxic challenge as a method for assessing treatment effects of sorafenib in an orthotopic rodent model of HCC.


N = 19 male Buffalo rats were implanted with 106 hepatoma McA-RH7777 cells in the inferior left liver. N = 9 rats were treated with a daily dose of 7.5 mg/kg sorafenib by oral gavage starting two weeks after tumor inoculation, while N = 10 rats served as untreated controls. All animals were imaged on a Bruker Biospec 4.7T preclinical MRI system four weeks after HCC cell implantation. 2D Multi-gradient echo (MGE) images of the liver were acquired (12 echoes, TE1 = 2.8 ms, ΔTE = 3.4 ms, 30° excitation angle, 100 kHz BW, 6x6 cm FOV, 256x144 matrix, 12 slices, 1.5 mm slice thickness with 0.5 mm gap) while medical air was delivered via nose cone, then repeated approximately 10 minutes after switching animals to oxygen gas inhalation. Image acquisitions were respiratory gated and isoflurane at a concentration of 2-4% was delivered in both inhalation conditions to maintain a respiratory rate of ~30 bpm (~2 s TR). T2* maps were generated in ParaVision 5 by voxel-wise fitting of a 3-parameter transverse relaxation model to MGE images. BOLD effect was quantified as the difference in T2* relaxation time constant between oxygen and medical air inhalation for ROIs including tumor, normal liver tissue and paraspinal muscle. The Wilcoxon rank-sum test was used to compare the differences in T2* relaxation times between sorafenib-treated and untreated animals.


Representative images are shown in figure 1. Increases in T2* were typically observed in the tumor, normal liver and other well-perfused tissues following hyperoxic challenge. In rats treated with sorafenib, this BOLD effect (ΔT2*) was reduced in HCC tumor (p = 0.0095) and background liver (p = 0.0016) compared to untreated rats. No significant change in T2* was observed in paraspinal muscle with treatment (p = 0.068), figure 2.


The use of the BOLD MRI technique presented here to assess oxygenation state of HCC tumors is appealing because it is non-invasive and utilizes widely available medical gases. The changes in T2* quantified in this work can be a consequence of a variety of changes in tissue state following sorafenib treatment. We expect that the antiangionenic effects of sorafenib resulted in deficient tumor vasculature in treated rats, reducing blood volume and blood flow and causing a smaller change in T2* with hyperoxic challenge. The heterogeneity of BOLD effect seen in tumors could identify regions of hypoxia non-invasively and without administration of exogenous contrast agents. Our study demonstrated no significant change in T2* of paraspinal muscle, which served as an internal control and replicated results shown in preliminary studies using BOLD MRI in HCC patients.3 It should be noted that the orthotopic model of HCC used here does not perfectly recapitulate the vascular characteristics of HCC observed in patients, namely the predominance of blood supply via abnormal hepatic arteries.2 Nevertheless, the significant reduction in BOLD effect we have observed in tumors is demonstrative of the potential for this technique to provide measurements sensitive to sorafenib treatment and inform clinical decision making for patients with HCC.


The authors acknowledge funding from CPRIT RP160229 and NIH P30-CA016672.


  1. Dutta R, Mahato RI. Recent advances in hepatocellular carcinoma therapy. Pharmacol Ther. 2017 May;173:106-117.
  2. Clark T, Maximin S, Meier J, et al. Hepatocellular Carcinoma: Review of Epidemiology, Screening, Imaging Diagnosis, Response Assessment, and Treatment. Curr Probl Diagn Radiol. 2015 Nov-Dec;44(6):479-86.
  3. Bane O, Besa C, Wagner M, et al. Feasibility and reproducibility of BOLD and TOLD measurements in the liver with oxygen and carbogen gas challenge in healthy volunteers and patients with hepatocellular carcinoma. J Magn Reson Imaging. 2016 Apr;43(4):866-76.


Figure 1. Representative T2* maps for medical air and oxygen inhalation acquired from a rat treated with sorafenib and an untreated control. BOLD overlay images depict the T2* values for medical air inhalation subtracted from those for oxygen, for ROIs in paraspinal muscle, normal liver tissue and HCC tumor (orange arrow). A greater BOLD effect (larger ΔT2*) was typically observed in tumor and liver for untreated animals than in rats treated with a daily oral dose of sorafenib for 2 weeks.

Figure 2. Sorafenib treatment reduces BOLD effect observed in orthotopic HCC tumor (p = 0.0095) and normal background liver (p = 0.0016) but not in paraspinal muscle (p = 0.068).

Proc. Intl. Soc. Mag. Reson. Med. 27 (2019)