Paul Kennedy1,2, Sara Lewis3, Octavia Bane1,2, Stefanie Hectors1,2,4, Edward Kim5, and Bachir Taouli1,2
1BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States, 2Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States, 3Radiology, Icahn School of Medicine at Mount Sinai, NY, NY, United States, 4Department of Radiology, Weill Cornell Medicine, New York, NY, United States, 5Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, NY, NY, United States
Synopsis
In this
study we assess early changes following 90Y radioembolization (RE)
in hepatocellular carcinoma and liver parenchyma using MR elastography and
predict response at 6 weeks/6 months. Tumor stiffness (TS) and liver stiffness
(LS) adjacent to the tumor were significantly increased 6w following RE. Baseline
TS and LS adjacent to the tumor were significantly lower in patients who
achieved complete response. Baseline TS correlated with necrosis at 6w and was
a significant predictor of partial response or stable disease based on mRECIST
criteria following RE. MR elastography may be a useful tool for predicting
necrosis and tumor response to RE.
Introduction
Locoregional therapy
such as Yttrium 90 radioembolization (RE) has been used to successfully
downstage HCC tumors and act as a bridge to liver transplantation1 in advanced cases unsuitable for resection.
Post-treatment effects include perivascular edema, inflammation, extracellular
matrix remodeling and hepatic fibrosis2,3. These changes are likely to have an effect on
the mechanical microenvironment and may be measurable as a change in tissue
stiffness. The aim of the current study
was to quantify the change in tumor and liver parenchyma stiffness secondary to
RE by imaging before and 6 weeks (6w) following treatment, and determine the
value of pretreatment stiffness measurement for assessing tumor response and
degree of necrosis at 6w and 6 months (6m). Methods
In this prospective IRB approved study 23 patients with untreated HCC referred
for RE (M/F 18/5, mean age 68.3±9.3 y, range 55-93 y) underwent the research protocol at baseline,
with 20 of those also imaged at 6w post RE. The mean duration between baseline MR
imaging and RE was 37±25 days
(range 3-117 days) with follow up imaging occurring 42±2 days (range 39-47 days) after RE. Baseline and follow-up imaging was
performed on a 1.5 T MRI system (MAGNETOM Aera, Siemens Healthcare, Erlangen, Germany). 2D MRE data at 60Hz were
acquired using a prototype spin-echo echo planar imaging (SE-EPI) sequence. 10 axial
slices were acquired centered over the index lesion. Acquired 2D MRE data were
reconstructed inline using a commercially available 2D multi-model direct
inversion (MMDI) algorithm4. An MR physicist with 4 years’ experience drew ROIs around the index
lesion, the liver parenchyma immediately adjacent to the lesion site (a 2 cm
circular region around the lesion where possible avoiding vessels and staying
1cm away from the liver capsule) and in liver parenchyma remote to the treated
liver segment/lobe on the MRE magnitude images using ImageJ software. Stiffness
change and percentage stiffness change with respect to the baseline were
determined for tumor (TS), and liver parenchyma (LS) near tumor and remote
liver parenchyma. Treatment response was assessed from 6w and 6m clinical
follow-up following RE by an abdominal radiologist with 8 years’ experience. Degree
of tumor necrosis was determined from subtracted post-contrast 3D T1-weighted
images. Treatment response was also based on modified response evaluation
criteria in solid tumors (mRECIST). Differences in TS and LS (near tumor and
remote LS) pre and post RE were tested for significance
using Wilcoxon signed rank tests. Spearman correlation analysis was used to
determine significant relationships between MRE parameters, tumor size, degree
of necrosis at follow-up and mRECIST classification. ROC analysis was used to
determine the accuracy of MRE in predicting response.Results
Mean tumor size at baseline was 3.6±1.7 cm (range 1.5 - 6.3 cm). At 6w follow-up, 17/23 tumors exhibited PR
(n=6) or CR (n=11) with 6 classified as SD based on mRECIST criteria. 6m
clinical follow-up imaging was available in 13 patients who did not undergo
interval retreatment. All tumors exhibited CR (n=10) or PR (n=3) at 6m. MRE failed
pre and post RE in 3 cases with full datasets not available in 6 further cases.
Example pre and post RE images are shown in Figure 1. At baseline, mean LS remote to the tumor and LS adjacent
to tumor were not significantly different from TS (5.42±2.06 vs 4.52±1.33 vs.
5.41±2.58 kPa, p=0.562). TS pre RE was found to significantly correlate with tumor diameter
(r=0.746, p=0.001; Figure 2).
Mean TS (5.41±2.58 kPa vs 7.06±3.85 kPa, p=0.016) and LS adjacent to the tumor (4.52±1.33 vs 5.70±2.07 kPa, p=0.039) were significantly increased following
RE while LS remote to the
tumor was unchanged (Table 1, Figure 3). Baseline LS adjacent to tumor (p=0.021) and TS (p=0.023)
were found to be significantly lower in patients that achieved CR at 6w post RE
(Figure 4). TS at baseline was found
to significantly correlate with percentage of tumor necrosis at 6w (r=-0.580, p=0.015, Figure 2). TS and LS adjacent to the tumor were not predictors of
CR, however they were good predictors of PR or SD (AUC=0.841, p=0.023 and AUC=0.857,
p=0.021 respectively). At 6m clinical
follow-up baseline TS and LS adjacent to tumor were still strong predictors of
non CR outcomes although these results did not reach statistical significance (AUC=0.905,
p=0.053 and AUC=0.857, p=0.087 respectively). Discussion
These results
suggest TS and LS adjacent to the tumor are significantly elevated following RE
and are predictors of non CR outcomes at 6w. Our results are discordant to previous
animal5,6 and human studies7 which report decreased tumor stiffness following locoregional
therapy. Our study differs from the human study in that it is prospective with
pre and post RE measures and has a shorter interval between RE and imaging (42
vs 84 days). The animal studies were imaged 1-4 days post therapy and used
different cancer types and treatments than our study. Conclusion
The results
indicate mechanical properties of tumor tissue and surrounding liver parenchyma
change significantly early after RE therapy. Baseline TS and LS may be useful
markers for prediction of response and necrosis at 6w. Acknowledgements
This research was
supported by NCI grant U01 CA172320. Many thanks to Bradley D. Bolster Jr, Stephan Kannengiesser and Michael Bush from Siemens Healthcare for providing the prototype sequence for use at our institution and their technical support. References
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