Rationale and Objectives
Tumor vascular heterogeneity is a recognized biomarker for cancer progression. Our purpose was to assess the tumor perfusion heterogeneity during antiangiogenic therapy in hepatocellular carcinoma (HCC) by means of fractal analysis on computed tomography perfusion (CTP) images.
Materials and Methods
Twenty-two patients (15 men and 7 women; mean age: 61.5 years) with advanced HCC underwent CTP at baseline and 2 weeks after administration of bevacizumab. Perfusion maps of blood flow (BF) were generated by the adiabatic approximation to the tissue homogeneity model with a motion registration, and fractal analyses were applied to gray-scale perfusion maps using a plugin tool on ImageJ software (NIH, Bethesda, MD). A differential box-counting method was applied, and the fractal dimension (FD) was calculated as a heterogeneity parameter.
Results
Patients were grouped into favorable progression-free survival (PFS) group (PFS>6 months, 11 patients) and unfavorable PFS group (PFS≤6, 11 patients). After 2 weeks of antiangiogenic therapy, the BF decreased significantly ( P < .0001), whereas the FD showed no significant change ( P = .69). The percent change of the FD in tumor BF was significantly different between patients with favorable PFS and those without (−2.52% vs. 3.72%, P = .01), whereas the change of tumor BF showed no significant difference between them (−28.93% vs. −25.47%, P = .64). In Kaplan–Meier analysis, patients with greater reduction in the percent change of FD and lower baseline FD in tumor BF showed significantly longer overall survival ( P = .009, P = .005).
Conclusions
Fractal analysis of tumor BF can be a biomarker for antiangiogenic therapy.
Despite various therapeutic options, hepatocellular carcinoma (HCC) is still the third most common cause of cancer-related mortality worldwide . HCC is a highly vascularized tumor with an elevated level of vascular endothelial growth factor (VEGF) and high microvessel density (MVD) . Greater expression of VEGF, which leads to focal leaks in tumor vessels, causing nonuniform blood flow (BF) and heterogeneous delivery of drugs and oxygen , has been associated with shorter survival in patients with HCC . Therefore, inhibition of angiogenesis represents a potential therapeutic target in HCC, and a large number of antiangiogenic agents are currently being tested for the treatment of HCC . For example, the Sorafenib HCC Assessment Randomized Protocol trials showed an improved overall survival (OS) in patients with advanced HCC on treatment with the antiangiogenic and antiproliferative agent sorafenib .
These responses are currently assessed by Response Evaluation Criteria in Solid Tumors (RECIST) . However, RECIST has been recognized for their limitation in assessing the antitumor activity of antiangiogenic therapies, because antiangiogenic agents suppress tumor growth by downregulating angiogenesis without causing much morphologic change . In this context, functional vascular imaging techniques such as computed tomography perfusion (CTP) or dynamic contrast-enhanced magnetic resonance imaging (MRI) are highly promising . In HCC, significant decreases in tumor blood perfusion measured by CTP or DCE-MRI after antiangiogenic treatments have been reported . These perfusion changes are consistent with the vascular normalization induced by antiangiogenic therapy . The reduction of heterogeneity in tumor perfusion has also been reported to be the process of vascular normalization during antiangiogenic therapy in in vitro studies . However, this heterogeneity change in tumor perfusion during antiangiogenic therapy has not yet been demonstrated in in vivo studies.
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Materials and methods
Patient Population
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Treatment
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Imaging Studies
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Image Processing
CTP technique
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Fractal Analysis
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Statistical Analysis
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Results
Patient Characteristics
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Changes of Tumor BF and FD in Tumor BF after 2 Weeks of Bevacizumab
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Table 1
Tumor BF and FD in Tumor BF at Baseline and 2 Weeks after Antiangiogenic Therapy
Baseline After 2 Weeks_P_ BF 28.33 ± 9.60 20.65 ± 10.24 <.0001 FD 1.07 ± 0.12 1.07 ± 0.12 .69
BF, blood flow; FD, fractal dimension.
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Tumor BF and FD in Tumor BF at Baseline and after 2 Weeks of Bevacizumab between Favorable and Unfavorable PFS Groups of HCC
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Table 2
Baseline Magnetic Resonance–derived Parameters and Clinical Features
Baseline After 2 Weeks PFS ≤ 6 Months PFS > 6 Months_P_ PFS ≤ 6 Months PFS > 6 Months_P_ BF 29.54 ± 9.93 27.11 ± 9.57 .55 20.87 ± 10.36 20.43 ± 10.61 .94 FD 1.05 ± 0.13 1.08 ± 0.12 .39 1.09 ± 0.13 1.05 ± 0.12 .47
BF, blood flow; FD, fractal dimension; PFS, progression-free survival.
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Correlations of the Changes of Tumor BF and FD in Tumor BF with PFS and OS
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Table 3
Correlation between Percent Changes of BF and FD and PFS
PFS ≤ 6 Months PFS > 6 Months_P_ ΔBF (%) −25.47 ± 30.79 −28.93 ± 15.06 .64 ΔFD (%) 3.72 ± 6.24 −2.51 ± 3.21.01
ΔBF, percent change of BF; ΔFD, percent change of FD in tumor BF; PFS, progression-free survival.
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Correlation between Baseline FD in Tumor BF and OS
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Discussion
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Conclusions
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