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Title: Decline of Tumor Vascular Function as Assessed by Dynamic Contrast-Enhanced Magnetic Resonance Imaging Is Associated With Poor Responses to Radiation Therapy and Chemotherapy

Abstract

Purpose: To investigate whether changes in the volume transfer coefficient (K{sup trans}) in a growing tumor could be used as a surrogate marker for predicting tumor responses to radiation therapy (RT) and chemotherapy (CT). Methods and Materials: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was consecutively performed on tumor-bearing mice, and temporal and spatial changes of K{sup trans} values were measured along with tumor growth. Tumor responses to RT and CT were studied before and after observed changes in K{sup trans} values with time. Results: Dynamic changes with an initial increase and subsequent decline in K{sup trans} values were found to be associated with tumor growth. When each tumor was divided into core and peripheral regions, the K{sup trans} decline was greater in core, although neither vascular structure or necrosis could be linked to this spatial difference. Tumor responses to RT were worse if applied after the decline of K{sup trans}, and there was less drug distribution and cell death in the tumor core after CT. Conclusion: The K{sup trans} value in growing tumors, reflecting the changes of tumor microenvironment and vascular function, is strongly associated with tumor responses to RT and CT and could be a potential surrogate marker formore » predicting the tumor response to these treatments.« less

Authors:
;  [1];  [2];  [2];  [3];  [4];  [5];  [2];  [6];  [4];  [1];  [2];  [2]
  1. Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan, Taiwan (China)
  2. (China)
  3. Department of Imaging Physics, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States)
  4. Department of Biomedical Engineering and Environmental Sciences, National TsingHua University, Hsinchu, Taiwan (China)
  5. Radiation Biology Research Center, Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan (China)
  6. Institute of Biomedical Sciences, Academic Sinica, Taipei, Taiwan (China)
Publication Date:
OSTI Identifier:
22648769
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 95; Journal Issue: 5; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; CHEMOTHERAPY; EVALUATION; NEOPLASMS; NMR IMAGING; RADIOTHERAPY

Citation Formats

Chen, Fang-Hsin, Wang, Chun-Chieh, Radiation Biology Research Center, Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan, Department of Radiation Oncology, Chang Gung Memorial Hospital-LinKou, Taoyuan, Taiwan, Liu, Ho-Ling, Fu, Sheng-Yung, Yu, Ching-Fang, Department of Radiation Oncology, Chang Gung Memorial Hospital-LinKou, Taoyuan, Taiwan, Chang, Chen, Chiang, Chi-Shiun, Hong, Ji-Hong, E-mail: jihong@adm.cgmh.org.tw, Radiation Biology Research Center, Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan, and Department of Radiation Oncology, Chang Gung Memorial Hospital-LinKou, Taoyuan, Taiwan. Decline of Tumor Vascular Function as Assessed by Dynamic Contrast-Enhanced Magnetic Resonance Imaging Is Associated With Poor Responses to Radiation Therapy and Chemotherapy. United States: N. p., 2016. Web. doi:10.1016/J.IJROBP.2016.03.051.
Chen, Fang-Hsin, Wang, Chun-Chieh, Radiation Biology Research Center, Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan, Department of Radiation Oncology, Chang Gung Memorial Hospital-LinKou, Taoyuan, Taiwan, Liu, Ho-Ling, Fu, Sheng-Yung, Yu, Ching-Fang, Department of Radiation Oncology, Chang Gung Memorial Hospital-LinKou, Taoyuan, Taiwan, Chang, Chen, Chiang, Chi-Shiun, Hong, Ji-Hong, E-mail: jihong@adm.cgmh.org.tw, Radiation Biology Research Center, Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan, & Department of Radiation Oncology, Chang Gung Memorial Hospital-LinKou, Taoyuan, Taiwan. Decline of Tumor Vascular Function as Assessed by Dynamic Contrast-Enhanced Magnetic Resonance Imaging Is Associated With Poor Responses to Radiation Therapy and Chemotherapy. United States. doi:10.1016/J.IJROBP.2016.03.051.
Chen, Fang-Hsin, Wang, Chun-Chieh, Radiation Biology Research Center, Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan, Department of Radiation Oncology, Chang Gung Memorial Hospital-LinKou, Taoyuan, Taiwan, Liu, Ho-Ling, Fu, Sheng-Yung, Yu, Ching-Fang, Department of Radiation Oncology, Chang Gung Memorial Hospital-LinKou, Taoyuan, Taiwan, Chang, Chen, Chiang, Chi-Shiun, Hong, Ji-Hong, E-mail: jihong@adm.cgmh.org.tw, Radiation Biology Research Center, Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan, and Department of Radiation Oncology, Chang Gung Memorial Hospital-LinKou, Taoyuan, Taiwan. 2016. "Decline of Tumor Vascular Function as Assessed by Dynamic Contrast-Enhanced Magnetic Resonance Imaging Is Associated With Poor Responses to Radiation Therapy and Chemotherapy". United States. doi:10.1016/J.IJROBP.2016.03.051.
@article{osti_22648769,
title = {Decline of Tumor Vascular Function as Assessed by Dynamic Contrast-Enhanced Magnetic Resonance Imaging Is Associated With Poor Responses to Radiation Therapy and Chemotherapy},
author = {Chen, Fang-Hsin and Wang, Chun-Chieh and Radiation Biology Research Center, Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan and Department of Radiation Oncology, Chang Gung Memorial Hospital-LinKou, Taoyuan, Taiwan and Liu, Ho-Ling and Fu, Sheng-Yung and Yu, Ching-Fang and Department of Radiation Oncology, Chang Gung Memorial Hospital-LinKou, Taoyuan, Taiwan and Chang, Chen and Chiang, Chi-Shiun and Hong, Ji-Hong, E-mail: jihong@adm.cgmh.org.tw and Radiation Biology Research Center, Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan and Department of Radiation Oncology, Chang Gung Memorial Hospital-LinKou, Taoyuan, Taiwan},
abstractNote = {Purpose: To investigate whether changes in the volume transfer coefficient (K{sup trans}) in a growing tumor could be used as a surrogate marker for predicting tumor responses to radiation therapy (RT) and chemotherapy (CT). Methods and Materials: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was consecutively performed on tumor-bearing mice, and temporal and spatial changes of K{sup trans} values were measured along with tumor growth. Tumor responses to RT and CT were studied before and after observed changes in K{sup trans} values with time. Results: Dynamic changes with an initial increase and subsequent decline in K{sup trans} values were found to be associated with tumor growth. When each tumor was divided into core and peripheral regions, the K{sup trans} decline was greater in core, although neither vascular structure or necrosis could be linked to this spatial difference. Tumor responses to RT were worse if applied after the decline of K{sup trans}, and there was less drug distribution and cell death in the tumor core after CT. Conclusion: The K{sup trans} value in growing tumors, reflecting the changes of tumor microenvironment and vascular function, is strongly associated with tumor responses to RT and CT and could be a potential surrogate marker for predicting the tumor response to these treatments.},
doi = {10.1016/J.IJROBP.2016.03.051},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 5,
volume = 95,
place = {United States},
year = 2016,
month = 8
}
  • Purpose: Dynamic contrast-enhanced T1-weighted magnetic resonance imaging (DCE-MRI) allows noninvasive evaluation of tumor microvasculature characteristics. This study evaluated radiation therapy related microvascular changes in locally advanced rectal cancer by DCE-MRI and histology. Methods and Materials: Dynamic contrast-enhanced-MRI was performed in 17 patients with primary rectal cancer. Seven patients underwent 25 fractions of 1.8 Gy radiation therapy (RT) (long RT) before DCE-MRI and 10 did not. Of these 10, 3 patients underwent five fractions of 5 Gy RT (short RT) in the week before surgery. The RT treated and nontreated groups were compared in terms of endothelial transfer coefficient (K{sup PS},more » measured by DCE-MRI), microvessel density (MVD) (scored by immunoreactivity to CD31 and CD34), and tumor cell and endothelial cell proliferation (scored by immunoreactivity to Ki67). Results: Tumor K{sup PS} was 77% (p = 0.03) lower in the RT-treated group. Histogram analyses showed that RT reduced both magnitude and intratumor heterogeneity of K{sup PS} (p = 0.01). MVD was significantly lower (37%, p 0.03) in tumors treated with long RT than in nonirradiated tumors, but this was not the case with short RT. Endothelial cell proliferation was reduced with short RT (81%, p = 0.02) just before surgery, but not with long RT (p > 0.8). Tumor cell proliferation was reduced with both long (57%, p < 0.001) and short RT (52%, p = 0.002). Conclusion: Dynamic contrast-enhanced-MRI-derived K{sup PS} values showed significant radiation therapy related reductions in microvessel blood flow in locally advanced rectal cancer. These findings may be useful in evaluating effects of radiation combination therapies (e.g., chemoradiation or RT combined with antiangiogenesis therapy), to account for effects of RT alone.« less
  • Purpose: To analyze, in a pilot study, rapidly acquired dynamic contrast-enhanced (DCE)-MRI data with a general two-compartment exchange tracer kinetic model and correlate parameters obtained with measurements of hypoxia and vascular endothelial growth factor (VEGF) expression in patients with squamous cell carcinoma of the head and neck. Methods and Materials: Eight patients were scanned before surgery. The DCE-MRI data were acquired with 1.5-s temporal resolution and analyzed using the two-compartment exchange tracer kinetic model to obtain estimates of parameters including perfusion and permeability surface area. Twelve to 16 h before surgery, patients received an intravenous injection of pimonidazole. Samples takenmore » during surgery were used to determine the level of pimonidazole staining using immunohistochemistry and VEGF expression using quantitative real-time polymerase chain reaction. Correlations between the biological and imaging data were examined. Results: Of the seven tumors fully analyzed, those that were poorly perfused tended to have high levels of pimonidazole staining (r = -0.79, p = 0.03) and VEGF expression (r = -0.82, p = 0.02). Tumors with low permeability surface area also tended to have high levels of hypoxia (r = -0.75, p = 0.05). Hypoxic tumors also expressed higher levels of VEGF (r = 0.82, p = 0.02). Conclusions: Estimates of perfusion obtained with rapid DCE-MRI data in patients with head-and-neck cancer correlate inversely with pimonidazole staining and VEGF expression.« less
  • Purpose: To assess noninvasively the tumor microenvironment of neck nodal metastases in patients with head-and-neck cancer by investigating the relationship between tumor perfusion measured using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and hypoxia measured by {sup 18}F-fluoromisonidazole ({sup 18}F-FMISO) positron emission tomography (PET). Methods and Materials: Thirteen newly diagnosed head-and-neck cancer patients with metastatic neck nodes underwent DCE-MRI and {sup 18}F-FMISO PET imaging before chemotherapy and radiotherapy. The matched regions of interests from both modalities were analyzed. To examine the correlations between DCE-MRI parameters and standard uptake value (SUV) measurements from {sup 18}F-FMISO PET, the nonparametric Spearman correlation coefficient wasmore » calculated. Furthermore, DCE-MRI parameters were compared between nodes with {sup 18}F-FMISO uptake and nodes with no {sup 18}F-FMISO uptake using Mann-Whitney U tests. Results: For the 13 patients, a total of 18 nodes were analyzed. The nodal size strongly correlated with the {sup 18}F-FMISO SUV ({rho} = 0.74, p < 0.001). There was a strong negative correlation between the median k{sub ep} (redistribution rate constant) value ({rho} = -0.58, p = 0.042) and the {sup 18}F-FMISO SUV. Hypoxic nodes (moderate to severe {sup 18}F-FMISO uptake) had significantly lower median K{sup trans} (volume transfer constant) (p = 0.049) and median k{sub ep} (p = 0.027) values than did nonhypoxic nodes (no {sup 18}F-FMISO uptake). Conclusion: This initial evaluation of the preliminary results support the hypothesis that in metastatic neck lymph nodes, hypoxic nodes are poorly perfused (i.e., have significantly lower K{sup trans} and k{sub ep} values) compared with nonhypoxic nodes.« less
  • Purpose: For focal boost strategies in the prostate, the robustness of magnetic resonance imaging-based tumor delineations needs to be improved. To this end we developed a statistical model that predicts tumor presence on a voxel level (2.5 Multiplication-Sign 2.5 Multiplication-Sign 2.5 mm3) inside the peripheral zone. Furthermore, we show how this model can be used to derive a valuable input for radiotherapy treatment planning. Methods and Materials: The model was created on 87 radiotherapy patients. For the validation of the voxelwise performance of the model, an independent group of 12 prostatectomy patients was used. After model validation, the model wasmore » stratified to create three different risk levels for tumor presence: gross tumor volume (GTV), high-risk clinical target volume (CTV), and low-risk CTV. Results: The model gave an area under the receiver operating characteristic curve of 0.70 for the prediction of tumor presence in the prostatectomy group. When the registration error between magnetic resonance images and pathologic delineation was taken into account, the area under the curve further improved to 0.89. We propose that model outcome values with a high positive predictive value can be used to define the GTV. Model outcome values with a high negative predictive value can be used to define low-risk CTV regions. The intermediate outcome values can be used to define a high-risk CTV. Conclusions: We developed a logistic regression with a high diagnostic performance for voxelwise prediction of tumor presence. The model output can be used to define different risk levels for tumor presence, which in turn could serve as an input for dose planning. In this way the robustness of tumor delineations for focal boost therapy can be greatly improved.« less
  • Purpose: To examine dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with a macromolecular contrast agent (P792) to visualize effects of radiotherapy (RT) on microvascular leakage in a colorectal cancer model. Methods and Materials: CC531 tumors were induced in WAG/Rij rats. DCE-MRI was performed before and 5 days after 5 x 5 Gy of RT and parametric maps generated of the endothelial transfer constant (K{sup trans} ) and the fractional interstitial space (V{sub e} ) according to the Tofts model. Tissue pO{sub 2} mapping was performed in each tumor core and rim before and after RT. Microvessel density (MVD), vascular endothelial growthmore » factor (VEGF) expression, and pimonidazole hypoxia staining were compared with a control group of tumor-bearing rats. Results: Mean K{sup trans} and v{sub e} were significantly reduced after RT in all tumor regions. Mean pO{sub 2} was 6.8 mm Hg before RT vs. 7.7 mm Hg after RT (p < 0.001) in the tumor rim and 3.5 mm Hg before RT vs. 4.4 mm Hg after RT (p < 0.001) in the tumor core. Mean MVD in the tumor rim was 10.4 in the RT treated group vs. 16.9 in the control group (p = 0.061). VEGF expression was significantly higher in RT-treated rats. After RT, no correlation was found between DCE-MRI parameters and histologic parameters. A correlation was seen after RT between pO{sub 2} and K{sup trans} (r -0.57, p = 0.08) and between pO{sub 2} and v{sub e} (r = -0.65, p = 0.04). Conclusions: Dynamic contrast-enhanced-MRI with P792 allows quantification of microvascular changes in this colorectal model. RT significantly reduces neovascular leakage and enhances tissue oxygenation and VEGF expression. After RT, DCE-MRI parameters are related to tumor pO{sub 2}, but not to MVD or VEGF expression.« less