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Title: Dynamic contrast-enhanced magnetic resonance imaging of radiation therapy-induced microcirculation changes in rectal cancer

Abstract

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}, 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 withmore » 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

Authors:
 [1];  [2];  [3];  [4];  [5];  [3];  [4];  [6];  [7];  [6];  [7];  [8];  [2];  [9];  [2];  [7]
  1. Department of Radiology, Maastricht University Hospital, Maastricht (Netherlands) and Cardiovascular Research Institute Maastricht - CARIM, Maastricht University, Maastricht (Netherlands). E-mail: qdlu@rdia.azm.nl
  2. Department of Radiology, Maastricht University Hospital, Maastricht (Netherlands)
  3. Angiogenesis Laboratory, Department of Pathology and Internal Medicine, Maastricht University Hospital, Maastricht (Netherlands)
  4. (GROW), Maastricht University, Maastricht (Netherlands)
  5. Paul Strickland Scanner Centre, Mount Vernon Hospital, Northwood, Middlesex (United Kingdom)
  6. Research Institute for Growth and Development (GROW), Maastricht University, Maastricht (Netherlands)
  7. (Netherlands)
  8. Department of Surgical Oncology, Maastricht University Hospital, Maastricht (Netherlands)
  9. (CARIM), Maastricht University, Maastricht (Netherlands)
Publication Date:
OSTI Identifier:
20788220
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 63; Journal Issue: 5; Other Information: DOI: 10.1016/j.ijrobp.2005.04.052; PII: S0360-3016(05)00840-0; Copyright (c) 2005 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; BLOOD FLOW; CELL PROLIFERATION; EVALUATION; HISTOLOGY; NEOPLASMS; NMR IMAGING; PATIENTS; RADIOTHERAPY; SURGERY; TUMOR CELLS

Citation Formats

Lussanet, Quido G. de, Backes, Walter H., Griffioen, Arjan W., Research Institute for Growth and Development, Padhani, Anwar R., Baeten, Coen I., Research Institute for Growth and Development, Baardwijk, Angela van, Department of Radiation Therapy, Maastro Clinic, Maastricht University Hospital, Maastricht, Lambin, Philippe, Department of Radiation Therapy, Maastro Clinic, Maastricht University Hospital, Maastricht, Beets, Geerard L., Engelshoven, Jos van, Cardiovascular Research Institute Maastricht, Beets-Tan, Regina G.H., and Angiogenesis Laboratory, Department of Pathology and Internal Medicine, Maastricht University Hospital, Maastricht. Dynamic contrast-enhanced magnetic resonance imaging of radiation therapy-induced microcirculation changes in rectal cancer. United States: N. p., 2005. Web. doi:10.1016/J.IJROBP.2005.0.
Lussanet, Quido G. de, Backes, Walter H., Griffioen, Arjan W., Research Institute for Growth and Development, Padhani, Anwar R., Baeten, Coen I., Research Institute for Growth and Development, Baardwijk, Angela van, Department of Radiation Therapy, Maastro Clinic, Maastricht University Hospital, Maastricht, Lambin, Philippe, Department of Radiation Therapy, Maastro Clinic, Maastricht University Hospital, Maastricht, Beets, Geerard L., Engelshoven, Jos van, Cardiovascular Research Institute Maastricht, Beets-Tan, Regina G.H., & Angiogenesis Laboratory, Department of Pathology and Internal Medicine, Maastricht University Hospital, Maastricht. Dynamic contrast-enhanced magnetic resonance imaging of radiation therapy-induced microcirculation changes in rectal cancer. United States. doi:10.1016/J.IJROBP.2005.0.
Lussanet, Quido G. de, Backes, Walter H., Griffioen, Arjan W., Research Institute for Growth and Development, Padhani, Anwar R., Baeten, Coen I., Research Institute for Growth and Development, Baardwijk, Angela van, Department of Radiation Therapy, Maastro Clinic, Maastricht University Hospital, Maastricht, Lambin, Philippe, Department of Radiation Therapy, Maastro Clinic, Maastricht University Hospital, Maastricht, Beets, Geerard L., Engelshoven, Jos van, Cardiovascular Research Institute Maastricht, Beets-Tan, Regina G.H., and Angiogenesis Laboratory, Department of Pathology and Internal Medicine, Maastricht University Hospital, Maastricht. Thu . "Dynamic contrast-enhanced magnetic resonance imaging of radiation therapy-induced microcirculation changes in rectal cancer". United States. doi:10.1016/J.IJROBP.2005.0.
@article{osti_20788220,
title = {Dynamic contrast-enhanced magnetic resonance imaging of radiation therapy-induced microcirculation changes in rectal cancer},
author = {Lussanet, Quido G. de and Backes, Walter H. and Griffioen, Arjan W. and Research Institute for Growth and Development and Padhani, Anwar R. and Baeten, Coen I. and Research Institute for Growth and Development and Baardwijk, Angela van and Department of Radiation Therapy, Maastro Clinic, Maastricht University Hospital, Maastricht and Lambin, Philippe and Department of Radiation Therapy, Maastro Clinic, Maastricht University Hospital, Maastricht and Beets, Geerard L. and Engelshoven, Jos van and Cardiovascular Research Institute Maastricht and Beets-Tan, Regina G.H. and Angiogenesis Laboratory, Department of Pathology and Internal Medicine, Maastricht University Hospital, Maastricht},
abstractNote = {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}, 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.},
doi = {10.1016/J.IJROBP.2005.0},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 5,
volume = 63,
place = {United States},
year = {Thu Dec 01 00:00:00 EST 2005},
month = {Thu Dec 01 00:00:00 EST 2005}
}
  • Purpose: To investigate the prognostic value of the perfusion index (PI), a microcirculatory parameter estimated from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), which integrates information on both flow and permeability, to predict overall survival and disease-free survival in patients with primary rectal cancer. Methods and Materials: A total of 83 patients with stage cT3 rectal cancer requiring neoadjuvant chemoradiation were investigated with DCE-MRI before start of therapy. Contrast-enhanced dynamic T{sub 1} mapping was obtained, and a simple data analysis strategy based on the calculation of the maximum slope of the tissue concentration–time curve divided by the maximum of the arterial inputmore » function was used as a measure of tumor microcirculation (PI), which integrates information on both flow and permeability. Results: In 39 patients (47.0%), T downstaging (ypT0-2) was observed. During a mean (±SD) follow-up period of 71 ± 29 months, 58 patients (69.9%) survived, and disease-free survival was achieved in 45 patients (54.2%). The mean PI (PImean) averaged over the group of nonresponders was significantly higher than for responders. Additionally, higher PImean in age- and gender-adjusted analyses was strongly predictive of therapy nonresponse. Most importantly, PImean strongly and significantly predicted disease-free survival (unadjusted hazard ratio [HR], 1.85 [ 95% confidence interval, 1.35-2.54; P<.001)]; HR adjusted for age and sex, 1.81 [1.30-2.51]; P<.001) as well as overall survival (unadjusted HR 1.42 [1.02-1.99], P=.040; HR adjusted for age and sex, 1.43 [1.03-1.98]; P=.034). Conclusions: This analysis identifies PImean as a novel biomarker that is predictive for therapy response, disease-free survival, and overall survival in patients with primary locally advanced rectal cancer.« less
  • Purpose: To compare pretreatment scans with perfusion computed tomography (pCT) vs. dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in rectal tumors. Methods and Materials: Nineteen patients diagnosed with rectal cancer were included in this prospective study. All patients underwent both pCT and DCE-MRI. Imaging was performed on a dedicated 40-slice CT-positron emission tomography system and a 3-T MRI system. Dynamic contrast enhancement was measured in tumor tissue and the external iliac artery. Tumor perfusion was quantified in terms of pharmacokinetic parameters: transfer constant K{sup trans}, fractional extravascular-extracellular space v{sub e}, and fractional plasma volume v{sub p}. Pharmacokinetic parameter values and theirmore » heterogeneity (by 80% quantile value) were compared between pCT and DCE-MRI. Results: Tumor K{sup trans} values correlated significantly for the voxel-by-voxel-derived median (Kendall's tau correlation, tau = 0.81, p < 0.001) and 80% quantile (tau = 0.54, p = 0.04), as well as for the averaged uptake (tau = 0.58, p = 0.03). However, no significant correlations were found for v{sub e} and v{sub p} derived from the voxel-by-voxel-derived median and 80% quantile and derived from the averaged uptake curves. Conclusions: This study demonstrated for the first time that pCT provides K{sup trans} values comparable to those of DCE-MRI. However, no correlation was found for the v{sub e} and v{sub p} parameters between CT and MRI. Computed tomography can serve as an alternative modality to MRI for the in vivo evaluation of tumor angiogenesis in terms of the transfer constant K{sup trans}.« less
  • Purpose: The purpose of this study was to investigate the effect of α-particle-emitting {sup 227}Th-trastuzumab radioimmunotherapy on tumor vasculature to increase the knowledge about the mechanisms of action of {sup 227}Th-trastuzumab. Methods and Materials: Human HER2-expressing SKOV-3 ovarian cancer xenografts were grown bilaterally in athymic nude mice. Mice with tumor volumes 253 ± 36 mm{sup 3} (mean ± SEM) were treated with a single injection of either {sup 227}Th-trastuzumab at a dose of 1000 kBq/kg body weight (treated group, n=14 tumors) or 0.9% NaCl (control group, n=10 tumors). Dynamic T1-weighted contrast-enhanced magnetic resonance imaging (DCEMRI) was used to study themore » effect of {sup 227}Th-trastuzumab on tumor vasculature. DCEMRI was performed before treatment and 1, 2, and 3 weeks after therapy. Tumor contrast-enhancement curves were extracted voxel by voxel and fitted to the Brix pharmacokinetic model. Pharmacokinetic parameters for the tumors that underwent radioimmunotherapy were compared with the corresponding parameters of control tumors. Results: Significant increases of k{sub ep}, the rate constant of diffusion from the extravascular extracellular space to the plasma (P<.05), and k{sub el,} the rate of clearance of contrast agent from the plasma (P<.01), were seen in the radioimmunotherapy group 2 and 3 weeks after injection, compared with the control group. The product of k{sub ep} and the amplitude parameter A, associated with increased vessel permeability and perfusion, was also significantly increased in the radioimmunotherapy group 2 and 3 weeks after injection (P<.01). Conclusions: Pharmacokinetic modeling of MRI contrast-enhancement curves evidenced significant alterations in parameters associated with increased tumor vessel permeability and tumor perfusion after {sup 227}Th-trastuzumab treatment of HER2-expressing ovarian cancer xenografts.« 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
  • 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 tomore » 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.« less