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Title: Monitoring Tumor Response to Carbogen Breathing by Oxygen-Sensitive Magnetic Resonance Parameters to Predict the Outcome of Radiation Therapy: A Preclinical Study

Abstract

Purpose: In an effort to develop noninvasive in vivo methods for mapping tumor oxygenation, magnetic resonance (MR)-derived parameters are being considered, including global R{sub 1}, water R{sub 1}, lipids R{sub 1}, and R{sub 2}*. R{sub 1} is sensitive to dissolved molecular oxygen, whereas R{sub 2}* is sensitive to blood oxygenation, detecting changes in dHb. This work compares global R{sub 1}, water R{sub 1}, lipids R{sub 1}, and R{sub 2}* with pO{sub 2} assessed by electron paramagnetic resonance (EPR) oximetry, as potential markers of the outcome of radiation therapy (RT). Methods and Materials: R{sub 1}, R{sub 2}*, and EPR were performed on rhabdomyosarcoma and 9L-glioma tumor models, under air and carbogen breathing conditions (95% O{sub 2}, 5% CO{sub 2}). Because the models demonstrated different radiosensitivity properties toward carbogen, a growth delay (GD) assay was performed on the rhabdomyosarcoma model and a tumor control dose 50% (TCD50) was performed on the 9L-glioma model. Results: Magnetic resonance imaging oxygen-sensitive parameters detected the positive changes in oxygenation induced by carbogen within tumors. No consistent correlation was seen throughout the study between MR parameters and pO{sub 2}. Global and lipids R{sub 1} were found to be correlated to pO{sub 2} in the rhabdomyosarcoma model, whereas R{submore » 2}* was found to be inversely correlated to pO{sub 2} in the 9L-glioma model (P=.05 and .03). Carbogen increased the TCD50 of 9L-glioma but did not increase the GD of rhabdomyosarcoma. Only R{sub 2}* was predictive (P<.05) for the curability of 9L-glioma at 40 Gy, a dose that showed a difference in response to RT between carbogen and air-breathing groups. {sup 18}F-FAZA positron emission tomography imaging has been shown to be a predictive marker under the same conditions. Conclusion: This work illustrates the sensitivity of oxygen-sensitive R{sub 1} and R{sub 2}* parameters to changes in tumor oxygenation. However, R{sub 1} parameters showed limitations in terms of predicting the outcome of RT in the tumor models studied, whereas R{sub 2}* was found to be correlated with the outcome in the responsive model.« less

Authors:
; ; ;  [1];  [2];  [3]; ;  [1];  [1]
  1. Université Catholique de Louvain, Louvain Drug Research Institute, Biomedical Magnetic Resonance Research Group, Brussels (Belgium)
  2. Université Catholique de Louvain, IMMAQ Technological Platform, Methodology and Statistical Support, Louvain-la-Neuve (Belgium)
  3. Université Catholique de Louvain, Institute of Experimental and Clinical Research, Center for Molecular Imaging, Radiotherapy and Oncology, Brussels (Belgium)
Publication Date:
OSTI Identifier:
22648792
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 96; Journal Issue: 1; 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; BIOMEDICAL RADIOGRAPHY; CONNECTIVE TISSUE; ELECTRON SPIN RESONANCE; GY RANGE 10-100; IN VIVO; LIPIDS; NMR IMAGING; PARTIAL PRESSURE; POSITRON COMPUTED TOMOGRAPHY; RADIOSENSITIVITY; RADIOTHERAPY; RESPIRATION; RHABDOMYOSARCOMAS

Citation Formats

Cao-Pham, Thanh-Trang, Tran, Ly-Binh-An, Colliez, Florence, Joudiou, Nicolas, El Bachiri, Sabrina, Grégoire, Vincent, Levêque, Philippe, Gallez, Bernard, and Jordan, Bénédicte F., E-mail: benedicte.jordan@uclouvain.be. Monitoring Tumor Response to Carbogen Breathing by Oxygen-Sensitive Magnetic Resonance Parameters to Predict the Outcome of Radiation Therapy: A Preclinical Study. United States: N. p., 2016. Web. doi:10.1016/J.IJROBP.2016.04.029.
Cao-Pham, Thanh-Trang, Tran, Ly-Binh-An, Colliez, Florence, Joudiou, Nicolas, El Bachiri, Sabrina, Grégoire, Vincent, Levêque, Philippe, Gallez, Bernard, & Jordan, Bénédicte F., E-mail: benedicte.jordan@uclouvain.be. Monitoring Tumor Response to Carbogen Breathing by Oxygen-Sensitive Magnetic Resonance Parameters to Predict the Outcome of Radiation Therapy: A Preclinical Study. United States. doi:10.1016/J.IJROBP.2016.04.029.
Cao-Pham, Thanh-Trang, Tran, Ly-Binh-An, Colliez, Florence, Joudiou, Nicolas, El Bachiri, Sabrina, Grégoire, Vincent, Levêque, Philippe, Gallez, Bernard, and Jordan, Bénédicte F., E-mail: benedicte.jordan@uclouvain.be. 2016. "Monitoring Tumor Response to Carbogen Breathing by Oxygen-Sensitive Magnetic Resonance Parameters to Predict the Outcome of Radiation Therapy: A Preclinical Study". United States. doi:10.1016/J.IJROBP.2016.04.029.
@article{osti_22648792,
title = {Monitoring Tumor Response to Carbogen Breathing by Oxygen-Sensitive Magnetic Resonance Parameters to Predict the Outcome of Radiation Therapy: A Preclinical Study},
author = {Cao-Pham, Thanh-Trang and Tran, Ly-Binh-An and Colliez, Florence and Joudiou, Nicolas and El Bachiri, Sabrina and Grégoire, Vincent and Levêque, Philippe and Gallez, Bernard and Jordan, Bénédicte F., E-mail: benedicte.jordan@uclouvain.be},
abstractNote = {Purpose: In an effort to develop noninvasive in vivo methods for mapping tumor oxygenation, magnetic resonance (MR)-derived parameters are being considered, including global R{sub 1}, water R{sub 1}, lipids R{sub 1}, and R{sub 2}*. R{sub 1} is sensitive to dissolved molecular oxygen, whereas R{sub 2}* is sensitive to blood oxygenation, detecting changes in dHb. This work compares global R{sub 1}, water R{sub 1}, lipids R{sub 1}, and R{sub 2}* with pO{sub 2} assessed by electron paramagnetic resonance (EPR) oximetry, as potential markers of the outcome of radiation therapy (RT). Methods and Materials: R{sub 1}, R{sub 2}*, and EPR were performed on rhabdomyosarcoma and 9L-glioma tumor models, under air and carbogen breathing conditions (95% O{sub 2}, 5% CO{sub 2}). Because the models demonstrated different radiosensitivity properties toward carbogen, a growth delay (GD) assay was performed on the rhabdomyosarcoma model and a tumor control dose 50% (TCD50) was performed on the 9L-glioma model. Results: Magnetic resonance imaging oxygen-sensitive parameters detected the positive changes in oxygenation induced by carbogen within tumors. No consistent correlation was seen throughout the study between MR parameters and pO{sub 2}. Global and lipids R{sub 1} were found to be correlated to pO{sub 2} in the rhabdomyosarcoma model, whereas R{sub 2}* was found to be inversely correlated to pO{sub 2} in the 9L-glioma model (P=.05 and .03). Carbogen increased the TCD50 of 9L-glioma but did not increase the GD of rhabdomyosarcoma. Only R{sub 2}* was predictive (P<.05) for the curability of 9L-glioma at 40 Gy, a dose that showed a difference in response to RT between carbogen and air-breathing groups. {sup 18}F-FAZA positron emission tomography imaging has been shown to be a predictive marker under the same conditions. Conclusion: This work illustrates the sensitivity of oxygen-sensitive R{sub 1} and R{sub 2}* parameters to changes in tumor oxygenation. However, R{sub 1} parameters showed limitations in terms of predicting the outcome of RT in the tumor models studied, whereas R{sub 2}* was found to be correlated with the outcome in the responsive model.},
doi = {10.1016/J.IJROBP.2016.04.029},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 1,
volume = 96,
place = {United States},
year = 2016,
month = 9
}
  • The Radiation Therapy Oncology Group (RTOG) Study, in which 254 patients were analyzed, adjunctive carbogen breathing in irradiation of carcinomas of the oral cavity, oropharynx, nasopharynx, hypopharynx, and larynx failed to bring aboout a gain in survival at any of these sites. In only two of the five regional subgroups did results show any improvement with respect to patients in the Carbogen group as compared to those in the Air group, i.e., the larynx and hypopharynx subgroups. Since both of these subgroups contained relatively small numbers of patients (42 larynx, 39 hypopharynx), it was not possible to declare these improvementsmore » as definitely due to carbogen breathing. In the case of the larynx subgroup, improvement might have been due to the slightly unequal distribution with respect to T-stage; in either subgroup, the possibility that apparent improvement was due to nothing more than random variation could not be ruled out. In the subgroups with larger numbers of patients, i.e., the oral cavity and oropharynx groups, there was no demonstrated improvement accompanying carbogen breathing.« less
  • The effect of localized radiation on the transplantable KHT sarcoma in unanesthetized C3H mice was investigated while the mice breathed either oxygen (O/sub 2/) or 5 percent CO/sub 2/: 95 percent O/sub 2/ (carbogen) for times ranging from 0.5 to 120 min prior to irradiation. Tumors were irradiated with a single dose of 2000 rad at a dose rate of 1140 rad/min and tumor cell survival was determined using a lung colony assay. The results for O/sub 2/ breathing indicate that survival varies as a function of pre-irradiation breathing time (PIBT). Whereas 10 and 30 min give survival values threemore » times lower than air survival, 15 to 20 min and very long times (1 to 2 hr) yield results which are similar to those obtained under air breathing conditions. In animals breathing carbogen there is a minimum in the survival level (factor of three lower than air survival) after 10 min of gas exposure followed by a slow rise in survival over the next 90 min at which time there is no sensitization by this gas mixture relative to air. During a course of seven 500 rad fractions given daily with carbogen, a 5 min PIBT was found to give significantly greater sensitization than a 0.5 min PIBT. These findings give a clear indication that the PIBT of O/sub 2/ and carbogen has a strong influence on the effectiveness of the radiation treatment and suggest the need to control this factor carefully in the clinic.« less
  • Purpose: To develop a combination treatment consisting of combretastatin A-4-phosphate (CA4P) with radiation based on tumor oxygenation status. Methods and Materials: In vivo near-infrared spectroscopy (NIRS) and diffusion-weighted (DW) magnetic resonance imaging (MRI) were applied to noninvasively monitor changes in tumor blood oxygenation and necrosis induced by CA4P (30 mg/kg) in rat mammary 13762NF adenocarcinoma, and the evidence was used to optimize combinations of CA4P and radiation treatment (a single dose of 5 Gy). Results: NIRS showed decreasing concentrations of tumor vascular oxyhemoglobin and total hemoglobin during the first 2 h after CA4P treatment, indicating significant reductions in tumor bloodmore » oxygenation and perfusion levels (p < 0.001). Twenty-four hours later, in response to oxygen inhalation, significant recovery was observed in tumor vascular and tissue oxygenation according to NIRS and pimonidazole staining results, respectively (p < 0.05). DW MRI revealed significantly increased water diffusion in tumors measured by apparent diffusion coefficient at 24 h (p < 0.05), suggesting that CA4P-induced central necrosis. In concordance with the observed tumor oxygen dynamics, we found that treatment efficacy depended on the timing of the combined therapy. The most significant delay in tumor growth was seen in the group of tumors treated with radiation while the rats breathed oxygen 24 h after CA4P administration. Conclusions: Noninvasive evaluation of tumor oxygen dynamics allowed us to rationally enhance the response of syngeneic rat breast tumors to combined treatment of CA4P with radiation.« less
  • Purpose: Tumor cells, in contrast to normal cells, frequently overexpress heat shock protein 70 (Hsp70) in the cytosol, present it on their cell surface, and actively release it. Therefore, soluble Hsp70 (sHsp70) was investigated as a potential tumor biomarker for monitoring the outcome of radiation therapy. Methods and Materials: Plasma from mice bearing membrane Hsp70 (mHsp70)-positive FaDu human squamous cell carcinoma of the head and neck and spontaneous pancreatic ductal adenocarcinoma (PDAC) was investigated. A cohort of mice with FaDu tumors (0.32 cm{sup 3}) was irradiated with 30 Gy, and plasma was collected 24 hours after irradiation, after the tumors had shrunk tomore » 50% of their starting volume and after complete remission. sHsp70 levels in the plasma were quantified by enzyme-linked immunosorbent assay. Results: sHsp70 levels were significantly higher in the blood of tumor-bearing mice than that of control animals. A correlation between increasing sHsp70 plasma levels and tumor volume in the range of 0.01 cm{sup 3} to 0.66 cm{sup 3} was observed. Radiation-induced regression of the tumors was associated with significantly decreased sHsp70 levels, which returned to the level of control animals after complete remission. Conclusion: We propose sHsp70 as an innovative biomarker for detecting tumors and for monitoring the clinical outcome of radiation therapy in cancer patients.« less
  • Purpose: To assess the effect of pre-treatment Magnetic Resonance Imaging (MRI) on cell survival following orthovoltage radiation therapy. Methods: This in vitro study examined the survival of FSa cells (extracted from methylcholanthrene-induced fibrosarcoma in the flank of a C3H female mouse) and SA-NH cells (derived from a spontaneously arising murine sarcoma tumor) having undergone an MRI scan prior to radiation exposure. Cell cultures were kept at 37 C, in a humidified environment with 5% CO2, and were grown to confluence prior to the start of the experiment. Each cell culture underwent two, 25 minute MRIs spaced 24 hours apart usingmore » a standard brain imaging protocol. The cultures were exposed to a 2 Gy dose of radiation beginning 15 minutes after the end of each MRI scan. Irradiations were performed by a Philips RT250 X-ray generator at 250 kVp and 15 mA. All MR imaging was performed on a 1.5 T Philips Achieva scanner using a head and neck vasculature coil. Results: Cells given an MRI scan prior to radiation exhibited an increase in mean surviving fraction of 10.8% and 9.6% in FSa and SA-NH cells, respectively. The difference was found to be statistically significant in both cell types by a student two-tailed t test with P = 0.011 and P < 0.001 for FSa and SA-NH, respectively. Conclusion: MRI may cause an increase in radio-resistance in FSa and SA-NH cells. If this biological effect is found to be consistent across other cell types and voltage ranges, these results could help inform treatment planning by improving our understanding of the joint effects of MRI and ionizing radiation. This work was supported in part under NIH grant numbers T32 EB002103, NCI R01-CA 132998, DOE Low Dose Program/Project Grant DE-413 SC0001271. DJ Grdina is a paid consultant to Pinnacle Biologics. DJ Grdina and JS Murley are minority equity partners in Pinnacle Oncology LLC.« less