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Title: Real-time Tumor Oxygenation Changes After Single High-dose Radiation Therapy in Orthotopic and Subcutaneous Lung Cancer in Mice: Clinical Implication for Stereotactic Ablative Radiation Therapy Schedule Optimization

Abstract

Purpose: To investigate the serial changes of tumor hypoxia in response to single high-dose irradiation by various clinical and preclinical methods to propose an optimal fractionation schedule for stereotactic ablative radiation therapy. Methods and Materials: Syngeneic Lewis lung carcinomas were grown either orthotopically or subcutaneously in C57BL/6 mice and irradiated with a single dose of 15 Gy to mimic stereotactic ablative radiation therapy used in the clinic. Serial [{sup 18}F]-misonidazole (F-MISO) positron emission tomography (PET) imaging, pimonidazole fluorescence-activated cell sorting analyses, hypoxia-responsive element-driven bioluminescence, and Hoechst 33342 perfusion were performed before irradiation (day −1), at 6 hours (day 0), and 2 (day 2) and 6 (day 6) days after irradiation for both subcutaneous and orthotopic lung tumors. For F-MISO, the tumor/brain ratio was analyzed. Results: Hypoxic signals were too low to quantitate for orthotopic tumors using F-MISO PET or hypoxia-responsive element-driven bioluminescence imaging. In subcutaneous tumors, the maximum tumor/brain ratio was 2.87 ± 0.483 at day −1, 1.67 ± 0.116 at day 0, 2.92 ± 0.334 at day 2, and 2.13 ± 0.385 at day 6, indicating that tumor hypoxia was decreased immediately after irradiation and had returned to the pretreatment levels at day 2, followed by a slight decrease by day 6 after radiation. Pimonidazole analysis also revealed similarmore » patterns. Using Hoechst 33342 vascular perfusion dye, CD31, and cleaved caspase 3 co-immunostaining, we found a rapid and transient vascular collapse, which might have resulted in poor intratumor perfusion of F-MISO PET tracer or pimonidazole delivered at day 0, leading to decreased hypoxic signals at day 0 by PET or pimonidazole analyses. Conclusions: We found tumor hypoxia levels decreased immediately after delivery of a single dose of 15 Gy and had returned to the pretreatment levels 2 days after irradiation and had decreased slightly by day 6. Our results indicate that single high-dose irradiation can produce a rapid, but reversible, vascular collapse in tumors.« less

Authors:
 [1]; ; ; ;  [2];  [1];  [3];  [1];  [3];  [3];  [4];  [3]; ;  [5];  [3];  [3];  [6];
  1. Department of Radiation Oncology, Seoul National University College of Medicine, Seoul (Korea, Republic of)
  2. Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk (Korea, Republic of)
  3. (Korea, Republic of)
  4. Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul (Korea, Republic of)
  5. Cancer Research Institute, Seoul National University College of Medicine, Seoul (Korea, Republic of)
  6. Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut (United States)
Publication Date:
OSTI Identifier:
22648716
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 95; Journal Issue: 3; 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; ANOXIA; BIOMEDICAL RADIOGRAPHY; FLUORINE 18; FLUORINE COMPOUNDS; GY RANGE 10-100; IRRADIATION; LUNGS; MICE; NEOPLASMS; OPTIMIZATION; POSITRON COMPUTED TOMOGRAPHY; RADIATION DOSES; RADIOTHERAPY; SCHEDULES

Citation Formats

Song, Changhoon, Hong, Beom-Ju, Bok, Seoyeon, Lee, Chan-Ju, Kim, Young-Eun, Jeon, Sang-Rok, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Wu, Hong-Gyun, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Institute of Radiation Medicine, Medical Research Center, Seoul National University College of Medicine, Seoul, Lee, Yun-Sang, Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University College of Medicine, Seoul, Cheon, Gi Jeong, Paeng, Jin Chul, Institute of Radiation Medicine, Medical Research Center, Seoul National University College of Medicine, Seoul, Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Carlson, David J., and and others. Real-time Tumor Oxygenation Changes After Single High-dose Radiation Therapy in Orthotopic and Subcutaneous Lung Cancer in Mice: Clinical Implication for Stereotactic Ablative Radiation Therapy Schedule Optimization. United States: N. p., 2016. Web. doi:10.1016/J.IJROBP.2016.01.064.
Song, Changhoon, Hong, Beom-Ju, Bok, Seoyeon, Lee, Chan-Ju, Kim, Young-Eun, Jeon, Sang-Rok, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Wu, Hong-Gyun, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Institute of Radiation Medicine, Medical Research Center, Seoul National University College of Medicine, Seoul, Lee, Yun-Sang, Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University College of Medicine, Seoul, Cheon, Gi Jeong, Paeng, Jin Chul, Institute of Radiation Medicine, Medical Research Center, Seoul National University College of Medicine, Seoul, Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Carlson, David J., & and others. Real-time Tumor Oxygenation Changes After Single High-dose Radiation Therapy in Orthotopic and Subcutaneous Lung Cancer in Mice: Clinical Implication for Stereotactic Ablative Radiation Therapy Schedule Optimization. United States. doi:10.1016/J.IJROBP.2016.01.064.
Song, Changhoon, Hong, Beom-Ju, Bok, Seoyeon, Lee, Chan-Ju, Kim, Young-Eun, Jeon, Sang-Rok, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Wu, Hong-Gyun, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Institute of Radiation Medicine, Medical Research Center, Seoul National University College of Medicine, Seoul, Lee, Yun-Sang, Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University College of Medicine, Seoul, Cheon, Gi Jeong, Paeng, Jin Chul, Institute of Radiation Medicine, Medical Research Center, Seoul National University College of Medicine, Seoul, Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Carlson, David J., and and others. 2016. "Real-time Tumor Oxygenation Changes After Single High-dose Radiation Therapy in Orthotopic and Subcutaneous Lung Cancer in Mice: Clinical Implication for Stereotactic Ablative Radiation Therapy Schedule Optimization". United States. doi:10.1016/J.IJROBP.2016.01.064.
@article{osti_22648716,
title = {Real-time Tumor Oxygenation Changes After Single High-dose Radiation Therapy in Orthotopic and Subcutaneous Lung Cancer in Mice: Clinical Implication for Stereotactic Ablative Radiation Therapy Schedule Optimization},
author = {Song, Changhoon and Hong, Beom-Ju and Bok, Seoyeon and Lee, Chan-Ju and Kim, Young-Eun and Jeon, Sang-Rok and Cancer Research Institute, Seoul National University College of Medicine, Seoul and Wu, Hong-Gyun and Cancer Research Institute, Seoul National University College of Medicine, Seoul and Institute of Radiation Medicine, Medical Research Center, Seoul National University College of Medicine, Seoul and Lee, Yun-Sang and Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University College of Medicine, Seoul and Cheon, Gi Jeong and Paeng, Jin Chul and Institute of Radiation Medicine, Medical Research Center, Seoul National University College of Medicine, Seoul and Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul and Carlson, David J. and and others},
abstractNote = {Purpose: To investigate the serial changes of tumor hypoxia in response to single high-dose irradiation by various clinical and preclinical methods to propose an optimal fractionation schedule for stereotactic ablative radiation therapy. Methods and Materials: Syngeneic Lewis lung carcinomas were grown either orthotopically or subcutaneously in C57BL/6 mice and irradiated with a single dose of 15 Gy to mimic stereotactic ablative radiation therapy used in the clinic. Serial [{sup 18}F]-misonidazole (F-MISO) positron emission tomography (PET) imaging, pimonidazole fluorescence-activated cell sorting analyses, hypoxia-responsive element-driven bioluminescence, and Hoechst 33342 perfusion were performed before irradiation (day −1), at 6 hours (day 0), and 2 (day 2) and 6 (day 6) days after irradiation for both subcutaneous and orthotopic lung tumors. For F-MISO, the tumor/brain ratio was analyzed. Results: Hypoxic signals were too low to quantitate for orthotopic tumors using F-MISO PET or hypoxia-responsive element-driven bioluminescence imaging. In subcutaneous tumors, the maximum tumor/brain ratio was 2.87 ± 0.483 at day −1, 1.67 ± 0.116 at day 0, 2.92 ± 0.334 at day 2, and 2.13 ± 0.385 at day 6, indicating that tumor hypoxia was decreased immediately after irradiation and had returned to the pretreatment levels at day 2, followed by a slight decrease by day 6 after radiation. Pimonidazole analysis also revealed similar patterns. Using Hoechst 33342 vascular perfusion dye, CD31, and cleaved caspase 3 co-immunostaining, we found a rapid and transient vascular collapse, which might have resulted in poor intratumor perfusion of F-MISO PET tracer or pimonidazole delivered at day 0, leading to decreased hypoxic signals at day 0 by PET or pimonidazole analyses. Conclusions: We found tumor hypoxia levels decreased immediately after delivery of a single dose of 15 Gy and had returned to the pretreatment levels 2 days after irradiation and had decreased slightly by day 6. Our results indicate that single high-dose irradiation can produce a rapid, but reversible, vascular collapse in tumors.},
doi = {10.1016/J.IJROBP.2016.01.064},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 3,
volume = 95,
place = {United States},
year = 2016,
month = 7
}
  • Purpose: Benign computed tomography (CT) changes due to radiation induced lung injury (RILI) are common following stereotactic ablative radiotherapy (SABR) and can be difficult to differentiate from tumor recurrence. The authors measured the ability of CT image texture analysis, compared to more traditional measures of response, to predict eventual cancer recurrence based on CT images acquired within 5 months of treatment. Methods: A total of 24 lesions from 22 patients treated with SABR were selected for this study: 13 with moderate to severe benign RILI, and 11 with recurrence. Three-dimensional (3D) consolidative and ground-glass opacity (GGO) changes were manually delineatedmore » on all follow-up CT scans. Two size measures of the consolidation regions (longest axial diameter and 3D volume) and nine appearance features of the GGO were calculated: 2 first-order features [mean density and standard deviation of density (first-order texture)], and 7 second-order texture features [energy, entropy, correlation, inverse difference moment (IDM), inertia, cluster shade, and cluster prominence]. For comparison, the corresponding response evaluation criteria in solid tumors measures were also taken for the consolidation regions. Prediction accuracy was determined using the area under the receiver operating characteristic curve (AUC) and two-fold cross validation (CV). Results: For this analysis, 46 diagnostic CT scans scheduled for approximately 3 and 6 months post-treatment were binned based on their recorded scan dates into 2–5 month and 5–8 month follow-up time ranges. At 2–5 months post-treatment, first-order texture, energy, and entropy provided AUCs of 0.79–0.81 using a linear classifier. On two-fold CV, first-order texture yielded 73% accuracy versus 76%–77% with the second-order features. The size measures of the consolidative region, longest axial diameter and 3D volume, gave two-fold CV accuracies of 60% and 57%, and AUCs of 0.72 and 0.65, respectively. Conclusions: Texture measures of the GGO appearance following SABR demonstrated the ability to predict recurrence in individual patients within 5 months of SABR treatment. Appearance changes were also shown to be more accurately predictive of recurrence, as compared to size measures within the same time period. With further validation, these results could form the substrate for a clinically useful computer-aided diagnosis tool which could provide earlier salvage of patients with recurrence.« less
  • Purpose: To develop and clinically evaluate a volumetric imaging technique for assessing intrafraction geometric and dosimetric accuracy of stereotactic ablative radiation therapy (SABR). Methods and Materials: Twenty patients received SABR for lung tumors using volumetric modulated arc therapy (VMAT). At the beginning of each fraction, pretreatment cone beam computed tomography (CBCT) was used to align the soft-tissue tumor position with that in the planning CT. Concurrent with dose delivery, we acquired fluoroscopic radiograph projections during VMAT using the Varian on-board imaging system. Those kilovolt projections acquired during millivolt beam-on were automatically extracted, and intrafraction CBCT images were reconstructed using themore » filtered backprojection technique. We determined the time-averaged target shift during VMAT by calculating the center of mass of the tumor target in the intrafraction CBCT relative to the planning CT. To estimate the dosimetric impact of the target shift during treatment, we recalculated the dose to the GTV after shifting the entire patient anatomy according to the time-averaged target shift determined earlier. Results: The mean target shift from intrafraction CBCT to planning CT was 1.6, 1.0, and 1.5 mm; the 95th percentile shift was 5.2, 3.1, 3.6 mm; and the maximum shift was 5.7, 3.6, and 4.9 mm along the anterior-posterior, left-right, and superior-inferior directions. Thus, the time-averaged intrafraction gross tumor volume (GTV) position was always within the planning target volume. We observed some degree of target blurring in the intrafraction CBCT, indicating imperfect breath-hold reproducibility or residual motion of the GTV during treatment. By our estimated dose recalculation, the GTV was consistently covered by the prescription dose (PD), that is, V100% above 0.97 for all patients, and minimum dose to GTV >100% PD for 18 patients and >95% PD for all patients. Conclusions: Intrafraction CBCT during VMAT can provide geometric and dosimetric verification of SABR valuable for quality assurance and potentially for treatment adaptation.« less
  • Purpose: To evaluate the influence of tumor size, prescription dose, and dose to the lungs on posttreatment pulmonary function test (PFT) changes after stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC). Methods and Materials: The analysis is based on 191 patients treated at 5 international institutions: inclusion criteria were availability of pre- and post-SBRT PFTs and dose-volume histograms of the lung and planning target volume (PTV); patients treated with more than 1 SBRT course were excluded. Correlation between early (1-6 months, median 3 months) and late (7-24 months, median 12 months) PFT changes and tumor size, planning targetmore » volume (PTV) dose, and lung doses was assessed using linear regression analysis, receiver operating characteristics analysis, and Lyman's normal tissue complication probability model. The PTV doses were converted to biologically effective doses and lung doses to 2 Gy equivalent doses before correlation analyses. Results: Up to 6 months after SBRT, forced expiratory volume in 1 second and carbon monoxide diffusion capacity changed by −1.4% (95% confidence interval [CI], −3.4% to 0) and −7.6% (95% CI, −10.2% to −3.4%) compared with pretreatment values, respectively. A modest decrease in PFTs was observed 7-24 months after SBRT, with changes of −8.1% (95% CI, −13.3% to −5.3%) and −12.4% (95% CI, −15.5% to −6.9%), respectively. Using linear regression analysis, receiver operating characteristic analysis, and normal tissue complication probability modeling, all evaluated parameters of tumor size, PTV dose, mean lung dose, and absolute and relative volumes of the lung exposed to minimum doses of 5-70 Gy were not correlated with early and late PFT changes. Subgroup analysis based on pre-SBRT PFTs (greater or equal and less than median) did not identify any dose-effect relationship. Conclusions: This study failed to demonstrate a significant dose-effect relationship for changes of pulmonary function after SBRT for early-stage non-small cell lung cancer.« less
  • Purpose: Stereotactic ablative radiation therapy (SABR) is a guideline-specified treatment option for early-stage lung cancer. However, significant posttreatment fibrosis can occur and obfuscate the detection of local recurrence. The goal of this study was to assess physician ability to detect timely local recurrence and to compare physician performance with a radiomics tool. Methods and Materials: Posttreatment computed tomography (CT) scans (n=182) from 45 patients treated with SABR (15 with local recurrence matched to 30 with no local recurrence) were used to measure physician and radiomic performance in assessing response. Scans were individually scored by 3 thoracic radiation oncologists and 3more » thoracic radiologists, all of whom were blinded to clinical outcomes. Radiomic features were extracted from the same images. Performances of the physician assessors and the radiomics signature were compared. Results: When taking into account all CT scans during the whole follow-up period, median sensitivity for physician assessment of local recurrence was 83% (range, 67%-100%), and specificity was 75% (range, 67%-87%), with only moderate interobserver agreement (κ = 0.54) and a median time to detection of recurrence of 15.5 months. When determining the early prediction of recurrence within <6 months after SABR, physicians assessed the majority of images as benign injury/no recurrence, with a mean error of 35%, false positive rate (FPR) of 1%, and false negative rate (FNR) of 99%. At the same time point, a radiomic signature consisting of 5 image-appearance features demonstrated excellent discrimination, with an area under the receiver operating characteristic curve of 0.85, classification error of 24%, FPR of 24%, and FNR of 23%. Conclusions: These results suggest that radiomics can detect early changes associated with local recurrence that are not typically considered by physicians. This decision support system could potentially allow for early salvage therapy of patients with local recurrence after SABR.« less
  • Purpose: To estimate stereotactic ablative radiation therapy (SABR) efficacy and its potential role as an alternative to surgery for the treatment of lung metastases from colorectal cancer. Methods and Materials: Forty consecutive patients who received SABR as first local therapy at the time of lung progression were included, from 2004 to 2014. The primary study endpoint was overall survival. Secondary endpoints were progression-free survival and safety. Results: A single nodule was treated in 26 patients (65%), 2 nodules in 10 patients (25%), 3 in 3 patients (7.5%), and 4 in 1 patient (2.5%), for a total of 59 lesions. The medianmore » delivered biological effective dose was 96 Gy, in 1 to 8 daily fractions. Median follow-up time was 20 months (range, 3-72 months). Overall survival rates at 1, 2, and 5 years were, respectively, 84%, 73%, and 39%, with 14 patients (35%) dead. Median overall survival was 46 months. Progression occurred in 25 patients (62.5%), at a median interval of 8 months; failure at SABR site was observed in 3 patients (7.5%). Progression-free survival rates were 49% and 27% at 1 and 2 years, respectively. Discussion: The results of this retrospective exploratory analysis suggest safety and efficacy of SABR in patients affected with colorectal cancer lung oligometastases and urge inclusion of SABR in prospective clinical trials.« less