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Title: Water Exchange Rate Constant as a Biomarker of Treatment Efficacy in Patients With Brain Metastases Undergoing Stereotactic Radiosurgery

Abstract

Purpose: This study was designed to evaluate whether changes in metastatic brain tumors after stereotactic radiosurgery (SRS) can be seen with quantitative MRI early after treatment. Methods and Materials: Using contrast-enhanced MRI, a 3-water-compartment tissue model consisting of intracellular (I), extracellular-extravascular (E), and vascular (V) compartments was used to assess the intra–extracellular water exchange rate constant (k{sub IE}), efflux rate constant (k{sub ep}), and water compartment volume fractions (M{sub 0,I}, M{sub 0,E}, M{sub 0,V}). In this prospective study, 19 patients were MRI-scanned before treatment and 1 week and 1 month after SRS. The change in model parameters between the pretreatment and 1-week posttreatment scans was correlated to the change in tumor volume between pretreatment and 1-month posttreatment scans. Results: At 1 week k{sub IE} differentiated (P<.001) tumors that had partial response from tumors with stable and progressive disease, and a high correlation (R=−0.76, P<.001) was observed between early changes in the k{sub IE} and tumor volume change 1 month after treatment. Other model parameters had lower correlation (M{sub 0,E}) or no correlation (k{sub ep}, M{sub 0,V}). Conclusions: This is the first study that measured k{sub IE} early after SRS, and it found that early changes in k{sub IE} (1 week after treatment) highly correlated with long-termmore » tumor response and could predict the extent of tumor shrinkage at 1 month after SRS.« less

Authors:
 [1];  [2];  [3];  [4];  [5];  [6];  [3];  [2];  [1];  [2];  [2];  [7];  [1];  [2];  [1];  [2];  [8]
  1. Medical Biophysics, University of Toronto, Toronto, Ontario (Canada)
  2. (Canada)
  3. Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario (Canada)
  4. Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario (Canada)
  5. Computer Science Department, University College London, London (United Kingdom)
  6. Neurosurgery and Pediatric Neurosurgery, Medical University, Lublin (Poland)
  7. Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario (Canada)
  8. (Poland)
Publication Date:
OSTI Identifier:
22649906
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 98; Journal Issue: 1; Other Information: Copyright (c) 2017 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; BIOLOGICAL MARKERS; BRAIN; CORRELATIONS; FOREIGN EXCHANGE RATE; NEOPLASMS; NMR IMAGING; PATIENTS; RADIOTHERAPY; REACTION KINETICS; SURGERY

Citation Formats

Mehrabian, Hatef, E-mail: hatef.mehrabian@sri.utoronto.ca, Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Desmond, Kimberly L., Chavez, Sofia, Bailey, Colleen, Rola, Radoslaw, Sahgal, Arjun, Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Czarnota, Gregory J., Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Soliman, Hany, Martel, Anne L., Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Stanisz, Greg J., Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, and Neurosurgery and Pediatric Neurosurgery, Medical University, Lublin. Water Exchange Rate Constant as a Biomarker of Treatment Efficacy in Patients With Brain Metastases Undergoing Stereotactic Radiosurgery. United States: N. p., 2017. Web. doi:10.1016/J.IJROBP.2017.01.016.
Mehrabian, Hatef, E-mail: hatef.mehrabian@sri.utoronto.ca, Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Desmond, Kimberly L., Chavez, Sofia, Bailey, Colleen, Rola, Radoslaw, Sahgal, Arjun, Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Czarnota, Gregory J., Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Soliman, Hany, Martel, Anne L., Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Stanisz, Greg J., Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, & Neurosurgery and Pediatric Neurosurgery, Medical University, Lublin. Water Exchange Rate Constant as a Biomarker of Treatment Efficacy in Patients With Brain Metastases Undergoing Stereotactic Radiosurgery. United States. doi:10.1016/J.IJROBP.2017.01.016.
Mehrabian, Hatef, E-mail: hatef.mehrabian@sri.utoronto.ca, Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Desmond, Kimberly L., Chavez, Sofia, Bailey, Colleen, Rola, Radoslaw, Sahgal, Arjun, Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Czarnota, Gregory J., Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Soliman, Hany, Martel, Anne L., Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Stanisz, Greg J., Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, and Neurosurgery and Pediatric Neurosurgery, Medical University, Lublin. 2017. "Water Exchange Rate Constant as a Biomarker of Treatment Efficacy in Patients With Brain Metastases Undergoing Stereotactic Radiosurgery". United States. doi:10.1016/J.IJROBP.2017.01.016.
@article{osti_22649906,
title = {Water Exchange Rate Constant as a Biomarker of Treatment Efficacy in Patients With Brain Metastases Undergoing Stereotactic Radiosurgery},
author = {Mehrabian, Hatef, E-mail: hatef.mehrabian@sri.utoronto.ca and Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario and Desmond, Kimberly L. and Chavez, Sofia and Bailey, Colleen and Rola, Radoslaw and Sahgal, Arjun and Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario and Czarnota, Gregory J. and Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario and Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario and Soliman, Hany and Martel, Anne L. and Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario and Stanisz, Greg J. and Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario and Neurosurgery and Pediatric Neurosurgery, Medical University, Lublin},
abstractNote = {Purpose: This study was designed to evaluate whether changes in metastatic brain tumors after stereotactic radiosurgery (SRS) can be seen with quantitative MRI early after treatment. Methods and Materials: Using contrast-enhanced MRI, a 3-water-compartment tissue model consisting of intracellular (I), extracellular-extravascular (E), and vascular (V) compartments was used to assess the intra–extracellular water exchange rate constant (k{sub IE}), efflux rate constant (k{sub ep}), and water compartment volume fractions (M{sub 0,I}, M{sub 0,E}, M{sub 0,V}). In this prospective study, 19 patients were MRI-scanned before treatment and 1 week and 1 month after SRS. The change in model parameters between the pretreatment and 1-week posttreatment scans was correlated to the change in tumor volume between pretreatment and 1-month posttreatment scans. Results: At 1 week k{sub IE} differentiated (P<.001) tumors that had partial response from tumors with stable and progressive disease, and a high correlation (R=−0.76, P<.001) was observed between early changes in the k{sub IE} and tumor volume change 1 month after treatment. Other model parameters had lower correlation (M{sub 0,E}) or no correlation (k{sub ep}, M{sub 0,V}). Conclusions: This is the first study that measured k{sub IE} early after SRS, and it found that early changes in k{sub IE} (1 week after treatment) highly correlated with long-term tumor response and could predict the extent of tumor shrinkage at 1 month after SRS.},
doi = {10.1016/J.IJROBP.2017.01.016},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 1,
volume = 98,
place = {United States},
year = 2017,
month = 5
}
  • Purpose: Ipilimumab (Ipi), a monoclonal antibody against cytotoxic T-lymphocyte antigen-4, has been shown to improve survival in patients with metastatic melanoma. In this single-institution study, we investigated the safety and efficacy of stereotactic radiosurgery (SRS) for patients with melanoma brain metastases (BMs) who also received Ipi. Methods and Materials: From 2005 to 2011, 46 patients with melanoma received Ipi and underwent single-fraction SRS for BMs. A total of 113 BMs (91% intact, 9% postoperative) were treated with a median dose of 21 Gy (range, 15-24 Gy). Ipi was given at 3 mg/kg (54%) or 10 mg/kg (46%) for a median of 4 doses (range,more » 1-21). Adverse events were recorded with the use of the Common Terminology Criteria for Adverse Events 3.0. Kaplan-Meier methods were used to estimate survival, and Cox regression was used to investigate associations. Results: Fifteen patients received SRS during Ipi, 19 received SRS before Ipi, and 12 received SRS after Ipi. Overall survival (OS) was significantly associated with the timing of SRS/Ipi (P=.035) and melanoma-specific graded prognostic assessment (P=.013). Patients treated with SRS during or before Ipi had better OS and less regional recurrence than did those treated with SRS after Ipi (1-year OS 65% vs 56% vs 40%, P=.008; 1-year regional recurrence 69% vs 64% vs 92%, P=.003). SRS during Ipi also yielded a trend toward less local recurrence than did SRS before or after Ipi (1-year local recurrence 0% vs 13% vs 11%, P=.21). On magnetic resonance imaging, an increase in BM diameter to >150% was seen in 50% of patients treated during or before Ipi but in only 13% of patients treated after Ipi. Grade 3 to 4 toxicities were seen in 20% of patients. Conclusion: Overall, the combination of Ipi and SRS appears to be well tolerated. Concurrent delivery of Ipi and SRS is associated with favorable locoregional control and possibly longer survival. It may also cause a temporary increase in tumor size, possibly because of an enhanced immunomodulatory effect.« less
  • Purpose: To evaluate the outcomes of radiosurgery for brain metastases in patients 65 years or older. Patients and Methods: Between January 1994 and January 2003, 117 patients (47 women, 70 men), median age 71 years (range, 65-86 years), received radiosurgery for 227 metastases. Sixty-one patients (55%) presented symptoms in relation to the brain metastases. Thirty-eight patients (32%) received whole-brain radiotherapy. Median metastasis diameter and volume were 21 mm (range, 0.5-75 mm) and 1.7 cc (range, 0.02-71 cc), respectively. Results: Median follow-up was 7 months (range, 1-45 months), 9.5 months for alive patients (range, 1-45 months). Median minimum and maximum dosesmore » were 14.5 Gy (6.5 Gy, 19.5 Gy), and 20.4 Gy (13.2 Gy, 41.9 Gy), respectively. Median survival was 8 months from the date of radiosurgery. Overall survival rates at 6 and 24 months were 58% {+-} 5% and 13% {+-} 4%, respectively. According to multivariate analysis, a low Karnofsky performance status was an independent unfavorable prognostic factor for overall survival (p = 0.003; odds ratio [OR] = 0.28; 95% confidence interval [CI], 0.14-0.56). Median brain disease-free survival was 10 months. Brain disease-free survival rates at 6 and 24 months were 67% {+-} 6% and 40% {+-} 7%, respectively. According to multivariate analysis, a radiosensitive lesion was an independent favorable factor (p = 0.038; OR = 0.42; 95% CI, 0.18-0.95); more than two metastases and a low Karnofsky performance status were independent unfavorable factors for brain disease-free survival (p = 0.046; OR = 2.15; 95% CI, 1.01-4.58 and p = 0.003; OR = 30.4; 95% CI, 3.1-296, respectively). Local control rates were 98% {+-} 2% and 91% {+-} 8.5% at 6 and 24 months. Out of the 61 patients presenting symptoms before radiosurgery, complete symptomatic response was achieved in 12 patients (20%), partial improvement in 25 (41%), stabilization in 7 (11%), and worsening in 4 (6%) related to a progression of the irradiated metastasis. Seven cases of radionecrosis were described and were related to the margin dose (p = 0.03). Conclusion: Radiosurgery for elderly patients was effective and safe. Age alone should not be a criterion for denying radiosurgery to any patient with brain metastases.« less
  • Purpose: To ascertain predictors of distant brain failure (DBF) in patients treated initially with stereotactic radiosurgery alone for newly diagnosed brain metastases. We hypothesize that these factors may be used to group patients according to risk of DBF. Methods and Materials: We retrospectively analyzed 100 patients with newly diagnosed brain metastases treated from 2003 to 2005 at our Gamma Knife radiosurgery facility. The primary endpoint was DBF. Potential predictors included number of metastases, tumor volume, histologic characteristics, extracranial disease, and use of temozolomide. Results: One-year actuarial risk of DBF was 61% for all patients. Significant predictors of DBF included moremore » than three metastases (hazard ratio, 3.30; p = 0.004), stable or poorly controlled extracranial disease (hazard ratio, 2.16; p = 0.04), and melanoma histologic characteristics (hazard ratio, 2.14; p = 0.02). These were confirmed in multivariate analysis. Those with three or fewer metastases, no extracranial disease, and nonmelanoma histologic characteristics (N = 18) had a median time to DBF of 89 weeks vs. 33 weeks for all others. One-year actuarial freedom from DBF for this group was 83% vs. 26% for all others. Conclusions: Independent significant predictors of DBF in our series included number of metastases (more than three), present or uncontrolled extracranial disease, and melanoma histologic characteristics. These factors were combined to identify a lower risk subgroup with significantly longer time to DBF. These patients may be candidates for initial localized treatment, reserving whole-brain radiation therapy for salvage. Patients in the higher risk group may be candidates for initial whole-brain radiation therapy or should be considered for clinical trials.« less
  • Purpose: To evaluate prognostic factors for survival after stereotactic radiosurgery (SRS) for new, progressive, or recurrent brain metastases (BM) after prior whole brain radiotherapy (WBRT). Methods and Materials: Patients treated between 1991 and 2007 with Gamma Knife SRS for BM after prior WBRT were retrospectively reviewed. Potential prognostic factors were analyzed overall and by primary site using univariate and stepwise multivariate analyses and recursive partitioning analysis, including age, Karnofsky performance status (KPS), primary tumor control, extracranial metastases, number of BM treated, total SRS target volume, and interval from WBRT to SRS. Results: A total of 310 patients were analyzed, includingmore » 90 breast, 113 non-small-cell lung, 31 small-cell lung, 42 melanoma, and 34 miscellaneous patients. The median age was 56, KPS 80, number of BM treated 3, and interval from WBRT to SRS 8.1 months; 76% had controlled primary tumor and 60% had extracranial metastases. The median survival was 8.4 months overall and 12.0 vs. 7.9 months for single vs. multiple BM treated (p = 0.001). There was no relationship between number of BM and survival after excluding single-BM patients. On multivariate analysis, favorable prognostic factors included age <50, smaller total target volume, and longer interval from WBRT to SRS in breast cancer patients; smaller number of BM, KPS >60, and controlled primary in non-small-cell lung cancer patients; and smaller total target volume in melanoma patients. Conclusions: Among patients treated with salvage SRS for BM after prior WBRT, prognostic factors appeared to vary by primary site. Although survival time was significantly longer for patients with a single BM, the median survival time of 7.9 months for patients with multiple BM seems sufficiently long for salvage SRS to appear to be worthwhile, and no evidence was found to support the use of a cutoff for number of BM appropriate for salvage SRS.« less
  • Purpose: Radiation Therapy Oncology Group (RTOG) 9508 showed a survival advantage for patients with 1 but not 2 or 3 brain metastasis (BM) treated with whole-brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) versus WBRT alone. An improved prognostic index, the graded prognostic assessment (GPA) has been developed. Our hypothesis was that if the data from RTOG 9508 were poststratified by the GPA, the conclusions may vary. Methods and Materials: In this analysis, 252 of the 331 patients were evaluable by GPA. Of those, 211 had lung cancer. Breast cancer patients were excluded because the components of the breast GPAmore » are not in the RTOG database. Multiple Cox regression was used to compare survival between treatment groups, adjusting for GPA. Treatment comparisons within subgroups were performed with the log-rank test. A free online tool ( (brainmetgpa.com)) simplified GPA use. Results: The fundamental conclusions of the primary analysis were confirmed in that there was no survival benefit overall for patients with 1 to 3 metastases; however, there was a benefit for the subset of patients with GPA 3.5 to 4.0 (median survival time [MST] for WBRT + SRS vs WBRT alone was 21.0 versus 10.3 months, P=.05) regardless of the number of metastases. Among patients with GPA 3.5 to 4.0 treated with WBRT and SRS, the MST for patients with 1 versus 2 to 3 metastases was 21 and 14.1 months, respectively. Conclusions: This secondary analysis of predominantly lung cancer patients, consistent with the original analysis, shows no survival advantage for the group overall when treated with WBRT and SRS; however, in patients with high GPA (3.5-4), there is a survival advantage regardless of whether they have 1, 2, or 3 BM. This benefit did not extend to patients with lower GPA. Prospective validation of this survival benefit for patients with multiple BM and high GPA when treated with WBRT and SRS is warranted.« less