- Email: [email protected]
Psychological Stress Enhances Tumor Growth and Diminishes Radiation Response in Preclinical Model of Lung Cancer
E474
International Journal of Radiation Oncology Biology Physics
3165
Results: Of the 126 patients, 49 (38.9%) patients had no esophageal toxicity, 27 (21.4%) patients developed a maximum of Grade 1 esophagitis, 39 (31.0%) patients developed Grade 2 esophagitis, and 11 (8.7%) patients developed Grade 3 esophagitis. Concurrent chemotherapy was administered in 107 of 126 (84.9%) patients. All patients with Grade 3 esophagitis received chemotherapy. 38 of 39 patients with Grade 2 toxicity and 22 of 27 patients with Grade 1 toxicity also received concurrent chemoradiation. A higher risk of Grade 2 esophagitis was seen with both increasing gEUD (aZ10; consistent with lack of strong volume effect) and concurrent chemotherapy (OR 1.038; 95%CI 0.999 to 1.078; PZ0.058 and OR 7.4; 95%CI 1.3 to 141.8; PZ0.064 respectively). The area under the ROC curve (AUC) for this model was 0.68. Among patients receiving concurrent chemotherapy the risk of grade 2 esophagitis was 31% when gEUD 50 Gy and 68% when gEUD >50 Gy. Conclusion: Both higher RT dose delivered to the esophagus (using gEUD aZ10) and concurrent chemoradiation are associated with increased risk for the development of Grade 2 esophagitis in lung cancer patients treated with definitive radiation therapy. Furthermore, chemoradiation patients receiving >50 Gy gEUD esophageal dose had 37% increased risk of developing Grade 2 esophagitis compared to those receiving 50 Gy gEUD. These findings suggest that the use of gEUD aZ10, rather than mean esophageal dose alone, and limiting the dose to 50 Gy may reduce the risk of esophageal toxicity. Author Disclosure: S. Hobson: None. A. Abugharib: Visiting Fellow; University of Michigan. M. Schipper: Consultant; Armune Bioscience. M.M. Matuszak: Employee; William Beaumont Hospital. Research Grant; Varian Medical Systems. D. Owen: None. J.A. Hayman: Research Grant; Blue Cross Blue Shield of Michigan. BOD member; ASTRO. G.P. Kalemkerian: Research Grant; Pfizer, Merck, OncoMed, Astex, GlaxoSmithKline, Millennium. R.K. Ten Haken: Travel Expenses; Varian Medical Systems. F. Kong: Research Grant; Varian Medical Inc., NCI. Applied Technology, Lung Multidisciplinary Clinic, Lung and Esophageal Research Programs; GRU Cancer Center. T.S. Lawrence: Research Grant; NIH. Ownership; Degradon Holding, LLC. Advisor; Various medical and scientific advisory boards. President; Radiation Oncology Institute. S. Jolly: Employee; William Beaumont Hospital.
Psychological Stress Enhances Tumor Growth and Diminishes Radiation Response in Preclinical Model of Lung Cancer Y. Zhang,1 P. Zanos,1 I. Jackson,2 X. Zhang,2 X. Zhu,3 T. Gould,1 and Z. Vujaskovic2; 1University of Maryland Baltimore, Baltimore, MD, 2 University of Maryland School of Medicine, Baltimore, MD, 3Institute of Medical Psychology, Changsha, China Purpose/Objective(s): Patients with life-threatening illnesses, such as cancer, experience emotional distress. This study investigated the role of psychological distress on tumor growth and radioresistance, as well as associated molecular and cellular mechanisms. Materials/Methods: Stress was induced in C57BL/6J mice bearing LLC lung tumors by exposure to conspecific mice receiving inescapable foot shocks. Mice were irradiated at 7 Gy for 3 consecutive days. Behaviors were monitored by open field test (OFT), elevated plus maze (EPM), sucrose preference test (SPT), and learned helplessness (LH) test. Protein expression in tissues and cultured cells were measured by Western blot. Results: There was a main effect of stress on the distance the mice traveled in the OFT, percent sucrose consumed, and escape failures in the LH test. There was an overall effect of stress in increasing tumor growth but importantly, there was a main effect of stress on the effects of radiation. The increased plasma corticosterone and adrenaline levels were observed even 9 days after the last psychological stress session. A b2-adrenergic receptor agonist blocked irradiation-induced cell apoptosis and decreased cell viability, while silencing b2 AR expression reduced the protective effects of b2-adrenergic receptor agonist. b2-adrenergic receptor agonist obviously increased Wnt1 and Drosha expression in LLC-1 cells, while stress increased Wnt1, Drosha, and vimentin expression and decreased E-cadherin expression in tumor tissues. The combination of stress and irradiation enhanced radioresistance along with the increase in vimentin expression and decrease in cell death. Conclusion: Mice observing a conspecific mouse receiving foot shocks developed anhedonia, depressive-like behaviors, and helplessness. This stress-induced emotional impairment decreased the efficiency of radiation therapy in inhibiting tumor growth via an adrenergic-related activation of epithelial-mesenchymal transition (EMT) and associated genes-dependent mechanism. Author Disclosure: Y. Zhang: None. P. Zanos: None. I. Jackson: None. X. Zhang: None. X. Zhu: None. T. Gould: None. Z. Vujaskovic: None.
3166 Predictors of Acute Esophagitis in Lung Cancer Patients Treated With Definitive Radiation Therapy S. Hobson,1 A. Abugharib,1,2 M. Schipper,1 M.M. Matuszak,3 D. Owen,1 J.A. Hayman,1 G.P. Kalemkerian,1 R.K. Ten Haken,3 F.M. Kong,4 T.S. Lawrence,1 and S. Jolly1; 1University of Michigan, Ann Arbor, MI, 2 Sohag University Hospital, Sohag, Egypt, 3Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 4Department of Radiation Oncology, Augusta University, Augusta, GA Purpose/Objective(s): Lung cancer patients receiving definitive radiation therapy (RT), especially those with centrally located tumors, often experience acute esophagitis. This can cause significant discomfort, weight loss and impact patient quality of life. The primary objective of this study was to determine clinical and dosimetric predictors of esophageal toxicity. Materials/Methods: A cohort of 126 lung cancer patients treated on institutional prospective definitive radiation therapy protocols from 20042013 was selected for analyses. For all patients, the esophagus was contoured as an organ at risk according to RTOG guidelines and toxicity was graded according to CTCAE guidelines. Dosimetric data was based on modern dose calculations that have been biologically corrected to 2 Gy per fraction using the linear-quadratic model (EQD2, a/bZ10 Gy for esophagus). Factors predicting for esophagitis were analyzed using stepwise regression modeling.
3167 Esophageal Dose Tolerance in Patients Treated With Stereotactic Body Radiation Therapy (SBRT) J. Nuyttens,1 V. Moiseenko,2 and J. Grimm3; 1Erasmus MC Cancer Institute, Rotterdam, Netherlands, 2University of California, San Diego, La Jolla, CA, 3Holy Redeemer Hospital, Meadowbrook, PA Purpose/Objective(s): Mediastinal critical structures such as trachea, bronchus, and esophagus are among the dose limiting factors for stereotactic body radiation therapy (SBRT) to central lung lesions. The purpose of this study was to characterize the risk of esophagitis for patients treated with SBRT and to develop a statistical dose response model to assess the equivalent uniform dose (EUD), D10%, D5cc, D1cc, and Dmax to the esophagus, particularly to determine if the constraint of DmaxZ35 Gy in 5 fractions would result in acceptable toxicity. Materials/Methods: Among treatment plans for 58 tumors in 56 patients, 46 cases were close enough to the esophagus to warrant delineating the structure. Dose escalation began with 5 fractions of 9 Gy, followed by 5 fractions of 10 Gy and later to 5 fractions of 12 Gy. Depending on size, location, and other factors, some patients received 6 fractions of 8 Gy, 7 fractions of 8 Gy, or 3 fractions of 20 Gy. Five grade 2 esophageal complications occurred (Common Terminology Criteria for Adverse Events version 3.0). Four were early effects and one was a late effect. The median number of fractions was 5, so the linear-quadratic (LQ) model with a/bZ3 Gy was used to convert each bin of every DVH to 5-fraction equivalent doses prior to modeling the dose response. Maximum likelihood fitting of the probit model was performed in the DVH Evaluator software by reducing each DVH into a scalar dose descriptor that is a function of dose
International Journal of Radiation Oncology Biology Physics
3165
Results: Of the 126 patients, 49 (38.9%) patients had no esophageal toxicity, 27 (21.4%) patients developed a maximum of Grade 1 esophagitis, 39 (31.0%) patients developed Grade 2 esophagitis, and 11 (8.7%) patients developed Grade 3 esophagitis. Concurrent chemotherapy was administered in 107 of 126 (84.9%) patients. All patients with Grade 3 esophagitis received chemotherapy. 38 of 39 patients with Grade 2 toxicity and 22 of 27 patients with Grade 1 toxicity also received concurrent chemoradiation. A higher risk of Grade 2 esophagitis was seen with both increasing gEUD (aZ10; consistent with lack of strong volume effect) and concurrent chemotherapy (OR 1.038; 95%CI 0.999 to 1.078; PZ0.058 and OR 7.4; 95%CI 1.3 to 141.8; PZ0.064 respectively). The area under the ROC curve (AUC) for this model was 0.68. Among patients receiving concurrent chemotherapy the risk of grade 2 esophagitis was 31% when gEUD 50 Gy and 68% when gEUD >50 Gy. Conclusion: Both higher RT dose delivered to the esophagus (using gEUD aZ10) and concurrent chemoradiation are associated with increased risk for the development of Grade 2 esophagitis in lung cancer patients treated with definitive radiation therapy. Furthermore, chemoradiation patients receiving >50 Gy gEUD esophageal dose had 37% increased risk of developing Grade 2 esophagitis compared to those receiving 50 Gy gEUD. These findings suggest that the use of gEUD aZ10, rather than mean esophageal dose alone, and limiting the dose to 50 Gy may reduce the risk of esophageal toxicity. Author Disclosure: S. Hobson: None. A. Abugharib: Visiting Fellow; University of Michigan. M. Schipper: Consultant; Armune Bioscience. M.M. Matuszak: Employee; William Beaumont Hospital. Research Grant; Varian Medical Systems. D. Owen: None. J.A. Hayman: Research Grant; Blue Cross Blue Shield of Michigan. BOD member; ASTRO. G.P. Kalemkerian: Research Grant; Pfizer, Merck, OncoMed, Astex, GlaxoSmithKline, Millennium. R.K. Ten Haken: Travel Expenses; Varian Medical Systems. F. Kong: Research Grant; Varian Medical Inc., NCI. Applied Technology, Lung Multidisciplinary Clinic, Lung and Esophageal Research Programs; GRU Cancer Center. T.S. Lawrence: Research Grant; NIH. Ownership; Degradon Holding, LLC. Advisor; Various medical and scientific advisory boards. President; Radiation Oncology Institute. S. Jolly: Employee; William Beaumont Hospital.
Psychological Stress Enhances Tumor Growth and Diminishes Radiation Response in Preclinical Model of Lung Cancer Y. Zhang,1 P. Zanos,1 I. Jackson,2 X. Zhang,2 X. Zhu,3 T. Gould,1 and Z. Vujaskovic2; 1University of Maryland Baltimore, Baltimore, MD, 2 University of Maryland School of Medicine, Baltimore, MD, 3Institute of Medical Psychology, Changsha, China Purpose/Objective(s): Patients with life-threatening illnesses, such as cancer, experience emotional distress. This study investigated the role of psychological distress on tumor growth and radioresistance, as well as associated molecular and cellular mechanisms. Materials/Methods: Stress was induced in C57BL/6J mice bearing LLC lung tumors by exposure to conspecific mice receiving inescapable foot shocks. Mice were irradiated at 7 Gy for 3 consecutive days. Behaviors were monitored by open field test (OFT), elevated plus maze (EPM), sucrose preference test (SPT), and learned helplessness (LH) test. Protein expression in tissues and cultured cells were measured by Western blot. Results: There was a main effect of stress on the distance the mice traveled in the OFT, percent sucrose consumed, and escape failures in the LH test. There was an overall effect of stress in increasing tumor growth but importantly, there was a main effect of stress on the effects of radiation. The increased plasma corticosterone and adrenaline levels were observed even 9 days after the last psychological stress session. A b2-adrenergic receptor agonist blocked irradiation-induced cell apoptosis and decreased cell viability, while silencing b2 AR expression reduced the protective effects of b2-adrenergic receptor agonist. b2-adrenergic receptor agonist obviously increased Wnt1 and Drosha expression in LLC-1 cells, while stress increased Wnt1, Drosha, and vimentin expression and decreased E-cadherin expression in tumor tissues. The combination of stress and irradiation enhanced radioresistance along with the increase in vimentin expression and decrease in cell death. Conclusion: Mice observing a conspecific mouse receiving foot shocks developed anhedonia, depressive-like behaviors, and helplessness. This stress-induced emotional impairment decreased the efficiency of radiation therapy in inhibiting tumor growth via an adrenergic-related activation of epithelial-mesenchymal transition (EMT) and associated genes-dependent mechanism. Author Disclosure: Y. Zhang: None. P. Zanos: None. I. Jackson: None. X. Zhang: None. X. Zhu: None. T. Gould: None. Z. Vujaskovic: None.
3166 Predictors of Acute Esophagitis in Lung Cancer Patients Treated With Definitive Radiation Therapy S. Hobson,1 A. Abugharib,1,2 M. Schipper,1 M.M. Matuszak,3 D. Owen,1 J.A. Hayman,1 G.P. Kalemkerian,1 R.K. Ten Haken,3 F.M. Kong,4 T.S. Lawrence,1 and S. Jolly1; 1University of Michigan, Ann Arbor, MI, 2 Sohag University Hospital, Sohag, Egypt, 3Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 4Department of Radiation Oncology, Augusta University, Augusta, GA Purpose/Objective(s): Lung cancer patients receiving definitive radiation therapy (RT), especially those with centrally located tumors, often experience acute esophagitis. This can cause significant discomfort, weight loss and impact patient quality of life. The primary objective of this study was to determine clinical and dosimetric predictors of esophageal toxicity. Materials/Methods: A cohort of 126 lung cancer patients treated on institutional prospective definitive radiation therapy protocols from 20042013 was selected for analyses. For all patients, the esophagus was contoured as an organ at risk according to RTOG guidelines and toxicity was graded according to CTCAE guidelines. Dosimetric data was based on modern dose calculations that have been biologically corrected to 2 Gy per fraction using the linear-quadratic model (EQD2, a/bZ10 Gy for esophagus). Factors predicting for esophagitis were analyzed using stepwise regression modeling.
3167 Esophageal Dose Tolerance in Patients Treated With Stereotactic Body Radiation Therapy (SBRT) J. Nuyttens,1 V. Moiseenko,2 and J. Grimm3; 1Erasmus MC Cancer Institute, Rotterdam, Netherlands, 2University of California, San Diego, La Jolla, CA, 3Holy Redeemer Hospital, Meadowbrook, PA Purpose/Objective(s): Mediastinal critical structures such as trachea, bronchus, and esophagus are among the dose limiting factors for stereotactic body radiation therapy (SBRT) to central lung lesions. The purpose of this study was to characterize the risk of esophagitis for patients treated with SBRT and to develop a statistical dose response model to assess the equivalent uniform dose (EUD), D10%, D5cc, D1cc, and Dmax to the esophagus, particularly to determine if the constraint of DmaxZ35 Gy in 5 fractions would result in acceptable toxicity. Materials/Methods: Among treatment plans for 58 tumors in 56 patients, 46 cases were close enough to the esophagus to warrant delineating the structure. Dose escalation began with 5 fractions of 9 Gy, followed by 5 fractions of 10 Gy and later to 5 fractions of 12 Gy. Depending on size, location, and other factors, some patients received 6 fractions of 8 Gy, 7 fractions of 8 Gy, or 3 fractions of 20 Gy. Five grade 2 esophageal complications occurred (Common Terminology Criteria for Adverse Events version 3.0). Four were early effects and one was a late effect. The median number of fractions was 5, so the linear-quadratic (LQ) model with a/bZ3 Gy was used to convert each bin of every DVH to 5-fraction equivalent doses prior to modeling the dose response. Maximum likelihood fitting of the probit model was performed in the DVH Evaluator software by reducing each DVH into a scalar dose descriptor that is a function of dose