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Mean In-field Esophagus Dose Predicts for Esophagitis in Lung Cancer Patients Treated with 3D-CRT and Concurrent Chemotherapy
Proceedings of the 50th Annual ASTRO Meeting evidence demonstrates that IGFBP-8/CTGF plays an important role in the pathogenesis of fibrotic disorders. It has been reported that IGFBP-8/CTGF can induce fibrosis either in a transforming growth factor (TGF)-b-dependent or -independent manner. Recent studies have implicated TGFß in the pathogenesis of RT-induced fibrosis. However, we have recently shown that blocking the effects of TGF-ß with an anti-TGF-ß antibody does not completely eliminate RT-induced fibrosis in an animal model, suggesting IGFBP-8/CTGF may play a key role in this process. Materials/Methods: Fischer 344 rats were irradiated to the right hemithorax (28 Gy in 1 fraction) and lung tissue samples collected pre-irradiation and at 4, 14- and 20-week post-irradiation. Immunohistochemistry for IGFBP-8/CTGF (sc-14939, 1:500) and trichrome staining for detection of fibrosis was performed using paraffin-embedded samples. For in vitro studies, HFL-1 human normal lung fibroblasts were irradiated at doses ranging 1-5 Gy using a 60Co irradiator or treated with TGF-b1 for 3 days. Cell lysates and the conditioned media were collected and subjected to WIB using specific antibodies for IGFBP-8/CTGF (sc14939, 1:600) and fibronectin (sc-9068, 1:600). Results: In vivo, trichrome staining was clearly observed in the lung tissue at 14- and 20-week post-irradiation, consistent with the known time course of RILF in this animal model. Concomitantly, increased expression of IGFBP-8/CTGF was detected after 14week post-irradiation. In HFL-1 cells, IGFBP-8/CTGF expression was greatly increased by treatment with 5 ng/ml TGF-b1 for 3 days. When these cells were irradiated at doses ranging 1-5 Gy using a 60Co irradiator, an increase in IGFBP-8/CTGF expression was demonstrated in a dose-dependent manner at 3 day post-irradiation. We have further observed that 5 Gy exposure to HFL-1 results in an increased expression of fibronectin in a time-dependent manner with maximal increase at day 3. Conclusions: Taken together, these data strongly suggest that radiation-induced IGFBP-8/CTGF might be responsible for enhanced expression of pro-fibrotic factors, such as fibronectin, and thereby contribute to the development of fibrosis in irradiated lungs. Studies are ongoing to determine whether induction of TGFBP8/CTGF is dependent on TGFß or not in the HFL-1 cell line. A fuller understanding of the mechanisms of action of IGFBP-8/CTGF in RT-induced fibrosis may provide a novel intervention strategy for prevention and treatment of fibrosis after RT. Author Disclosure: C. Li, None; M. Idowu, None; Z. Vujaskovic, None; Y. Oh, None; M.S. Anscher, CivaTech, F. Consultant/ Advisory Board.
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Mean In-field Esophagus Dose Predicts for Esophagitis in Lung Cancer Patients Treated with 3D-CRT and Concurrent Chemotherapy
H. B. Caglar, M. Othus, A. M. Allen Brigham and Women’s Hospital / Dana Farber Cancer Institute, Boston, MA Purpose/Objective(s): To determine the dosimetric factors for acute esophagitis and esophageal stricture in non small cell lung cancer (NSCLC) patients treated with concurrent chemotherapy (CT) and three-dimensional conformal radiotherapy (3D-CRT). Materials/Methods: One hundred and nine stage III NSCLC patients treated with 3D-CRT and concurrent CT between 3/2000 and 11/2006 in Dana Farber/Brigham and Women’s Cancer Center were analyzed with IRB approval. Acute esophageal toxicity was evaluated weekly by treating physician and nurse during and after chemoradiation and the presence of strictures were evaluated for the patients who had persistent dysphagia after treatment. Acute esophagitis was scored according to CTCv3. The esophagus was contoured in two ways. First, as traditionally done using the entire esophagus from thoracic inlet to GE junction. A separate structure was also created for the esophagus only in the treatment field. Variables examined for correlation with the clinical factors (use of induction CT, RT dose and type of concurrent CT) as well as the radiation doses to esophagus in field and whole esophagus. Correlation between toxicity events and the variables was assessed by univariate logistic regression. Results: Median age was 60 (33-81), 53% were male. 48 (44%) were stage IIIA patients the remainder had stage IIIB disease. Among the 109 patients 37 of them received 2 cycles of induction CT prior to CRT and 31 pts received consolidation CT after CRT. Median RT dose was 60 Gy in 30 fractions, 26 of the patients (24%) received \ 60 Gy and the rest (76%) received $60 Gy. The CT regimens were: cisplatin/etoposide every 3 weeks (35%) or weekly carboplatin/paclitaxel (65%). 27 pts (25%) had $ grade 3 esophagitis; 6 pts (5%) had a stricture following RT, all of which were dilated. None of the clinical factors were significant with esophagitis on univariate analysis. V45-V60 of the esophagus both infield and whole esophagus were significant discriminators for esophagitis. However, the strongest discriminator for esophagitis was the mean dose to the in-field esophagus (p \0.001) such that a mean dose of 50 Gy or greater predicted for a 75% change of esophagitis and a mean dose below 50 Gy had only a 25% chance of esophagitis. V50, V55 and V60 were all significantly correlated with stricture as well as the mean esophageal dose. (p = 0.05, 0.04 and 0.01 respectively). Conclusions: RT doses above 45 Gy when given with concurrent CT to the esophagus are correlated with clinically relevant esophagitis and stricture. The use of mean esophageal dose in-field is a novel predictor which should be considered in future trials. Author Disclosure: H.B. Caglar, None; M. Othus, None; A.M. Allen, None.
2579
Autocontouring and Manual Contouring: What is the Best Method for Target Delineation using PET CT in Non-small Cell Lung Cancer?
K. Wu1, Y. C. Ung2, D. Hwang3, M. Tsao3, G. Darling4, D. Maziak5, R. Tirona1, K. Mah2, C. S. Wong2 1 Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada, 2Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada, 3Princess Margaret Hospital, University Health Network, University of Toronto, Toronto, ON, Canada, 4Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada, 5Ottawa Regional Cancer Center, University of Ottawa, Ottawa, ON, Canada
Purpose/Objective(s): Previously our results showed that CT setting of window/level of 1600/-300 Hounsfield units (HU) and autocontouring using PET 50% intensity level had the best correlation compared with pathology results. The aim of this study was to use PET 50% intensity level compared with manual contouring using a gradient method (defining GTV edge positions to be at the maximum local gradient magnitude), to determine which one is better.
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2578
Mean In-field Esophagus Dose Predicts for Esophagitis in Lung Cancer Patients Treated with 3D-CRT and Concurrent Chemotherapy
H. B. Caglar, M. Othus, A. M. Allen Brigham and Women’s Hospital / Dana Farber Cancer Institute, Boston, MA Purpose/Objective(s): To determine the dosimetric factors for acute esophagitis and esophageal stricture in non small cell lung cancer (NSCLC) patients treated with concurrent chemotherapy (CT) and three-dimensional conformal radiotherapy (3D-CRT). Materials/Methods: One hundred and nine stage III NSCLC patients treated with 3D-CRT and concurrent CT between 3/2000 and 11/2006 in Dana Farber/Brigham and Women’s Cancer Center were analyzed with IRB approval. Acute esophageal toxicity was evaluated weekly by treating physician and nurse during and after chemoradiation and the presence of strictures were evaluated for the patients who had persistent dysphagia after treatment. Acute esophagitis was scored according to CTCv3. The esophagus was contoured in two ways. First, as traditionally done using the entire esophagus from thoracic inlet to GE junction. A separate structure was also created for the esophagus only in the treatment field. Variables examined for correlation with the clinical factors (use of induction CT, RT dose and type of concurrent CT) as well as the radiation doses to esophagus in field and whole esophagus. Correlation between toxicity events and the variables was assessed by univariate logistic regression. Results: Median age was 60 (33-81), 53% were male. 48 (44%) were stage IIIA patients the remainder had stage IIIB disease. Among the 109 patients 37 of them received 2 cycles of induction CT prior to CRT and 31 pts received consolidation CT after CRT. Median RT dose was 60 Gy in 30 fractions, 26 of the patients (24%) received \ 60 Gy and the rest (76%) received $60 Gy. The CT regimens were: cisplatin/etoposide every 3 weeks (35%) or weekly carboplatin/paclitaxel (65%). 27 pts (25%) had $ grade 3 esophagitis; 6 pts (5%) had a stricture following RT, all of which were dilated. None of the clinical factors were significant with esophagitis on univariate analysis. V45-V60 of the esophagus both infield and whole esophagus were significant discriminators for esophagitis. However, the strongest discriminator for esophagitis was the mean dose to the in-field esophagus (p \0.001) such that a mean dose of 50 Gy or greater predicted for a 75% change of esophagitis and a mean dose below 50 Gy had only a 25% chance of esophagitis. V50, V55 and V60 were all significantly correlated with stricture as well as the mean esophageal dose. (p = 0.05, 0.04 and 0.01 respectively). Conclusions: RT doses above 45 Gy when given with concurrent CT to the esophagus are correlated with clinically relevant esophagitis and stricture. The use of mean esophageal dose in-field is a novel predictor which should be considered in future trials. Author Disclosure: H.B. Caglar, None; M. Othus, None; A.M. Allen, None.
2579
Autocontouring and Manual Contouring: What is the Best Method for Target Delineation using PET CT in Non-small Cell Lung Cancer?
K. Wu1, Y. C. Ung2, D. Hwang3, M. Tsao3, G. Darling4, D. Maziak5, R. Tirona1, K. Mah2, C. S. Wong2 1 Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada, 2Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada, 3Princess Margaret Hospital, University Health Network, University of Toronto, Toronto, ON, Canada, 4Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada, 5Ottawa Regional Cancer Center, University of Ottawa, Ottawa, ON, Canada
Purpose/Objective(s): Previously our results showed that CT setting of window/level of 1600/-300 Hounsfield units (HU) and autocontouring using PET 50% intensity level had the best correlation compared with pathology results. The aim of this study was to use PET 50% intensity level compared with manual contouring using a gradient method (defining GTV edge positions to be at the maximum local gradient magnitude), to determine which one is better.
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