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Esophageal Toxicity with High Dose, Single Fraction Paraspinal Stereotactic Radiosurgery
I. J. Radiation Oncology d Biology d Physics
S110
Volume 81, Number 2, Supplement, 2011
Materials/Methods: There were 303 evaluable prostate cancer cases in the parent cohort of the randomized trial. There were 152 patients randomized to conventional IMRT and 151 to hypofractionated IMRT. Of these, there were 124 in whom DNA from peripheral blood lymphocytes and the full de-archived 3D treatment plans were available. SNPs were processed using the HumanOmni2.5-4v1_C beadchip (Illumina, Inc.), which measured 2.5 million SNPs. Targeted SNPs (n = 2145) of DNA repair and inflammatory pathways were extracted from the data set. SNP status was evaluated for their association with the maximum late gastrointestinal (GI) and/or genitourinary (GU) toxicity. The quality control process included allele frequencies and HWE (in whites only). We first invested single locus SNP model to evaluate GI, GU, and both GI/GU toxicity considering they may share similar etiology. Results: At a significance level of 0.01 without taking multiple comparisons into consideration, we identified 10, 8, and 4 SNPs that were associated with GI, GU, and GI/GU toxicity, respectively. For GI toxicity, the 10 associated SNPs/genes were: rs9901673 (CD68), rs11552708 (TNFSF13, TNFSF12-TNFSF13), rs1626154 (P2RY2), rs6330 (NGF), rs2700 (PARP2), rs2229869 (SOS2), rs2230112 (NFATC1), rs2228006 (PMS2), rs3742106 (ABCC4), and rs4149313 (ABCA1). For GU toxicity, the 8 associated SNPs/genes were: rs709932 (SERPINA1), rs244303 (STXBP4), rs13421115 (CD207), rs2280897 (MYOM2), rs352140 (TLR9), rs244298 (STXBP4), rs1513181 (LPP), and rs9350 (EXO1). For combined GI/GU toxicity, the 4 associated SNPs/genes were: rs13421115 (CD207), rs2155209 (MRE11A), rs4488761 (BCL2L13), and rs9350 (EXO1). Two of these four genes play roles in DNA repair. The MRE11A gene is involved in telomere length maintenance and DNA double-strand break repair. The EXO1 gene is involved in DNA mismatch repair and homologous recombination. Conclusions: This is the first pilot study of genetic factors in DNA repair and inflammatory responses related to GI and/or GU toxicity induced by radiotherapy in a randomized trial of prostate cancer patients. With limited sample size, our data suggest that SNPs/genes in mismatch repair and DNA double-strand break repair may be associated with GI and/or GU toxicity. Future larger studies are warranted to further test our findings. Author DisclosureJ.J. Hu: None. R. Stoyanova: None. J.O. Deasy: None. R. Chung: None. E. Martin: None. M.K. Buyyounouski: None. G.O. Allen: None. A. Pollack: None.
219
Esophageal Toxicity with High Dose, Single Fraction Paraspinal Stereotactic Radiosurgery
B. W. Cox, A. Jackson, D. Cyran, M. Hunt, Y. Yamada Memorial Sloan-Kettering Cancer Center, New York, NY Purpose/Objective(s): High dose, single fraction paraspinal stereotactic radiosurgery (SRS) is transforming spine tumor management due to local control rates of 90% and increased patient convenience. The toxicity profile of paraspinal SRS remains incompletely defined. We report the esophageal toxicities from single fraction SRS to the cervical and thoracic spine. Materials/Methods: We reviewed all patients undergoing single fraction paraspinal SRS at our institution between 1993 and 2010. Radiosurgery simulation, treatment planning, and delivery were performed as previously described. Esophageal toxicity was scored using NCI CTCAE 4.0 criteria. DVH atlas analyses and clinical reviews were correlated with toxicity. Wilcoxon rank sum tests and Fisher’s exact tests (split at median values) were performed for absolute esophageal volumes exposed to at least 10, 15, 20, and 22 Gy. Results: A total of 235 patients were treated to 266 sites (49 cervical, 217 thoracic). The median prescribed dose to the PTV was 24 Gy (range, 18-24 Gy). Median follow-up was 12 months. The overall Grade .3 toxicity rate was 6% (16 patients). There were 40 (15%) acute esophageal toxicities: 0 (0%) Grade 1, 37 (14%) Grade 2, 1 (0.4%) Grade 3, 2 (0.7%) Grade 4, and 0 (0%) Grade 5. The 3 (1.1%) acute Grade .3 toxicities were: esophagitis (1), esophageal stenosis (1), and esophageal ulcer (1). There were 28 (11%) late esophageal toxicities: 1 (0.4%) Grade 1, 14 (5%) Grade 2, 7 (3%) Grade 3, 5 (2%) Grade 4, and 1 (0.3%) Grade 5. The 13 (5%) late Grade .3 toxicities were: esophageal ulcer (2), esophageal stenosis (4), esophageal fistula (5), esophageal stricture (1), and esophageal infection (1). Upon DVH analysis, Fisher’s exact test resulted in significant splits at median V15 = 2.7 cc (p = 0.02); V20 = 0.67 cc (p = 0.002); V22 = 0.26 cc (p = 0.002). The p values for Wilcoxon rank sum tests at V15, V20, and V22 were 0.005, 0.001, and 0.001, respectively. The relative risk of Grade .3 toxicity was 4.8 for esophageal V15 .2.7 cc, 10.6 for V20 .0.67 cc, and 10.6 for V22 .0.26 cc. Seven of 8 (88%) of the Grade .4 toxicities were associated with radiation recall reactions after administration of Adriamycin or gemcitabine chemotherapy (1), iatrogenic manipulation of the irradiated esophagus (3), or both (3). Conclusions: High dose, single fraction paraspinal SRS has a low rate of Grade .3 esophageal toxicity. We recommend using the following esophageal constraints to minimize the likelihood of Grade .3 toxicity: V15 \2.7 cc, V20 \.67 cc, and V22 \.26 cc. Practitioners of paraspinal SRS should discourage unnecessary iatrogenic manipulation of the irradiated esophagus and avoid non-essential administration of systemic agents classically associated with radiation recall reactions. Acknowledgment: Supported in part by NCI 1RO1CA129182-01A2. Author Disclosure: B.W. Cox: None. A. Jackson: None. D. Cyran: None. M. Hunt: None. Y. Yamada: None.
220
Dose Constraints to Prevent Radiation-induced Brachial Plexopathy in Patients Treated for Lung Cancer
A. Amini1,2, J. W. Welsh1, J. Yang1, M. L. McBurney1, R. T. Williamson1, M. Karhade1, P. K. Allen1, J. Erasmus1, L. Dong1, Z. Liao1 1
The University of Texas MD Anderson Cancer Center, Houston, TX, 2UC Irvine School of Medicine, Irvine, CA
Purpose/Objective(s): As the definitive radiation doses for Non-small cell lung cancer continue to increase, meeting dose constraints for critical structures like the brachial plexus becomes increasingly challenging. This is especially true for apical superior sulcus tumors or supraclavicular adenopathy, as gross disease is located close to the brachial plexus. We used deformable image registration to uniformly contour the brachial plexus and analyzed the incidence of plexopathy and the maximum tolerable dose to this critical structure.
S110
Volume 81, Number 2, Supplement, 2011
Materials/Methods: There were 303 evaluable prostate cancer cases in the parent cohort of the randomized trial. There were 152 patients randomized to conventional IMRT and 151 to hypofractionated IMRT. Of these, there were 124 in whom DNA from peripheral blood lymphocytes and the full de-archived 3D treatment plans were available. SNPs were processed using the HumanOmni2.5-4v1_C beadchip (Illumina, Inc.), which measured 2.5 million SNPs. Targeted SNPs (n = 2145) of DNA repair and inflammatory pathways were extracted from the data set. SNP status was evaluated for their association with the maximum late gastrointestinal (GI) and/or genitourinary (GU) toxicity. The quality control process included allele frequencies and HWE (in whites only). We first invested single locus SNP model to evaluate GI, GU, and both GI/GU toxicity considering they may share similar etiology. Results: At a significance level of 0.01 without taking multiple comparisons into consideration, we identified 10, 8, and 4 SNPs that were associated with GI, GU, and GI/GU toxicity, respectively. For GI toxicity, the 10 associated SNPs/genes were: rs9901673 (CD68), rs11552708 (TNFSF13, TNFSF12-TNFSF13), rs1626154 (P2RY2), rs6330 (NGF), rs2700 (PARP2), rs2229869 (SOS2), rs2230112 (NFATC1), rs2228006 (PMS2), rs3742106 (ABCC4), and rs4149313 (ABCA1). For GU toxicity, the 8 associated SNPs/genes were: rs709932 (SERPINA1), rs244303 (STXBP4), rs13421115 (CD207), rs2280897 (MYOM2), rs352140 (TLR9), rs244298 (STXBP4), rs1513181 (LPP), and rs9350 (EXO1). For combined GI/GU toxicity, the 4 associated SNPs/genes were: rs13421115 (CD207), rs2155209 (MRE11A), rs4488761 (BCL2L13), and rs9350 (EXO1). Two of these four genes play roles in DNA repair. The MRE11A gene is involved in telomere length maintenance and DNA double-strand break repair. The EXO1 gene is involved in DNA mismatch repair and homologous recombination. Conclusions: This is the first pilot study of genetic factors in DNA repair and inflammatory responses related to GI and/or GU toxicity induced by radiotherapy in a randomized trial of prostate cancer patients. With limited sample size, our data suggest that SNPs/genes in mismatch repair and DNA double-strand break repair may be associated with GI and/or GU toxicity. Future larger studies are warranted to further test our findings. Author DisclosureJ.J. Hu: None. R. Stoyanova: None. J.O. Deasy: None. R. Chung: None. E. Martin: None. M.K. Buyyounouski: None. G.O. Allen: None. A. Pollack: None.
219
Esophageal Toxicity with High Dose, Single Fraction Paraspinal Stereotactic Radiosurgery
B. W. Cox, A. Jackson, D. Cyran, M. Hunt, Y. Yamada Memorial Sloan-Kettering Cancer Center, New York, NY Purpose/Objective(s): High dose, single fraction paraspinal stereotactic radiosurgery (SRS) is transforming spine tumor management due to local control rates of 90% and increased patient convenience. The toxicity profile of paraspinal SRS remains incompletely defined. We report the esophageal toxicities from single fraction SRS to the cervical and thoracic spine. Materials/Methods: We reviewed all patients undergoing single fraction paraspinal SRS at our institution between 1993 and 2010. Radiosurgery simulation, treatment planning, and delivery were performed as previously described. Esophageal toxicity was scored using NCI CTCAE 4.0 criteria. DVH atlas analyses and clinical reviews were correlated with toxicity. Wilcoxon rank sum tests and Fisher’s exact tests (split at median values) were performed for absolute esophageal volumes exposed to at least 10, 15, 20, and 22 Gy. Results: A total of 235 patients were treated to 266 sites (49 cervical, 217 thoracic). The median prescribed dose to the PTV was 24 Gy (range, 18-24 Gy). Median follow-up was 12 months. The overall Grade .3 toxicity rate was 6% (16 patients). There were 40 (15%) acute esophageal toxicities: 0 (0%) Grade 1, 37 (14%) Grade 2, 1 (0.4%) Grade 3, 2 (0.7%) Grade 4, and 0 (0%) Grade 5. The 3 (1.1%) acute Grade .3 toxicities were: esophagitis (1), esophageal stenosis (1), and esophageal ulcer (1). There were 28 (11%) late esophageal toxicities: 1 (0.4%) Grade 1, 14 (5%) Grade 2, 7 (3%) Grade 3, 5 (2%) Grade 4, and 1 (0.3%) Grade 5. The 13 (5%) late Grade .3 toxicities were: esophageal ulcer (2), esophageal stenosis (4), esophageal fistula (5), esophageal stricture (1), and esophageal infection (1). Upon DVH analysis, Fisher’s exact test resulted in significant splits at median V15 = 2.7 cc (p = 0.02); V20 = 0.67 cc (p = 0.002); V22 = 0.26 cc (p = 0.002). The p values for Wilcoxon rank sum tests at V15, V20, and V22 were 0.005, 0.001, and 0.001, respectively. The relative risk of Grade .3 toxicity was 4.8 for esophageal V15 .2.7 cc, 10.6 for V20 .0.67 cc, and 10.6 for V22 .0.26 cc. Seven of 8 (88%) of the Grade .4 toxicities were associated with radiation recall reactions after administration of Adriamycin or gemcitabine chemotherapy (1), iatrogenic manipulation of the irradiated esophagus (3), or both (3). Conclusions: High dose, single fraction paraspinal SRS has a low rate of Grade .3 esophageal toxicity. We recommend using the following esophageal constraints to minimize the likelihood of Grade .3 toxicity: V15 \2.7 cc, V20 \.67 cc, and V22 \.26 cc. Practitioners of paraspinal SRS should discourage unnecessary iatrogenic manipulation of the irradiated esophagus and avoid non-essential administration of systemic agents classically associated with radiation recall reactions. Acknowledgment: Supported in part by NCI 1RO1CA129182-01A2. Author Disclosure: B.W. Cox: None. A. Jackson: None. D. Cyran: None. M. Hunt: None. Y. Yamada: None.
220
Dose Constraints to Prevent Radiation-induced Brachial Plexopathy in Patients Treated for Lung Cancer
A. Amini1,2, J. W. Welsh1, J. Yang1, M. L. McBurney1, R. T. Williamson1, M. Karhade1, P. K. Allen1, J. Erasmus1, L. Dong1, Z. Liao1 1
The University of Texas MD Anderson Cancer Center, Houston, TX, 2UC Irvine School of Medicine, Irvine, CA
Purpose/Objective(s): As the definitive radiation doses for Non-small cell lung cancer continue to increase, meeting dose constraints for critical structures like the brachial plexus becomes increasingly challenging. This is especially true for apical superior sulcus tumors or supraclavicular adenopathy, as gross disease is located close to the brachial plexus. We used deformable image registration to uniformly contour the brachial plexus and analyzed the incidence of plexopathy and the maximum tolerable dose to this critical structure.