- Email: [email protected]
Clinical Impact of Spatial Variations in Proton Relative Biological Effectiveness (RBE) Among Patients Receiving Radiation to the Prostate and Thorax
S214
International Journal of Radiation Oncology Biology Physics
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based assay for targeting resequencing. PDXs were treated with focal radiation or chemotherapy selected based on the genomic profile of the cancer. Tumor size was measured over time and comparisons between treatment groups made by the extra-sum-of-squares f test. Target inhibition was confirmed in vivo via tumor lysates. Results: The histologic and physical characteristics of the primary human tumor are maintained in this ACC PDX. Mutations in the receptor tyrosine kinases (RTKs) cKit and KDR/VEGFR2 were identified. No mutations were identified in EGFR, RAS, or PIK3CA. Several targeted therapies were selected including dovitinib, a multi-RTK inhibitor, BEZ235, a PI3K/ mTORC inhibitor, and cetuximab, an EGFR mAB. Focal radiation was delivered at 5 Gy x 8 fractions twice weekly. Target inhibition was confirmed by western blot of tumor lysates. Radiation temporarily halted tumor growth. Treatment with molecularly targeted agents prolonged time to tumor doubling compared to control treatment (P < 0.05 for each). Chemoradiation resulted in significant tumor regression which persisted more than 2 months after the end of treatment. The role of identified cKIT and KDR mutations radiation response is being further investigated. Conclusion: PDXs are a powerful model system for investigating potential radiosensitizers based on individual tumor genomics. These preliminary data identify the rationale to investigate selected molecular drug/radiation combinations for ACC, particularly when driven by tumor specific genetic biomarkers. Expansion of these studies may be valuable to advance the design of new treatment strategies for ACC. Author Disclosure: P. Prabakaran: None. A.D. Swick: None. K.P. Nickel: None. D.T. Yang: None. L. Werner: None. J.Y. Bruce: None. A. Wieland: None. T.M. McCulloch: None. G.K. Hartig: None. P.M. Harari: None. R.J. Kimple: Employee; university of Wisconsin. Research Grant; Threshold Pharm.
A Genetic Basis for Variation in the Vulnerability of Cancer to Ionizing Radiation B. Yard,1 D. Adams,2 P. Tamayo,3 P. Hammerman,4 and M. Abazeed1; 1 Cleveland Clinic, Cleveland, OH, 2Case Western Reserve University, Cleveland, OH, 3UCSD, La Jolla, CA, 4Dana-Farber Cancer Institute, Boston, MA Purpose/Objective(s): Clinical radiotherapy has made significant advances since its inception, growing into a tertiary specialty with significant contributions to curative and palliative treatments of cancer and health care costs. A major limitation to its appropriate application, however, has been the lack of measurable biological indicators, or biomarkers that can reliably identify patients with cancers that are more or less likely to respond to these treatments. Materials/Methods: We conducted large-scale profiling of cellular survival after exposure to radiation in a diverse collection of 534 genetically annotated human tumor cell lines. Using data derived from a single, validated experimental platform we studied the genetic determinants of survival after radiation in 534 human cancer cell lines across 26 cancer types. We correlated radiation sensitivity and genomic parameters using the information-based similarity index, which is sensitive to non-linear relationships and offers better resolution at the high end of the matching range. Results: We showed that individual SCNA, gene mutations, and the basal expression of individual genes and gene sets correlate with radiation survival. By studying a large number of cancer types, we found that genetic correlates in any single cancer type can be found in other cancer types as well (e.g., Nrf2 activation in non-small cell lung cancer and hepatobiliary cancer and AR expression in prostate and breast adenocarcinomas). This supports the view that although diverse, cancer genomes reflect combinations of a limited number of functionally relevant events that can confer therapeutic resistance across cancer types. Conclusion: We identified several new genetic determinants of response to DNA damage that can have predictive capacity by identifying the likelihood of response to therapy and, consequently, prognosis. The potential for stratification of patients from heterogeneous populations to genetically similar subgroups can help guide the transition of radiotherapy from a generic population-based approach to one that is more personalized. Author Disclosure: B. Yard: None. D. Adams: None. P. Tamayo: None. P. Hammerman: None. M. Abazeed: None.
1118 Patient-Derived Adenoid Cystic Carcinoma Xenografts to Examine Personalized Radiation Therapy P. Prabakaran,1 A.D. Swick,2 K.P. Nickel,1 D.T. Yang,1 L. Werner,2 J.Y. Bruce,1 A. Wieland,3 T.M. McCulloch,3 G.K. Hartig,3 P.M. Harari,4 and R.J. Kimple2,4; 1University of Wisconsin, Madison, WI, 2University of Wisconsin School of Medicine and Public Health, Madison, WI, 3 Department of Otolaryngology, University of Wisconsin Hospital and Clinics, Madison, WI, 4Department of Human Oncology, University of Wisconsin Hospital and Clinics, Madison, WI Purpose/Objective(s): Adenoid cystic carcinoma (ACC) is a relatively rare cancer that typically arises in salivary tissues of the head and neck. There are currently no approved systemic agents for ACC and no data supporting the delivery of chemoradiation for ACC patients. The scarcity of validated model systems has hampered research efforts. We report the establishment and propagation of an ACC patient derived xenograft (PDX), genomic evaluation of cancer associated mutations, and in vivo response profiles to personalized radiosensitization agents based on nextgeneration sequencing. Materials/Methods: An ACC PDX was established and maintained in NOD-SCID gamma (NSG) mice directly from the patient. Common cancer-associated mutations were identified using a customizable amplicon-
1119 Clinical Impact of Spatial Variations in Proton Relative Biological Effectiveness (RBE) Among Patients Receiving Radiation to the Prostate and Thorax E. Lee,1 J. Saini,2 Y.D. Tseng,3 R. Rengan,3 G.E. Laramore,1 J. Zeng,3 C. Bloch,1 E. Traneus,4 and R.D. Stewart1; 1University of Washington, Department of Radiation Oncology, Seattle, WA, 2Seattle Cancer Care Alliance Proton Therapy Center, Seattle, WA, 3University of Washington, Seattle, WA, 4Raysearch Laboratories, Stockholm, Sweden Purpose/Objective(s): Spatial variations in proton relative biological effectiveness (RBE) near beam edges and beyond the tip of the Bragg peak may potentially increase treatment complications or, alternatively, are a missed opportunity to enhance the therapeutic ratio. We used a newly implemented model in our treatment planning system to examine the impact of spatial variations in proton RBE on tumor targets and selected organs at risk (OAR) in 8 patients treated to the prostate or thorax with proton pencil beam scanning. Materials/Methods: A research build of our treatment planning software combines a new dose algorithm with a published model for DNA double strand break (DSB) induction as a function of proton linear energy transfer (LET). Trends in the model computed RBE for DSB induction with proton LET is predictive of trends in reproductive cell survival in vitro. Dose and (RBE x dose) distributions were re-computed using our in-house treatment planning system for 8 patients (n Z 4 to prostate, n Z 4 to thorax). Doseaveraged RBE values were computed by dividing the (RBE x absorbed dose) for the tumor and OAR volume by the average absorbed dose to the same volume without corrections for spatial variations in proton RBE. The patient-specific RBE estimates were determined for the composite plan (all beams) as well as on a beam by beam basis. To identify putative biological hot and cold spots, plans that correct for spatial variations in proton RBE were compared to plans with a constant (spatially invariant) RBE of 1.1. Results: The dose-averaged RBE for tumor targets ranged from 1.02 to 1.04 among prostate patients, whereas the dose-averaged RBE for OARs (bladder, rectum, femoral heads, penile bulb) ranged from 1.01 (femoral
Volume 96 Number 2S Supplement 2016 head) to 1.11 (rectum) for the composite plan and from 1.00 to 1.27 for individual treatment beams. For the thorax, estimates of the tumor RBE ranged from 1.05 to 1.06; composite plan RBE estimates for OARs (heart, lungs, spinal cord, esophagus, breast, brachial plexus) ranged from 1.02 (breast) to 1.2 (spinal cord). Biological hot spots (RBE up to 1.27) were noted to arise near the distal edge of the Bragg peak. Conclusion: Patient- and tumor-specific RBE estimates from a model that accounts for spatial variations in LET are within +5% of a constant clinical RBE of 1.1. Estimates of the RBE among patients can differ from 1.1 by as much at 15% (RBE w 1.0 to 1.3) for some OAR. The OAR RBE values for individual beams can differ substantially from the RBE for the composite plan, which suggests that beam by beam optimization of (variable RBE x dose) might be exploited to reduce treatment complications (reduce the OAR RBE from w 1.3 to 1.0). This could potentially allow room to increase the therapeutic ratio by 10% to 20% of the total treatment dose. Author Disclosure: E. Lee: None. J. Saini: None. Y.D. Tseng: None. R. Rengan: None. G.E. Laramore: None. J. Zeng: None. C. Bloch: None. E. Traneus: None. R.D. Stewart: None.
1120 Inferior Outcomes With Concurrent Coincident Use of Metformin During Lung Stereotactic Body Radiation Therapy K. Stang,1 F. Alite,1 B. Altoos,1 E. Melian,2 B. Emami,1 and M.M. Harkenrider1; 1Stritch School of Medicine, Loyola University Chicago, Maywood, IL, 2Loyola University Medical Center, Maywood, IL Purpose/Objective(s): Recent data suggest improved outcomes with the addition of metformin (MET) to chemoradiotherapy in locally advanced non-small cell lung cancer (NSCLC). It remains unclear what role MET plays in patients treated with lung stereotactic body radiation therapy (SBRT) for early stage NSCLC. We analyzed the role of MET on local control (LC), survival (OS) and toxicity in the setting of SBRT to the lung. Materials/Methods: In a database of 345 lung SBRT patients, we identified 34 who were on MET and treated for early stage NSCLC with lung SBRT. 100 similarly treated random patients were chosen as the control. Patients were characterized based on diabetes diagnosis status and whether MET was prescribed at time of SBRT. LC, survival, and CTCAE V4.0 toxicity grades were collected and compared between MET and non-MET group. LC and OS analysis was performed using the Kaplan-Meier method and log-rank test for comparing subgroups. Fisher Exact test was used for categorical comparisons of toxicity. A propensity score analysis was performed to correct for possible confounders in LC based on the following criteria: age, performance status, histology, stage, treatment dose, and era treated (before vs. after 2009). Results: Median follow-up was 19.6 months (range 3.2-87.7). Forty-nine patients were diabetic. The 2-year LC of MET users was 74% vs. 90% for Non-MET users (P Z 0.07). Among diabetic patients, 2-year LC of MET users was 74% vs. 100% for MET non-users (P Z 0.039). In a propensity score matched group, MET users had LC of 74% vs. 96% for MET nonusers (P Z 0.076). When controlling for treatment era, MET users had inferior LC of 75% vs. 96% (P Z 0.003). Median OS was 27.7 months for MET users vs. 43.9 months for non-users (P Z 0.35). Analyzing only diabetic patients, MET users had OS of 27.7 months, while diabetic MET non-users had not reached median survival (3-year OS 66.8%) (P Z 0.141). Development of any grade 2 toxicity was not significantly different between the two groups (P Z 0.51). There were no grade 3 acute or chronic toxicities in either group. Conclusion: Lung SBRT MET users displayed a trend towards inferior LC and OS when compared to non-MET users and a significantly inferior LC and OS when compared to diabetic non-MET users. Because SBRT and conventional RT may have different mechanisms of cell kill, MET may actually be detrimental when administered concurrently with SBRT. These results should be validated and we await the results of ongoing clinical trials. Author Disclosure: K. Stang: None. F. Alite: None. B. Altoos: None. E. Melian: None. B. Emami: None. M.M. Harkenrider: None.
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1121 Lyman-Kutcher-Burmanp Pelvic Radiation Dosimetric Prediction Model of Acute Hematologic Toxicity for Rectal Cancer Patients X. Wan, X. Fan, and Y. Cheng; the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China Purpose/Objective(s): To design Lyman-Kutcher-Burmanp (LKB) dosimetric algorithm to predict pelvic radiation related acute hematologic toxicity for rectal cancer patients received neoadjuvant intensity-modulated radiotherapy. Materials/Methods: We analyzed 130 rectal cancer patients in single institution who were treated with concurrent chemotherapy and neoadjuvant intensity-modulated pelvic radiotherapy. Pelvic bone marrow (BM) was contoured for each patient and divided into three subsites: lumbosacral spine (LSSP), ilium, and lower pelvis (LP) and dose-volume parameters were extracted. HT was graded according to the Common Terminology Criteria for Adverse Events V4.0. Logistic regression was used to test associations between HT and dosimetric/clinical parameters on HT. Receiver operating characteristic (ROC) curves were used to assess the dose tolerances for the significant dosimetric factors with respect to severe ( grade 3) HT. LKB model was utilized to identify the co-relationship between radiotherapy dosimetry and hematologic toxicity. Results: Of 130 patients, 17 (13.1%), 15 (11.5%), 5 (3.8%), 1 (0.8%) experienced acute Grade 3e4 leukopenia, neutropenia, anemia, and thrombocytopenia, respectively. Patients with BMI 25 had higher rates of Grade 3 or worse leukopenia (P Z 0.006). Increased iliac BM V15 was associated with an increased Grade 3 or worse leukopenia (P Z 0.047). Patients with increased iliac BM V20 were more likely to have Grade 3 or worse leukopenia (P Z 0.049). ROC curve indicated a V15 of 89.71% (area under ROC curves, 0.680; P Z 0.017) and V20 of 86.15% (area under ROC curves, 0.672; P Z 0.022) were the tolerated doses for Grade 3 or worse leukopenia. The LKB prediction model showed that the TD45, TD40, TD35, TD30, TD25, and TD20 were 55.3 Gy, 51.0 Gy, 46.5 Gy, 42.0 Gy, 36.5 Gy, and 30.5 Gy, respectively. Moreover, the best fit was m Z 0.583 with the Td50 of 59.6 Gy. Conclusion: The volume of iliac BM receiving low-dose radiation is associated with severe acute HT. Our study suggest a potential way to predict hematologic toxicity based on the pelvic radiation dosimetric volume for rectal cancer patients received neoadjuvant intensity-modulated radiotherapy. Author Disclosure: X. Wan: None. X. Fan: None. Y. Cheng: None.
1122 A Genomic Framework for Precision Radiation Therapy J.G. Scott,1 J.F. Torres-Roca,1 L.B. Harrison,1 A.E. Berglund,1 M. Schell,2 I.B. Mihaylov,3 W.J. Fulp,1 B. Yue,2 E.A. Welsh,1 J.J. Caudell,1 K.A. Ahmed,1 T. Strom,1 E.A. Mellon,1 P.S. Venkat,1 P.A.S. Johnstone,1 E.G. Moros,1 J. Lee,4 J. Foekens,5 W.S. Dalton,4 S.A. Eschrich,1 and H.L. McLeod1; 1H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 2Moffitt Cancer Center, Tampa, FL, 3University of Miami, Miami, FL, 4H Lee Moffitt Cancer Center, Tampa, FL, 5Erasmus Medical Center, Erasmus, Netherlands Purpose/Objective(s): Radiation therapy, the most commonly utilized therapeutic agent in oncology, has not yet entered the era of precision medicine. We hypothesize that a patient specific molecular signature of radiation sensitivity, together with the canonical equations governing radiation response, can form the basis for precision medicine in radiation oncology. Materials/Methods: We used a clinically validated genomic radiation sensitivity index (RSI) to evaluate 8,271 primary tumors from 20 disease sites from a prospective observational trial. All tumor samples were arrayed on Affymetrix Hu-RSTA-2a520709. RSI was determined using the previously described rank-based algorithm. To make RSI comparisons we used an arbitrary RSI Z 0.37 and the Fisher Exact test. The genomic
International Journal of Radiation Oncology Biology Physics
1117
based assay for targeting resequencing. PDXs were treated with focal radiation or chemotherapy selected based on the genomic profile of the cancer. Tumor size was measured over time and comparisons between treatment groups made by the extra-sum-of-squares f test. Target inhibition was confirmed in vivo via tumor lysates. Results: The histologic and physical characteristics of the primary human tumor are maintained in this ACC PDX. Mutations in the receptor tyrosine kinases (RTKs) cKit and KDR/VEGFR2 were identified. No mutations were identified in EGFR, RAS, or PIK3CA. Several targeted therapies were selected including dovitinib, a multi-RTK inhibitor, BEZ235, a PI3K/ mTORC inhibitor, and cetuximab, an EGFR mAB. Focal radiation was delivered at 5 Gy x 8 fractions twice weekly. Target inhibition was confirmed by western blot of tumor lysates. Radiation temporarily halted tumor growth. Treatment with molecularly targeted agents prolonged time to tumor doubling compared to control treatment (P < 0.05 for each). Chemoradiation resulted in significant tumor regression which persisted more than 2 months after the end of treatment. The role of identified cKIT and KDR mutations radiation response is being further investigated. Conclusion: PDXs are a powerful model system for investigating potential radiosensitizers based on individual tumor genomics. These preliminary data identify the rationale to investigate selected molecular drug/radiation combinations for ACC, particularly when driven by tumor specific genetic biomarkers. Expansion of these studies may be valuable to advance the design of new treatment strategies for ACC. Author Disclosure: P. Prabakaran: None. A.D. Swick: None. K.P. Nickel: None. D.T. Yang: None. L. Werner: None. J.Y. Bruce: None. A. Wieland: None. T.M. McCulloch: None. G.K. Hartig: None. P.M. Harari: None. R.J. Kimple: Employee; university of Wisconsin. Research Grant; Threshold Pharm.
A Genetic Basis for Variation in the Vulnerability of Cancer to Ionizing Radiation B. Yard,1 D. Adams,2 P. Tamayo,3 P. Hammerman,4 and M. Abazeed1; 1 Cleveland Clinic, Cleveland, OH, 2Case Western Reserve University, Cleveland, OH, 3UCSD, La Jolla, CA, 4Dana-Farber Cancer Institute, Boston, MA Purpose/Objective(s): Clinical radiotherapy has made significant advances since its inception, growing into a tertiary specialty with significant contributions to curative and palliative treatments of cancer and health care costs. A major limitation to its appropriate application, however, has been the lack of measurable biological indicators, or biomarkers that can reliably identify patients with cancers that are more or less likely to respond to these treatments. Materials/Methods: We conducted large-scale profiling of cellular survival after exposure to radiation in a diverse collection of 534 genetically annotated human tumor cell lines. Using data derived from a single, validated experimental platform we studied the genetic determinants of survival after radiation in 534 human cancer cell lines across 26 cancer types. We correlated radiation sensitivity and genomic parameters using the information-based similarity index, which is sensitive to non-linear relationships and offers better resolution at the high end of the matching range. Results: We showed that individual SCNA, gene mutations, and the basal expression of individual genes and gene sets correlate with radiation survival. By studying a large number of cancer types, we found that genetic correlates in any single cancer type can be found in other cancer types as well (e.g., Nrf2 activation in non-small cell lung cancer and hepatobiliary cancer and AR expression in prostate and breast adenocarcinomas). This supports the view that although diverse, cancer genomes reflect combinations of a limited number of functionally relevant events that can confer therapeutic resistance across cancer types. Conclusion: We identified several new genetic determinants of response to DNA damage that can have predictive capacity by identifying the likelihood of response to therapy and, consequently, prognosis. The potential for stratification of patients from heterogeneous populations to genetically similar subgroups can help guide the transition of radiotherapy from a generic population-based approach to one that is more personalized. Author Disclosure: B. Yard: None. D. Adams: None. P. Tamayo: None. P. Hammerman: None. M. Abazeed: None.
1118 Patient-Derived Adenoid Cystic Carcinoma Xenografts to Examine Personalized Radiation Therapy P. Prabakaran,1 A.D. Swick,2 K.P. Nickel,1 D.T. Yang,1 L. Werner,2 J.Y. Bruce,1 A. Wieland,3 T.M. McCulloch,3 G.K. Hartig,3 P.M. Harari,4 and R.J. Kimple2,4; 1University of Wisconsin, Madison, WI, 2University of Wisconsin School of Medicine and Public Health, Madison, WI, 3 Department of Otolaryngology, University of Wisconsin Hospital and Clinics, Madison, WI, 4Department of Human Oncology, University of Wisconsin Hospital and Clinics, Madison, WI Purpose/Objective(s): Adenoid cystic carcinoma (ACC) is a relatively rare cancer that typically arises in salivary tissues of the head and neck. There are currently no approved systemic agents for ACC and no data supporting the delivery of chemoradiation for ACC patients. The scarcity of validated model systems has hampered research efforts. We report the establishment and propagation of an ACC patient derived xenograft (PDX), genomic evaluation of cancer associated mutations, and in vivo response profiles to personalized radiosensitization agents based on nextgeneration sequencing. Materials/Methods: An ACC PDX was established and maintained in NOD-SCID gamma (NSG) mice directly from the patient. Common cancer-associated mutations were identified using a customizable amplicon-
1119 Clinical Impact of Spatial Variations in Proton Relative Biological Effectiveness (RBE) Among Patients Receiving Radiation to the Prostate and Thorax E. Lee,1 J. Saini,2 Y.D. Tseng,3 R. Rengan,3 G.E. Laramore,1 J. Zeng,3 C. Bloch,1 E. Traneus,4 and R.D. Stewart1; 1University of Washington, Department of Radiation Oncology, Seattle, WA, 2Seattle Cancer Care Alliance Proton Therapy Center, Seattle, WA, 3University of Washington, Seattle, WA, 4Raysearch Laboratories, Stockholm, Sweden Purpose/Objective(s): Spatial variations in proton relative biological effectiveness (RBE) near beam edges and beyond the tip of the Bragg peak may potentially increase treatment complications or, alternatively, are a missed opportunity to enhance the therapeutic ratio. We used a newly implemented model in our treatment planning system to examine the impact of spatial variations in proton RBE on tumor targets and selected organs at risk (OAR) in 8 patients treated to the prostate or thorax with proton pencil beam scanning. Materials/Methods: A research build of our treatment planning software combines a new dose algorithm with a published model for DNA double strand break (DSB) induction as a function of proton linear energy transfer (LET). Trends in the model computed RBE for DSB induction with proton LET is predictive of trends in reproductive cell survival in vitro. Dose and (RBE x dose) distributions were re-computed using our in-house treatment planning system for 8 patients (n Z 4 to prostate, n Z 4 to thorax). Doseaveraged RBE values were computed by dividing the (RBE x absorbed dose) for the tumor and OAR volume by the average absorbed dose to the same volume without corrections for spatial variations in proton RBE. The patient-specific RBE estimates were determined for the composite plan (all beams) as well as on a beam by beam basis. To identify putative biological hot and cold spots, plans that correct for spatial variations in proton RBE were compared to plans with a constant (spatially invariant) RBE of 1.1. Results: The dose-averaged RBE for tumor targets ranged from 1.02 to 1.04 among prostate patients, whereas the dose-averaged RBE for OARs (bladder, rectum, femoral heads, penile bulb) ranged from 1.01 (femoral
Volume 96 Number 2S Supplement 2016 head) to 1.11 (rectum) for the composite plan and from 1.00 to 1.27 for individual treatment beams. For the thorax, estimates of the tumor RBE ranged from 1.05 to 1.06; composite plan RBE estimates for OARs (heart, lungs, spinal cord, esophagus, breast, brachial plexus) ranged from 1.02 (breast) to 1.2 (spinal cord). Biological hot spots (RBE up to 1.27) were noted to arise near the distal edge of the Bragg peak. Conclusion: Patient- and tumor-specific RBE estimates from a model that accounts for spatial variations in LET are within +5% of a constant clinical RBE of 1.1. Estimates of the RBE among patients can differ from 1.1 by as much at 15% (RBE w 1.0 to 1.3) for some OAR. The OAR RBE values for individual beams can differ substantially from the RBE for the composite plan, which suggests that beam by beam optimization of (variable RBE x dose) might be exploited to reduce treatment complications (reduce the OAR RBE from w 1.3 to 1.0). This could potentially allow room to increase the therapeutic ratio by 10% to 20% of the total treatment dose. Author Disclosure: E. Lee: None. J. Saini: None. Y.D. Tseng: None. R. Rengan: None. G.E. Laramore: None. J. Zeng: None. C. Bloch: None. E. Traneus: None. R.D. Stewart: None.
1120 Inferior Outcomes With Concurrent Coincident Use of Metformin During Lung Stereotactic Body Radiation Therapy K. Stang,1 F. Alite,1 B. Altoos,1 E. Melian,2 B. Emami,1 and M.M. Harkenrider1; 1Stritch School of Medicine, Loyola University Chicago, Maywood, IL, 2Loyola University Medical Center, Maywood, IL Purpose/Objective(s): Recent data suggest improved outcomes with the addition of metformin (MET) to chemoradiotherapy in locally advanced non-small cell lung cancer (NSCLC). It remains unclear what role MET plays in patients treated with lung stereotactic body radiation therapy (SBRT) for early stage NSCLC. We analyzed the role of MET on local control (LC), survival (OS) and toxicity in the setting of SBRT to the lung. Materials/Methods: In a database of 345 lung SBRT patients, we identified 34 who were on MET and treated for early stage NSCLC with lung SBRT. 100 similarly treated random patients were chosen as the control. Patients were characterized based on diabetes diagnosis status and whether MET was prescribed at time of SBRT. LC, survival, and CTCAE V4.0 toxicity grades were collected and compared between MET and non-MET group. LC and OS analysis was performed using the Kaplan-Meier method and log-rank test for comparing subgroups. Fisher Exact test was used for categorical comparisons of toxicity. A propensity score analysis was performed to correct for possible confounders in LC based on the following criteria: age, performance status, histology, stage, treatment dose, and era treated (before vs. after 2009). Results: Median follow-up was 19.6 months (range 3.2-87.7). Forty-nine patients were diabetic. The 2-year LC of MET users was 74% vs. 90% for Non-MET users (P Z 0.07). Among diabetic patients, 2-year LC of MET users was 74% vs. 100% for MET non-users (P Z 0.039). In a propensity score matched group, MET users had LC of 74% vs. 96% for MET nonusers (P Z 0.076). When controlling for treatment era, MET users had inferior LC of 75% vs. 96% (P Z 0.003). Median OS was 27.7 months for MET users vs. 43.9 months for non-users (P Z 0.35). Analyzing only diabetic patients, MET users had OS of 27.7 months, while diabetic MET non-users had not reached median survival (3-year OS 66.8%) (P Z 0.141). Development of any grade 2 toxicity was not significantly different between the two groups (P Z 0.51). There were no grade 3 acute or chronic toxicities in either group. Conclusion: Lung SBRT MET users displayed a trend towards inferior LC and OS when compared to non-MET users and a significantly inferior LC and OS when compared to diabetic non-MET users. Because SBRT and conventional RT may have different mechanisms of cell kill, MET may actually be detrimental when administered concurrently with SBRT. These results should be validated and we await the results of ongoing clinical trials. Author Disclosure: K. Stang: None. F. Alite: None. B. Altoos: None. E. Melian: None. B. Emami: None. M.M. Harkenrider: None.
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1121 Lyman-Kutcher-Burmanp Pelvic Radiation Dosimetric Prediction Model of Acute Hematologic Toxicity for Rectal Cancer Patients X. Wan, X. Fan, and Y. Cheng; the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China Purpose/Objective(s): To design Lyman-Kutcher-Burmanp (LKB) dosimetric algorithm to predict pelvic radiation related acute hematologic toxicity for rectal cancer patients received neoadjuvant intensity-modulated radiotherapy. Materials/Methods: We analyzed 130 rectal cancer patients in single institution who were treated with concurrent chemotherapy and neoadjuvant intensity-modulated pelvic radiotherapy. Pelvic bone marrow (BM) was contoured for each patient and divided into three subsites: lumbosacral spine (LSSP), ilium, and lower pelvis (LP) and dose-volume parameters were extracted. HT was graded according to the Common Terminology Criteria for Adverse Events V4.0. Logistic regression was used to test associations between HT and dosimetric/clinical parameters on HT. Receiver operating characteristic (ROC) curves were used to assess the dose tolerances for the significant dosimetric factors with respect to severe ( grade 3) HT. LKB model was utilized to identify the co-relationship between radiotherapy dosimetry and hematologic toxicity. Results: Of 130 patients, 17 (13.1%), 15 (11.5%), 5 (3.8%), 1 (0.8%) experienced acute Grade 3e4 leukopenia, neutropenia, anemia, and thrombocytopenia, respectively. Patients with BMI 25 had higher rates of Grade 3 or worse leukopenia (P Z 0.006). Increased iliac BM V15 was associated with an increased Grade 3 or worse leukopenia (P Z 0.047). Patients with increased iliac BM V20 were more likely to have Grade 3 or worse leukopenia (P Z 0.049). ROC curve indicated a V15 of 89.71% (area under ROC curves, 0.680; P Z 0.017) and V20 of 86.15% (area under ROC curves, 0.672; P Z 0.022) were the tolerated doses for Grade 3 or worse leukopenia. The LKB prediction model showed that the TD45, TD40, TD35, TD30, TD25, and TD20 were 55.3 Gy, 51.0 Gy, 46.5 Gy, 42.0 Gy, 36.5 Gy, and 30.5 Gy, respectively. Moreover, the best fit was m Z 0.583 with the Td50 of 59.6 Gy. Conclusion: The volume of iliac BM receiving low-dose radiation is associated with severe acute HT. Our study suggest a potential way to predict hematologic toxicity based on the pelvic radiation dosimetric volume for rectal cancer patients received neoadjuvant intensity-modulated radiotherapy. Author Disclosure: X. Wan: None. X. Fan: None. Y. Cheng: None.
1122 A Genomic Framework for Precision Radiation Therapy J.G. Scott,1 J.F. Torres-Roca,1 L.B. Harrison,1 A.E. Berglund,1 M. Schell,2 I.B. Mihaylov,3 W.J. Fulp,1 B. Yue,2 E.A. Welsh,1 J.J. Caudell,1 K.A. Ahmed,1 T. Strom,1 E.A. Mellon,1 P.S. Venkat,1 P.A.S. Johnstone,1 E.G. Moros,1 J. Lee,4 J. Foekens,5 W.S. Dalton,4 S.A. Eschrich,1 and H.L. McLeod1; 1H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 2Moffitt Cancer Center, Tampa, FL, 3University of Miami, Miami, FL, 4H Lee Moffitt Cancer Center, Tampa, FL, 5Erasmus Medical Center, Erasmus, Netherlands Purpose/Objective(s): Radiation therapy, the most commonly utilized therapeutic agent in oncology, has not yet entered the era of precision medicine. We hypothesize that a patient specific molecular signature of radiation sensitivity, together with the canonical equations governing radiation response, can form the basis for precision medicine in radiation oncology. Materials/Methods: We used a clinically validated genomic radiation sensitivity index (RSI) to evaluate 8,271 primary tumors from 20 disease sites from a prospective observational trial. All tumor samples were arrayed on Affymetrix Hu-RSTA-2a520709. RSI was determined using the previously described rank-based algorithm. To make RSI comparisons we used an arbitrary RSI Z 0.37 and the Fisher Exact test. The genomic