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Estimation of Toxicities Following Stereotactic Ablative Radiation Therapy Treatment of Locally Recurrent and Previously Irradiated Head and Neck Squamous Cell Carcinoma Based on a Normal Tissue Complication Probability Model
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International Journal of Radiation Oncology Biology Physics
the single most effective therapy in prolonging survival. Research continues in trying to optimize dosing and fractionation schemes, both to prolong survival and to assess alternative strategies, such as hypofractionation regimens, that have nearly equal efficacy to standard regimens but limit patient treatment time. Theoretical investigations of treatment response often involve simplified 1D isotropic models of tumor spread. The purpose of this work is to introduce a realistic treatment simulation tool by combining mathematical modeling with diffusion tensor (DT) MR imaging to develop an anisotropic 3D model of GBM growth guided by the direction of adjacent white matter tracts. This model is then used to simulate the effects of radiation therapy, and to study the complex dynamics of the effect of different dosing and fractionation schemes on tumor size and cell concentration. Materials/Methods: A reaction-diffusion partial differential equation that accounts for tumor cell diffusion and proliferation is used to model tumor concentration as a function of time and space. This model can be stated as: c(t,x)/dt Z V∙(D(x)V c)+pc(1-c/K)-R(x,c,t) where c, D, p, and K represent the concentration, diffusion, proliferation, and tissue carrying capacity of tumor cells respectively, and where R(x,c,t) represents a linear-quadratic radiation therapy term that can model different dosing schemes. In this work, D is the three-dimensional tumor cell diffusion tensor, calculated from scaled eigenvalues of the conventional MR spin diffusion tensor. For demonstration, the effects of a standard radiation therapy regimen of 61.2 Gy/34 doses are compared to a hypofractionation regimen of 35 Gy/5 doses administered once weekly. Results: The DT-MRI GBM growth model produces realistic-appearing tumors that infiltrate along white matter tracts, similar in appearance to MR imaging profiles of actual tumors. Radiation therapy simulations show that both the standard and hypofractionation schemes cause significant tumor shrinkage. Although the standard regimen produces smaller post-treatment tumors with lower cell-concentration profiles, the hypofractionated scheme has a thinner penumbra zone of cells infiltrating beyond the MR visible tumor margins according to the model parameters, which may partially explain why it is nearly as efficacious as standard therapies with higher cumulative doses. Conclusion: Diffusion tensor MRI, which can account for anatomical boundaries and preferential diffusion in the direction of white matter tracts, can be combined with mathematical modeling to produce more realistic GBM tumor growth and radiation therapy simulations that may elucidate the complex dynamics of the effect of different therapeutic regimens. Author Disclosure: L. Hathout: None. V. Patel: None.
TD50 (n) and normalized slope g50 of the exponential form of the logistic dose response model. Results: Median age was 64 y/o (range: 45-87 y/o) with 14 (70%) males and 6 (30%) females. Thirteen (65%) patients received surgery and 12 (60%) patients received chemotherapy. The median previous radiation dose was 70 Gy (range: 63-118.2 Gy). The median time from prior radiation therapy to SABR was 12.5 months (range: 3-39 months). The median maximum SABR dose was 50 Gy (range: 47.3-55 Gy). The median prescribed SABR EQD2 was 88 Gy (range: 88-103.8 Gy) for a/b Z 3 Gy and was 60 Gy (range: 6068.9 Gy) for a/b Z 10 Gy, respectively. The median tumor volume was 27.3 cc (range: 4.4-75.7 cc). No Grade 4 or greater toxicity was observed. One (5%) patient had Grade 3 mucositis, 5 (25%) patients had Grade 2 mucositis, and 6 (30%) patients had Grade 1 mucositis. Grade 2-3 mucositis correlated with median composite EQD2 to oral mucosa (TD50 (n) Z 190.8 Gy, g50 Z 0.3876). Outcomes were better correlated with median composite EQD2 to structures than to doses for small volumes, possibly due to tight small-volume dose constraints in SABR plans. Conclusion: To keep the risk of Grade 2-3 mucositis below 25%, the median composite EQD2 to oral mucosa should be kept below 55.6 Gy. SABR has an acceptable toxicity profile in patients with previouslyirradiated, locally rSCCHN. Our DVH model can estimate the risk of common toxicities such as mucositis based on median composite radiation dose to critical organs such as oral mucosa. Author Disclosure: K. Quan: None. K.M. Xu: None. Y. Zhang: None. D.A. Clump: None. R. Lalonde: None. S.A. Burton: None. D.E. Heron: None.
1138 Estimation of Toxicities Following Stereotactic Ablative Radiation Therapy Treatment of Locally Recurrent and Previously Irradiated Head and Neck Squamous Cell Carcinoma Based on a Normal Tissue Complication Probability Model K. Quan,1,2 K.M. Xu,1 Y. Zhang,1 D.A. Clump, II,1 R. Lalonde,1 S.A. Burton,1 and D.E. Heron1; 1University of Pittsburgh Cancer Institute, Pittsburgh, PA, 2Division of Radiation Oncology, Walker Family Cancer Centre, McMaster University, St. Catharines, ON, Canada Purpose/Objective(s): Locoregional recurrence rate in squamous cell carcinoma of head and neck (SCCHN) following chemoradiation remains high. The objective of this study is to determine dose-volume relationship to toxicities of normal tissues in previously-irradiated, locally-recurrent SCCHN (rSCCHN) treated with stereotactic ablative radiotherapy (SABR). Materials/Methods: A retrospective review of 20 patients with previouslyirradiated, locally rSCCHN from 2008-2011 was conducted. Tumors with a GTV less than 25 cm3 received 8.0 Gy per fraction for 5 fractions (total dose of 40 Gy); tumors with a GTV more than 25 cm3 received 8.8 Gy per fraction for 5 fractions (total dose of 44 Gy). Toxicity was graded based on Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Physical dose was converted into 2 Gy-per-fraction equivalent dose (EQD2) to correct for different fractionation schemes and allow for summation of SABR and previous IMRT plans. Logistic regression of composite dose volume histogram (DVH) data was performed in the DVH Evaluator software. Maximum likelihood parameter fitting was applied to solve
1139 Online Adaptive Magnetic ResonanceeGuided (OAMR)-Stereotactic Body Radiation Therapy for Abdominal Malignancies: Prospective Dosimetric Results from a Phase 1 Trial L.E. Henke,1 J.R. Olsen,2 O.L. Green,3 D. Yang,3 T. Zhao,4 L.A. Olsen,5 H. Wooten,6 H. Li,3 V.L. Rodriguez,3 B. McClain,3 A. Curcuru,1 C.G. Robinson,4 J.D. Bradley,1 J.M. Michalski,3 S. Mutic,3 P.J. Parikh,3 and R. Kashani7; 1Washington University School of Medicine, Department of Radiation Oncology, St. Louis, MO, 2University of Colorado Denver School of Medicine, Denver, CO, 3Washington University School of Medicine, St. Louis, MO, 4Washington University in St. Louis, Department of Radiation Oncology, St. Louis, MO, 5Memorial Hospital e UCHealth, Colorado Springs, CO, 6Los Alamos National Laboratory, Los Alamos, NM, 7Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO Purpose/Objective(s): SBRT is an effective treatment for oligometastatic or unresectable primary malignancy, although target proximity to organs-atrisk (OAR) may limit safe delivery of an ablative dose for abdominal tumors. OAMR-SBRT may improve the therapeutic ratio using reoptimization to account for daily variation in target/OAR anatomy. This study characterizes dosimetric findings in patients treated with OAMR-SBRT on a prospective phase I trial for oligometastatic or unresectable abdominal malignancy. Materials/Methods: Eighteen patients with disease of the liver (n Z 9) or non-liver abdomen (NLA; n Z 9) were enrolled in a phase I prospective trial of OAMR-SBRT (NCT02264886) from 2/2015 to 12/2015, using a commercially available MR-IGRT system. Initial SBRT plans (PI) were created at CT/MRI simulation. Prescribed dose was 50 Gy/5 fractions (frx), with goal 95% PTV coverage, subject to hard OAR constraints. For frx1, PI was applied to the daily setup MR dataset and dose to PTV/OAR was recalculated, with physician verification of daily target/OAR anatomy. When application of PI to frx1 anatomy resulted in OAR violation or reduced PTV coverage, daily adaptive plans (PA, subject to PI constraints without dose accumulation) were created. Online re-planning, QA, and delivery of a new plan were performed with the patient on the treatment table. For subsequent frx, the delivered plan from the preceding frx was used as the new PI (e.g., frx1 PA used as frx2 PI). When favorable daily anatomy was observed, PTV dose escalation up to 15 Gy/frx was allowed in PA, provided that all OAR constraints were met. PTV/OAR dose resulting from application of PI and PA to anatomy from each frx were compared to characterize the dosimetric impact of online adaptation.
International Journal of Radiation Oncology Biology Physics
the single most effective therapy in prolonging survival. Research continues in trying to optimize dosing and fractionation schemes, both to prolong survival and to assess alternative strategies, such as hypofractionation regimens, that have nearly equal efficacy to standard regimens but limit patient treatment time. Theoretical investigations of treatment response often involve simplified 1D isotropic models of tumor spread. The purpose of this work is to introduce a realistic treatment simulation tool by combining mathematical modeling with diffusion tensor (DT) MR imaging to develop an anisotropic 3D model of GBM growth guided by the direction of adjacent white matter tracts. This model is then used to simulate the effects of radiation therapy, and to study the complex dynamics of the effect of different dosing and fractionation schemes on tumor size and cell concentration. Materials/Methods: A reaction-diffusion partial differential equation that accounts for tumor cell diffusion and proliferation is used to model tumor concentration as a function of time and space. This model can be stated as: c(t,x)/dt Z V∙(D(x)V c)+pc(1-c/K)-R(x,c,t) where c, D, p, and K represent the concentration, diffusion, proliferation, and tissue carrying capacity of tumor cells respectively, and where R(x,c,t) represents a linear-quadratic radiation therapy term that can model different dosing schemes. In this work, D is the three-dimensional tumor cell diffusion tensor, calculated from scaled eigenvalues of the conventional MR spin diffusion tensor. For demonstration, the effects of a standard radiation therapy regimen of 61.2 Gy/34 doses are compared to a hypofractionation regimen of 35 Gy/5 doses administered once weekly. Results: The DT-MRI GBM growth model produces realistic-appearing tumors that infiltrate along white matter tracts, similar in appearance to MR imaging profiles of actual tumors. Radiation therapy simulations show that both the standard and hypofractionation schemes cause significant tumor shrinkage. Although the standard regimen produces smaller post-treatment tumors with lower cell-concentration profiles, the hypofractionated scheme has a thinner penumbra zone of cells infiltrating beyond the MR visible tumor margins according to the model parameters, which may partially explain why it is nearly as efficacious as standard therapies with higher cumulative doses. Conclusion: Diffusion tensor MRI, which can account for anatomical boundaries and preferential diffusion in the direction of white matter tracts, can be combined with mathematical modeling to produce more realistic GBM tumor growth and radiation therapy simulations that may elucidate the complex dynamics of the effect of different therapeutic regimens. Author Disclosure: L. Hathout: None. V. Patel: None.
TD50 (n) and normalized slope g50 of the exponential form of the logistic dose response model. Results: Median age was 64 y/o (range: 45-87 y/o) with 14 (70%) males and 6 (30%) females. Thirteen (65%) patients received surgery and 12 (60%) patients received chemotherapy. The median previous radiation dose was 70 Gy (range: 63-118.2 Gy). The median time from prior radiation therapy to SABR was 12.5 months (range: 3-39 months). The median maximum SABR dose was 50 Gy (range: 47.3-55 Gy). The median prescribed SABR EQD2 was 88 Gy (range: 88-103.8 Gy) for a/b Z 3 Gy and was 60 Gy (range: 6068.9 Gy) for a/b Z 10 Gy, respectively. The median tumor volume was 27.3 cc (range: 4.4-75.7 cc). No Grade 4 or greater toxicity was observed. One (5%) patient had Grade 3 mucositis, 5 (25%) patients had Grade 2 mucositis, and 6 (30%) patients had Grade 1 mucositis. Grade 2-3 mucositis correlated with median composite EQD2 to oral mucosa (TD50 (n) Z 190.8 Gy, g50 Z 0.3876). Outcomes were better correlated with median composite EQD2 to structures than to doses for small volumes, possibly due to tight small-volume dose constraints in SABR plans. Conclusion: To keep the risk of Grade 2-3 mucositis below 25%, the median composite EQD2 to oral mucosa should be kept below 55.6 Gy. SABR has an acceptable toxicity profile in patients with previouslyirradiated, locally rSCCHN. Our DVH model can estimate the risk of common toxicities such as mucositis based on median composite radiation dose to critical organs such as oral mucosa. Author Disclosure: K. Quan: None. K.M. Xu: None. Y. Zhang: None. D.A. Clump: None. R. Lalonde: None. S.A. Burton: None. D.E. Heron: None.
1138 Estimation of Toxicities Following Stereotactic Ablative Radiation Therapy Treatment of Locally Recurrent and Previously Irradiated Head and Neck Squamous Cell Carcinoma Based on a Normal Tissue Complication Probability Model K. Quan,1,2 K.M. Xu,1 Y. Zhang,1 D.A. Clump, II,1 R. Lalonde,1 S.A. Burton,1 and D.E. Heron1; 1University of Pittsburgh Cancer Institute, Pittsburgh, PA, 2Division of Radiation Oncology, Walker Family Cancer Centre, McMaster University, St. Catharines, ON, Canada Purpose/Objective(s): Locoregional recurrence rate in squamous cell carcinoma of head and neck (SCCHN) following chemoradiation remains high. The objective of this study is to determine dose-volume relationship to toxicities of normal tissues in previously-irradiated, locally-recurrent SCCHN (rSCCHN) treated with stereotactic ablative radiotherapy (SABR). Materials/Methods: A retrospective review of 20 patients with previouslyirradiated, locally rSCCHN from 2008-2011 was conducted. Tumors with a GTV less than 25 cm3 received 8.0 Gy per fraction for 5 fractions (total dose of 40 Gy); tumors with a GTV more than 25 cm3 received 8.8 Gy per fraction for 5 fractions (total dose of 44 Gy). Toxicity was graded based on Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Physical dose was converted into 2 Gy-per-fraction equivalent dose (EQD2) to correct for different fractionation schemes and allow for summation of SABR and previous IMRT plans. Logistic regression of composite dose volume histogram (DVH) data was performed in the DVH Evaluator software. Maximum likelihood parameter fitting was applied to solve
1139 Online Adaptive Magnetic ResonanceeGuided (OAMR)-Stereotactic Body Radiation Therapy for Abdominal Malignancies: Prospective Dosimetric Results from a Phase 1 Trial L.E. Henke,1 J.R. Olsen,2 O.L. Green,3 D. Yang,3 T. Zhao,4 L.A. Olsen,5 H. Wooten,6 H. Li,3 V.L. Rodriguez,3 B. McClain,3 A. Curcuru,1 C.G. Robinson,4 J.D. Bradley,1 J.M. Michalski,3 S. Mutic,3 P.J. Parikh,3 and R. Kashani7; 1Washington University School of Medicine, Department of Radiation Oncology, St. Louis, MO, 2University of Colorado Denver School of Medicine, Denver, CO, 3Washington University School of Medicine, St. Louis, MO, 4Washington University in St. Louis, Department of Radiation Oncology, St. Louis, MO, 5Memorial Hospital e UCHealth, Colorado Springs, CO, 6Los Alamos National Laboratory, Los Alamos, NM, 7Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO Purpose/Objective(s): SBRT is an effective treatment for oligometastatic or unresectable primary malignancy, although target proximity to organs-atrisk (OAR) may limit safe delivery of an ablative dose for abdominal tumors. OAMR-SBRT may improve the therapeutic ratio using reoptimization to account for daily variation in target/OAR anatomy. This study characterizes dosimetric findings in patients treated with OAMR-SBRT on a prospective phase I trial for oligometastatic or unresectable abdominal malignancy. Materials/Methods: Eighteen patients with disease of the liver (n Z 9) or non-liver abdomen (NLA; n Z 9) were enrolled in a phase I prospective trial of OAMR-SBRT (NCT02264886) from 2/2015 to 12/2015, using a commercially available MR-IGRT system. Initial SBRT plans (PI) were created at CT/MRI simulation. Prescribed dose was 50 Gy/5 fractions (frx), with goal 95% PTV coverage, subject to hard OAR constraints. For frx1, PI was applied to the daily setup MR dataset and dose to PTV/OAR was recalculated, with physician verification of daily target/OAR anatomy. When application of PI to frx1 anatomy resulted in OAR violation or reduced PTV coverage, daily adaptive plans (PA, subject to PI constraints without dose accumulation) were created. Online re-planning, QA, and delivery of a new plan were performed with the patient on the treatment table. For subsequent frx, the delivered plan from the preceding frx was used as the new PI (e.g., frx1 PA used as frx2 PI). When favorable daily anatomy was observed, PTV dose escalation up to 15 Gy/frx was allowed in PA, provided that all OAR constraints were met. PTV/OAR dose resulting from application of PI and PA to anatomy from each frx were compared to characterize the dosimetric impact of online adaptation.