- Email: [email protected]
SBRT Boost Following Concurrent Chemoradiation for Locally Advanced NSCLCa: A Phase 1 Dose-Escalation Study
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International Journal of Radiation Oncology Biology Physics
two plans and isocenters leading to unacceptable conformity and OAR hotspots. Conclusion: While the majority of plans utilized VMAT, the range of conformity and dose fall-off away from PTV was large. The decision to prioritize either OAR or PTV coverage varied considerably suggesting toxicity outcomes in the trial may be affected if PTV coverage is chosen over OAR. Several benchmarks could meet DVH metrics while producing unacceptable plans due to low conformity. A frequently-asked-questions document was disseminated for clarification of planning priorities, improving the approval rate at first attempt. We believe benchmark credentialing, while time-consuming, has been an extremely valuable tool for protocol education. Pretreatment case reviews will be used to ensure protocol compliance as patient accrual begins. Acknowledgment(s): This project was supported by grants U10CA180868 and U10CA180822 from the National Cancer Institute (NCI). Author Disclosure: H.A. Al-Hallaq: royalties from CAD software licensed by university to a company; University of Chicago. S.J. Chmura: Employee; University of Illinois Chicago. J.K. Salama: Employee; Duke Medical Center. J. Leif: None. S. McNulty: None. J.M. Galvin: None. D. Followill: None. C.G. Robinson: None. J.R. White: None. Y. Xiao: None. M.M. Matuszak: None.
localized changes are informing the design of our prospective trial of patients who require repeat SBRT. Acknowledgment(s): Supported by P01 CA 059827 and NIH R01 CA 142840 (PI Kong). Author Disclosure: D. Owen: None. M.H. Stenmark: None. J. Foy: None. F.P. Kong: None. J. Hayman: None. T.S. Lawrence: None. R.K. Ten Haken: None. M.M. Matuszak: None.
195 SPECT-CT Ventilation and Perfusion Changes During and 3 Months After Lung SBRT D. Owen,1 M.H. Stenmark,2 J. Foy,1 F.M.P. Kong,3 J.A. Hayman,1 T.S. Lawrence,1 R. K. Ten Haken,1 and M.M. Matuszak1; 1University of Michigan, Ann Arbor, MI, 2University of Michigan, Ann Arbor, MI, 3 Georgia Regents University, Augusta, GA Purpose/Objective(s): Little is understood about local functional lung changes during and post lung SBRT. We hypothesized that lung SBRT would cause irreversible ventilation/perfusion changes on SPECT-CT. Materials/Methods: As part of a prospective imaging protocol, pre, during and 3 months posttreatment ventilation and perfusion SPECT-CT scans were obtained for 9 patients with stage I NSCLC undergoing lung SBRT with no prior history of radiation. The dose/fractionation regimens were: 55 Gy/5 fractions (fx) (n Z 3), 50 Gy/5 fx (n Z 2), and 54 Gy/3 fx (n Z 4); SPECT-CT scans during SBRT were acquired after the second or third fx in a 5 fx schema or after the second fx in a 3 fx schema. The planning CTs were rigidly registered to the SPECT scans. Longitudinal analysis of ventilation and perfusion was performed with an image management system. Isodose surfaces (IDS) for doses from 50e400 BED, corresponding to EQD2 doses of 13.8 e 138.9 Gy (with a/b Z 2.5), were extracted to account for varying fractionation schemes. The ventilation and perfusion signals were normalized to a low dose region of the contralateral lung (usually the apex). Percent changes in ventilation and perfusion signals at the different dose levels were calculated between the pretreatment, during treatment, and 3 months posttreatment SPECT scans. Results: Changes in lung perfusion during SBRT were variable with 5 of 9 patients exhibiting decreased perfusion for areas receiving 250e400 Gy BED (percent reduction from 11.7 e 37.1%). Three months post lung SBRT, 8 of 9 patients demonstrated decreased perfusion, with a mean reduction of 42% between 250e400 Gy BED, 38% between 100e250 Gy BED, and 30% between 50e100 Gy BED. Ventilation changes were less common during SBRT, with only 3 of 9 patients showing decreased ventilation in the 250e400 Gy BED range. By 3 months posttreatment, 7 of 9 patients demonstrated decreased ventilation in the 250e400 BED range (mean reduction 35%). The 3 fraction schema of 54 Gy was associated the greatest decrease in ventilation and perfusion both during and 3 months post-SBRT. Conclusion: Most patients experienced decreased ventilation and perfusion in the areas that received high ablative doses 3 months post SBRT. These
196 Phase 1 Study of Accelerated Hypofractionated Radiation Therapy With Concurrent Chemotherapy for Stage III Non-Small Cell Lung Cancer: CALGB 31102 (Alliance) J.J. Urbanic,1 X. Wang,2 J.A. Bogart,3 T. Stinchcombe,4 L. Hodgson,2 S.E. Schild,5 L. Bazhenova,1 R. Salgia,6 and E.E. Vokes6; 1University of California, San Diego, La Jolla, CA, 2Alliance Statistics and Data Center, Duke University, Durham, NC, 3SUNY Upstate Medical University, Syracuse, NY, 4University of North Carolina Hospitals, Chapel Hill, NC, 5 Mayo Clinic, Phoenix, AZ, 6University of Chicago, Chicago, IL Purpose/Objective(s): The safety of accelerated hypofractionated radiation therapy (AHRT) with concurrent chemotherapy (CT) for inoperable stage III non-small cell lung cancer (NSCLC) has not been defined. Materials/Methods: Cancer and Leukemia Group B trial 31102 prospectively assessed AHRT given once daily with CT for stage III NSCLC. The primary objectives were to define the maximally accelerated course of radiation therapy with CT and to describe the short-term and long-term toxicity of therapy. Nominal total radiation therapy dose remained at 60 Gy, while the number of daily fractions in each successive cohort was reduced. Cohort 1: 60 Gy 27 fx, Cohort 2: 60 Gy 24 fx, Cohort 3: 60 Gy 22 fx, and Cohort 4 was 60 Gy 20 fx; CT: weekly carboplatin AUC 2 and paclitaxel 45 mg /m2 concurrent with AHRT. Consolidation CT was carboplatin AUC 6 and paclitaxel 200 mg/ m2q 3 weeks x 2 cycles. Maximum tolerated dose was defined as: of 6 pts/cohort, 2 pts develop grade3 toxicity and 1 pt develops grade 4 toxicity. Grade 3 esophageal, heme, or hypersensitivity was not considered doselimiting. Results: Twenty-two patients were accrued, and 19 patients were evaluable (6 patients each on cohorts 1 to 3 and one patient on cohort 4) from July 2012 and May 2014. Four total grade 3 non-hematologic toxicity events observed. Grade 5 toxicity in 3 patients (1 pt cohort 2 (hemoptysis), 2 pts cohort 3 (hemoptysis and pneumonitis)). The MTD was therefore defined by Cohort 2 (60 Gy in 2.5 Gy/fx). Time to grade 5 toxicity was 10 months (mo), 4 mo, and 9 mo after completing AHRT. With median follow-up of 16.8 months in living patients, median overall survival has not yet been reached and median PFS is 12.2 months (95% CI Z 6.1e22.5 m). Conclusion: Only modest hypofractionation was achievable in a multi-institutional experience combining AHRTand CT in Stage III NSCLC; nevertheless, the MTD of 60 Gy given at 2.5 Gy/fx allows completion of RT in 20% fewer treatments than conventional therapy. Further investigation of AHRT may help define the therapeutic index. Author Disclosure: J.J. Urbanic: None. X. Wang: None. J.A. Bogart: Employee; State University of New York. Committee leadership; Alliance for Clinical Trials in Oncology. T. Stinchcombe: None. L. Hodgson: None. S.E. Schild: Committee leadership; Alliance for Clinical Trials in Oncology. L. Bazhenova: None. R. Salgia: None. E.E. Vokes: Committee leadership; Alliance for Clinical Trials in Oncology.
197 SBRT Boost Following Concurrent Chemoradiation for Locally Advanced NSCLCa: A Phase 1 Dose-Escalation Study J.T. Hepel,1,2 K.L. Leonard,1,2 S. Howard,2 T. Ng,2 A. Taber,3 H. Khurshid,2 A. Birnbaum,2 B.U.O.R.G. (BrUOG),4 D.E. Wazer,1,2
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Oral Scientific Abstracts 197; Table 1 Patient Cohort
1 cm3PBV [SBRT](Gy)
4 cm3PBV [SBRT](Gy)
1 cm3PBV [EBRT+SBRT](Gy)
4 cm3PBV [EBRT+SBRT](Gy)
A e 8 Gy x2 B e 10 Gy x2 C e 12 Gy x2 D e 14 Gy x2 Pt #9 e PBV Hemorrhage (Gr 5)
13.7 17.0 18.2 21.2 26.3
9.4 10.5 9.2 12.5 20.3
65.9 67.4 66.6 72.3 79.5
60.4 49.5 45.8 60.5 73.5
and T.A. DiPetrillo1,2; 1Tufts Medical Center, Tufts University School of Medicine, Boston, MA, 2Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, 3Miriam Hospital, Alpert Medical School of Brown University, Providence, RI, 4Alpert Medical School of Brown University, Providence, RI Purpose/Objective(s): Treatment of locally advanced NSCLCa remains suboptimal. A Phase 1 dose-escalation study was initiated in order to evaluate the maximum tolerated dose of SBRT delivered as boost to residual primary and nodal disease following chemoradiation with an ultimate goal to improve intrathoracic disease control. Materials/Methods: Eligible patients for this IRB-approved, prospective study received platinum-based chemoradiation to a dose of 50.4 Gy in 28 fractions and had primary and nodal volumes appropriate for SBRT boost (<120 cm3 and <60 cm3, respectively). Stereotactic body radiation therapy was delivered in 2 fx within 4 wks of chemoradiation. Dose was escalated from 16 to 28 Gy in 2 Gy/fx increments resulting in 4 dose cohorts: A-16 Gy, B-20 Gy, C-24 Gy, and D-28 Gy. Three patients per cohort were evaluated for dose-limiting toxicity (DLT) defined as treatment related Gr 3-5 toxicity within 4 weeks of treatment. Each cohort could be expanded to an additional 3 patients if a DLT was observed. Maximum tolerated dose was defined when 2 of 6 pts experienced DLT at any dose or the maximum dose was reached without DLT. Acute toxicity (<3m), late toxicity (>3m), disease control and survival were also evaluated. Results: The study has completed accrual. Twelve pts were treated, 3 pts at each dose level. Mean age was 64 yrs (32e76 yrs) with 8 males and 4 females. Stage was IIb (1), IIIa (8), and IIIb (3); 92% were medically inoperable. The maximum dose level was reached with no DLT observed. Stereotactic body RT was well tolerated with no treatment related grade 3e5 acute toxicities observed, but 1 pt each developed COPD exacerbation (Gr 3) and viral pneumonia (Gr 3). With a median follow-up of 12 mos, locoregional control (LRC) was achieved in 83.3%. The actuarial LRC at 1-yr was 75%. Locoregional control was 67% at <24 Gy and 100% at 24 Gy (P Z .1). No failures occurred marginal to the SBRT PTV. Five pts had distant failure, and 7 pts remain disease-free. Overall survival at 1-yr was 70.1%. Late toxicity (Gr 3e5) was seen in 1 pt (cohort C) who developed fatal bronchopulmonary hemorrhage (Gr 5). There were no predetermined dose constraints for the proximal bronchial-vascular tree (PBV) in this study. This patient’s 1 cm3 and 4 cm3PBV doses for SBRT were 26.3 Gy and 20.3 Gy, and for total treatment were 79.5 Gy and 73.5 Gy, respectively. This was substantially higher compared to other patients in all 4 cohorts (Table). Conclusion: Stereotactic body RT boost to both primary and nodal disease following chemoradiation is feasible. Local control rates are encouraging, especially at doses 24 Gy in 2 fractions. Toxicity at the PBV is a concern but can potentially be avoided with strict dose-volume constraints. Additional evaluation in a Phase 2 trial is warranted. Author Disclosure: J.T. Hepel: None. K.L. Leonard: None. S. Howard: None. T. Ng: None. A. Taber: None. H. Khurshid: None. A. Birnbaum: None. B. (BrUOG): None. D.E. Wazer: None. T.A. DiPetrillo: None.
198 Phase 1 Dose-Escalation Study of Accelerated Fractionation and Concurrent Chemotherapy for Locally Advanced Lung Cancer C.R. Kelsey,1 D.S. Yoo,1 S.K. Das,2 F. Dunphy,1 N. Ready,1 J. Crawford,1 and L.B. Marks2; 1Duke University Medical Center, Durham, NC, 2 University of North Carolina, Chapel Hill, NC Purpose/Objective(s): Local failure occurs in a majority of patients with locally advanced lung cancer treated with radiation therapy (RT). Both accelerated RT fractionation and concurrent chemotherapy (ChT) improve local control and survival. Incorporating both strategies has generally led to excessive toxicity, particularly high-grade esophagitis. In this prospective study, the maximum tolerated dose (MTD) of RT given in an accelerated fashion with concurrent ChT was investigated. Intensity modulated radiation therapy (IMRT) was used to reduce the risk of esophagitis, the primary dose-limiting toxicity (DLT) with both accelerated RT and concurrent ChT. Materials/Methods: Patients with locally advanced lung cancer (NSCLC and SCLC) with ECOG PS 0e1, weight loss <10%, and adequate hematologic/renal function were treated with concurrent cisplatin (50 mg/m2 days 1, 8, 29, 36) and etoposide (50 mg/m2days 1e5 and 29e33). Radiation therapy treatment planning utilized 4D CT imaging with respiratory motion management; RT was 2 Gy qd, 6 fractions/week (bid on Fridays with 6h interval). Intensity modulated RT with daily image guidance was used to facilitate esophageal avoidance with strict pulmonary constraints. The primary tumor + 5 mm and involved lymph nodes + 3 mm expansions comprised the CTV. The PTV consisted of the CTV + 3 mm expansion. Elective nodal irradiation (ENI) was optional. The dose was escalated from 58 to 74 Gy in 4 Gy increments in a standard 3+3 trial design. Doselimiting toxicity was defined as acute grade 3e5 non-hematologic toxicity. Maximum tolerated dose was defined as dose in which DLT does not occur in more than 1/6 patients. Results: Twenty-four patients were enrolled, filling all dose cohorts, all completing RT and ChT as prescribed. Median age 64 (range, 49e74). M Z 12; F Z 12. NSCLC Z 21; SCLC Z 3. ENI in 13/24 (44 Gy), including 5/6 in 74 Gy cohort. Median (range) dosimetric parameters: Lung V5 Z 43% (18e70), V20 Z 24% (5e39); Esophagus V20 Z 34% (21e65), V60 Z 5% (0e41); heart V5 Z 18% (0e100), V30 Z 4% (0e41), V45 Z 1% (0e29). Dose-limiting toxicity occurred in 1 patient at 58 Gy (grade 3 esophagitis) and 1 patient at 70 Gy (grade 5 esophageal fistula). The first patient had a 12 cm tumor close to the esophagus, and the second had a 10 cm tumor abutting the esophagus. Three additional patients were enrolled at both dose cohorts without further DLT. Zero out of 6 in 74 Gy cohort developed DLT. There was one case of late grade 3 pneumonitis that was self-limited. Conclusion: Dose-escalation to 74 Gy using accelerated RT (6 fractions/ week) with concurrent ChT was achieved. This strategy appears to facilitate the delivery of accelerated RT concurrently with ChT, sparing severe acute esophageal reactions and may improve outcomes for patients with lung cancer. High-grade esophageal complications appeared to be associated with large tumors adjacent to the esophagus. Author Disclosure: C.R. Kelsey: Research Grant; Varian Medical Systems. D.S. Yoo: None. S.K. Das: None. F. Dunphy: None. N. Ready: None. J. Crawford: None. L.B. Marks: None.
International Journal of Radiation Oncology Biology Physics
two plans and isocenters leading to unacceptable conformity and OAR hotspots. Conclusion: While the majority of plans utilized VMAT, the range of conformity and dose fall-off away from PTV was large. The decision to prioritize either OAR or PTV coverage varied considerably suggesting toxicity outcomes in the trial may be affected if PTV coverage is chosen over OAR. Several benchmarks could meet DVH metrics while producing unacceptable plans due to low conformity. A frequently-asked-questions document was disseminated for clarification of planning priorities, improving the approval rate at first attempt. We believe benchmark credentialing, while time-consuming, has been an extremely valuable tool for protocol education. Pretreatment case reviews will be used to ensure protocol compliance as patient accrual begins. Acknowledgment(s): This project was supported by grants U10CA180868 and U10CA180822 from the National Cancer Institute (NCI). Author Disclosure: H.A. Al-Hallaq: royalties from CAD software licensed by university to a company; University of Chicago. S.J. Chmura: Employee; University of Illinois Chicago. J.K. Salama: Employee; Duke Medical Center. J. Leif: None. S. McNulty: None. J.M. Galvin: None. D. Followill: None. C.G. Robinson: None. J.R. White: None. Y. Xiao: None. M.M. Matuszak: None.
localized changes are informing the design of our prospective trial of patients who require repeat SBRT. Acknowledgment(s): Supported by P01 CA 059827 and NIH R01 CA 142840 (PI Kong). Author Disclosure: D. Owen: None. M.H. Stenmark: None. J. Foy: None. F.P. Kong: None. J. Hayman: None. T.S. Lawrence: None. R.K. Ten Haken: None. M.M. Matuszak: None.
195 SPECT-CT Ventilation and Perfusion Changes During and 3 Months After Lung SBRT D. Owen,1 M.H. Stenmark,2 J. Foy,1 F.M.P. Kong,3 J.A. Hayman,1 T.S. Lawrence,1 R. K. Ten Haken,1 and M.M. Matuszak1; 1University of Michigan, Ann Arbor, MI, 2University of Michigan, Ann Arbor, MI, 3 Georgia Regents University, Augusta, GA Purpose/Objective(s): Little is understood about local functional lung changes during and post lung SBRT. We hypothesized that lung SBRT would cause irreversible ventilation/perfusion changes on SPECT-CT. Materials/Methods: As part of a prospective imaging protocol, pre, during and 3 months posttreatment ventilation and perfusion SPECT-CT scans were obtained for 9 patients with stage I NSCLC undergoing lung SBRT with no prior history of radiation. The dose/fractionation regimens were: 55 Gy/5 fractions (fx) (n Z 3), 50 Gy/5 fx (n Z 2), and 54 Gy/3 fx (n Z 4); SPECT-CT scans during SBRT were acquired after the second or third fx in a 5 fx schema or after the second fx in a 3 fx schema. The planning CTs were rigidly registered to the SPECT scans. Longitudinal analysis of ventilation and perfusion was performed with an image management system. Isodose surfaces (IDS) for doses from 50e400 BED, corresponding to EQD2 doses of 13.8 e 138.9 Gy (with a/b Z 2.5), were extracted to account for varying fractionation schemes. The ventilation and perfusion signals were normalized to a low dose region of the contralateral lung (usually the apex). Percent changes in ventilation and perfusion signals at the different dose levels were calculated between the pretreatment, during treatment, and 3 months posttreatment SPECT scans. Results: Changes in lung perfusion during SBRT were variable with 5 of 9 patients exhibiting decreased perfusion for areas receiving 250e400 Gy BED (percent reduction from 11.7 e 37.1%). Three months post lung SBRT, 8 of 9 patients demonstrated decreased perfusion, with a mean reduction of 42% between 250e400 Gy BED, 38% between 100e250 Gy BED, and 30% between 50e100 Gy BED. Ventilation changes were less common during SBRT, with only 3 of 9 patients showing decreased ventilation in the 250e400 Gy BED range. By 3 months posttreatment, 7 of 9 patients demonstrated decreased ventilation in the 250e400 BED range (mean reduction 35%). The 3 fraction schema of 54 Gy was associated the greatest decrease in ventilation and perfusion both during and 3 months post-SBRT. Conclusion: Most patients experienced decreased ventilation and perfusion in the areas that received high ablative doses 3 months post SBRT. These
196 Phase 1 Study of Accelerated Hypofractionated Radiation Therapy With Concurrent Chemotherapy for Stage III Non-Small Cell Lung Cancer: CALGB 31102 (Alliance) J.J. Urbanic,1 X. Wang,2 J.A. Bogart,3 T. Stinchcombe,4 L. Hodgson,2 S.E. Schild,5 L. Bazhenova,1 R. Salgia,6 and E.E. Vokes6; 1University of California, San Diego, La Jolla, CA, 2Alliance Statistics and Data Center, Duke University, Durham, NC, 3SUNY Upstate Medical University, Syracuse, NY, 4University of North Carolina Hospitals, Chapel Hill, NC, 5 Mayo Clinic, Phoenix, AZ, 6University of Chicago, Chicago, IL Purpose/Objective(s): The safety of accelerated hypofractionated radiation therapy (AHRT) with concurrent chemotherapy (CT) for inoperable stage III non-small cell lung cancer (NSCLC) has not been defined. Materials/Methods: Cancer and Leukemia Group B trial 31102 prospectively assessed AHRT given once daily with CT for stage III NSCLC. The primary objectives were to define the maximally accelerated course of radiation therapy with CT and to describe the short-term and long-term toxicity of therapy. Nominal total radiation therapy dose remained at 60 Gy, while the number of daily fractions in each successive cohort was reduced. Cohort 1: 60 Gy 27 fx, Cohort 2: 60 Gy 24 fx, Cohort 3: 60 Gy 22 fx, and Cohort 4 was 60 Gy 20 fx; CT: weekly carboplatin AUC 2 and paclitaxel 45 mg /m2 concurrent with AHRT. Consolidation CT was carboplatin AUC 6 and paclitaxel 200 mg/ m2q 3 weeks x 2 cycles. Maximum tolerated dose was defined as: of 6 pts/cohort, 2 pts develop grade3 toxicity and 1 pt develops grade 4 toxicity. Grade 3 esophageal, heme, or hypersensitivity was not considered doselimiting. Results: Twenty-two patients were accrued, and 19 patients were evaluable (6 patients each on cohorts 1 to 3 and one patient on cohort 4) from July 2012 and May 2014. Four total grade 3 non-hematologic toxicity events observed. Grade 5 toxicity in 3 patients (1 pt cohort 2 (hemoptysis), 2 pts cohort 3 (hemoptysis and pneumonitis)). The MTD was therefore defined by Cohort 2 (60 Gy in 2.5 Gy/fx). Time to grade 5 toxicity was 10 months (mo), 4 mo, and 9 mo after completing AHRT. With median follow-up of 16.8 months in living patients, median overall survival has not yet been reached and median PFS is 12.2 months (95% CI Z 6.1e22.5 m). Conclusion: Only modest hypofractionation was achievable in a multi-institutional experience combining AHRTand CT in Stage III NSCLC; nevertheless, the MTD of 60 Gy given at 2.5 Gy/fx allows completion of RT in 20% fewer treatments than conventional therapy. Further investigation of AHRT may help define the therapeutic index. Author Disclosure: J.J. Urbanic: None. X. Wang: None. J.A. Bogart: Employee; State University of New York. Committee leadership; Alliance for Clinical Trials in Oncology. T. Stinchcombe: None. L. Hodgson: None. S.E. Schild: Committee leadership; Alliance for Clinical Trials in Oncology. L. Bazhenova: None. R. Salgia: None. E.E. Vokes: Committee leadership; Alliance for Clinical Trials in Oncology.
197 SBRT Boost Following Concurrent Chemoradiation for Locally Advanced NSCLCa: A Phase 1 Dose-Escalation Study J.T. Hepel,1,2 K.L. Leonard,1,2 S. Howard,2 T. Ng,2 A. Taber,3 H. Khurshid,2 A. Birnbaum,2 B.U.O.R.G. (BrUOG),4 D.E. Wazer,1,2
Volume 93 Number 3S Supplement 2015
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Oral Scientific Abstracts 197; Table 1 Patient Cohort
1 cm3PBV [SBRT](Gy)
4 cm3PBV [SBRT](Gy)
1 cm3PBV [EBRT+SBRT](Gy)
4 cm3PBV [EBRT+SBRT](Gy)
A e 8 Gy x2 B e 10 Gy x2 C e 12 Gy x2 D e 14 Gy x2 Pt #9 e PBV Hemorrhage (Gr 5)
13.7 17.0 18.2 21.2 26.3
9.4 10.5 9.2 12.5 20.3
65.9 67.4 66.6 72.3 79.5
60.4 49.5 45.8 60.5 73.5
and T.A. DiPetrillo1,2; 1Tufts Medical Center, Tufts University School of Medicine, Boston, MA, 2Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, 3Miriam Hospital, Alpert Medical School of Brown University, Providence, RI, 4Alpert Medical School of Brown University, Providence, RI Purpose/Objective(s): Treatment of locally advanced NSCLCa remains suboptimal. A Phase 1 dose-escalation study was initiated in order to evaluate the maximum tolerated dose of SBRT delivered as boost to residual primary and nodal disease following chemoradiation with an ultimate goal to improve intrathoracic disease control. Materials/Methods: Eligible patients for this IRB-approved, prospective study received platinum-based chemoradiation to a dose of 50.4 Gy in 28 fractions and had primary and nodal volumes appropriate for SBRT boost (<120 cm3 and <60 cm3, respectively). Stereotactic body radiation therapy was delivered in 2 fx within 4 wks of chemoradiation. Dose was escalated from 16 to 28 Gy in 2 Gy/fx increments resulting in 4 dose cohorts: A-16 Gy, B-20 Gy, C-24 Gy, and D-28 Gy. Three patients per cohort were evaluated for dose-limiting toxicity (DLT) defined as treatment related Gr 3-5 toxicity within 4 weeks of treatment. Each cohort could be expanded to an additional 3 patients if a DLT was observed. Maximum tolerated dose was defined when 2 of 6 pts experienced DLT at any dose or the maximum dose was reached without DLT. Acute toxicity (<3m), late toxicity (>3m), disease control and survival were also evaluated. Results: The study has completed accrual. Twelve pts were treated, 3 pts at each dose level. Mean age was 64 yrs (32e76 yrs) with 8 males and 4 females. Stage was IIb (1), IIIa (8), and IIIb (3); 92% were medically inoperable. The maximum dose level was reached with no DLT observed. Stereotactic body RT was well tolerated with no treatment related grade 3e5 acute toxicities observed, but 1 pt each developed COPD exacerbation (Gr 3) and viral pneumonia (Gr 3). With a median follow-up of 12 mos, locoregional control (LRC) was achieved in 83.3%. The actuarial LRC at 1-yr was 75%. Locoregional control was 67% at <24 Gy and 100% at 24 Gy (P Z .1). No failures occurred marginal to the SBRT PTV. Five pts had distant failure, and 7 pts remain disease-free. Overall survival at 1-yr was 70.1%. Late toxicity (Gr 3e5) was seen in 1 pt (cohort C) who developed fatal bronchopulmonary hemorrhage (Gr 5). There were no predetermined dose constraints for the proximal bronchial-vascular tree (PBV) in this study. This patient’s 1 cm3 and 4 cm3PBV doses for SBRT were 26.3 Gy and 20.3 Gy, and for total treatment were 79.5 Gy and 73.5 Gy, respectively. This was substantially higher compared to other patients in all 4 cohorts (Table). Conclusion: Stereotactic body RT boost to both primary and nodal disease following chemoradiation is feasible. Local control rates are encouraging, especially at doses 24 Gy in 2 fractions. Toxicity at the PBV is a concern but can potentially be avoided with strict dose-volume constraints. Additional evaluation in a Phase 2 trial is warranted. Author Disclosure: J.T. Hepel: None. K.L. Leonard: None. S. Howard: None. T. Ng: None. A. Taber: None. H. Khurshid: None. A. Birnbaum: None. B. (BrUOG): None. D.E. Wazer: None. T.A. DiPetrillo: None.
198 Phase 1 Dose-Escalation Study of Accelerated Fractionation and Concurrent Chemotherapy for Locally Advanced Lung Cancer C.R. Kelsey,1 D.S. Yoo,1 S.K. Das,2 F. Dunphy,1 N. Ready,1 J. Crawford,1 and L.B. Marks2; 1Duke University Medical Center, Durham, NC, 2 University of North Carolina, Chapel Hill, NC Purpose/Objective(s): Local failure occurs in a majority of patients with locally advanced lung cancer treated with radiation therapy (RT). Both accelerated RT fractionation and concurrent chemotherapy (ChT) improve local control and survival. Incorporating both strategies has generally led to excessive toxicity, particularly high-grade esophagitis. In this prospective study, the maximum tolerated dose (MTD) of RT given in an accelerated fashion with concurrent ChT was investigated. Intensity modulated radiation therapy (IMRT) was used to reduce the risk of esophagitis, the primary dose-limiting toxicity (DLT) with both accelerated RT and concurrent ChT. Materials/Methods: Patients with locally advanced lung cancer (NSCLC and SCLC) with ECOG PS 0e1, weight loss <10%, and adequate hematologic/renal function were treated with concurrent cisplatin (50 mg/m2 days 1, 8, 29, 36) and etoposide (50 mg/m2days 1e5 and 29e33). Radiation therapy treatment planning utilized 4D CT imaging with respiratory motion management; RT was 2 Gy qd, 6 fractions/week (bid on Fridays with 6h interval). Intensity modulated RT with daily image guidance was used to facilitate esophageal avoidance with strict pulmonary constraints. The primary tumor + 5 mm and involved lymph nodes + 3 mm expansions comprised the CTV. The PTV consisted of the CTV + 3 mm expansion. Elective nodal irradiation (ENI) was optional. The dose was escalated from 58 to 74 Gy in 4 Gy increments in a standard 3+3 trial design. Doselimiting toxicity was defined as acute grade 3e5 non-hematologic toxicity. Maximum tolerated dose was defined as dose in which DLT does not occur in more than 1/6 patients. Results: Twenty-four patients were enrolled, filling all dose cohorts, all completing RT and ChT as prescribed. Median age 64 (range, 49e74). M Z 12; F Z 12. NSCLC Z 21; SCLC Z 3. ENI in 13/24 (44 Gy), including 5/6 in 74 Gy cohort. Median (range) dosimetric parameters: Lung V5 Z 43% (18e70), V20 Z 24% (5e39); Esophagus V20 Z 34% (21e65), V60 Z 5% (0e41); heart V5 Z 18% (0e100), V30 Z 4% (0e41), V45 Z 1% (0e29). Dose-limiting toxicity occurred in 1 patient at 58 Gy (grade 3 esophagitis) and 1 patient at 70 Gy (grade 5 esophageal fistula). The first patient had a 12 cm tumor close to the esophagus, and the second had a 10 cm tumor abutting the esophagus. Three additional patients were enrolled at both dose cohorts without further DLT. Zero out of 6 in 74 Gy cohort developed DLT. There was one case of late grade 3 pneumonitis that was self-limited. Conclusion: Dose-escalation to 74 Gy using accelerated RT (6 fractions/ week) with concurrent ChT was achieved. This strategy appears to facilitate the delivery of accelerated RT concurrently with ChT, sparing severe acute esophageal reactions and may improve outcomes for patients with lung cancer. High-grade esophageal complications appeared to be associated with large tumors adjacent to the esophagus. Author Disclosure: C.R. Kelsey: Research Grant; Varian Medical Systems. D.S. Yoo: None. S.K. Das: None. F. Dunphy: None. N. Ready: None. J. Crawford: None. L.B. Marks: None.