Combined Versus Sequential Radiation and Immunotherapy in Advanced Lung Cancer

Volume 99  Number 2S  Supplement 2017 Conclusion: A full range of dose-function metrics and functional thresholds were examined. The AUC values for the most predictive functional models occupied a narrow range (0.66-0.70) and all demonstrated improvements over AUC from traditional lung dose metrics (0.55). Identifying the dose-function parameters most predictive of grade 3+ RP provides valuable data for treatment planning and plan evaluation parameters. With prospective clinical trials of functional guided radiotherapy using 4DCT-ventilation imaging underway, this work provides seminal data to help establish guidelines for the implementation of functional guided radiotherapy. Author Disclosure: A.M. Faught: None. T. Yamamoto: None. R. Castillo: None. E. Castillo: None. J. Zhang: None. M. Miften: None. Y. Vinogradskiy: None.

3081 Tumor Volume Reduction Evaluated by CBCT during SBRT Treatment for Stage I/II NSCLC D.K. Gaines,1 C.B. Simone, II,2 C. Hadzitheodorou,1 S. Kim,3 B. Osorio,1 J. Malhotra,4 K. Nie,3 W. Zou,5 J. Aisner,3 and S.K. Jabbour3; 1Rutgers Cancer Institute of New Jersey, Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, 2University of Maryland Medical Center, Baltimore, MD, 3 Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 4Rutgers University- Robert Wood Johnson Medical School, New Brunswick, NJ, 5 Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA Purpose/Objective(s): Stereotactic body radiation therapy (SBRT) is a standard of care of for high-risk surgical candidates with stage I/II nonsmall cell lung cancer (NSCLC). Despite excellent local control rates with SBRT, the overall survival rates for NSCLC are still suboptimal, with 5year survival rates at approximately at 50-70% and subsets of patients experiencing locoregional and distant recurrences. Several studies across various tumor types have demonstrated the utility of measuring tumor volume reduction (TVR) rates as an effective prognostic marker, but such assessments in SBRT-treated patients are currently lacking. We examined the significance of tumor volume reduction in early stage NSCLC and hypothesized that tumors with a higher TVR rate will be less likely to experience tumor recurrence. Materials/Methods: Under an IRB approved protocol, we retrospectively reviewed 73 patients across 2 institutions that were screened for recurrence of node-negative early stage NSCLC after SBRT. We specifically included patients who experienced local (nZ5), regional (nZ11), and distant (nZ11) recurrences to assess whether TVR would be a useful predictive factor. Gross tumor volume (GTV) was calculated from cone beam computed tomography (CBCT) images taken before each radiation fraction, and these images were also used to calculate TVR which was defined by the percentage change in GTV between the fraction start date and last fraction. Using median TVR, we stratified study participants into 2 main groups: TVR  median reduction and TVR < median reduction. Log rank test was used to statistically analyze survival and recurrence outcomes. Results: Our cohort included 37 men and 35 women with a median age at treatment of 75 years (range 48-90). These patients received a median total radiation dose of 5000cGy (range 4250-6000cGy) over a median of 5 fractions (range 3-5). The median baseline GTV, median post-SBRT GTV and median TVR were 10.28cm3 (range 0.42-93.31 cm3), 8.44cm3 (range 0.25-87.49 cm3), and 10.08%, respectively. Median overall survival was 30.7 months (95% C.I. Z [22.79, -]) for TVR  median reduction and 28.62 months (95% C.I. Z [12.1, -]) for TVR< median reduction (pZ0.473). There were no observed relationships between TVR and local (pZ0.406), regional (pZ0.423), or distant (pZ0.374) recurrences. Conclusion: Our data suggests that TVR is not prognostic for early stage NSCLC. Additional assessment of a larger cohort of patients with and without recurrence is currently being conducted to determine whether TVR can provide additional insight into early stage NSCLC recurrence and overall survival.

Poster Viewing E455 Author Disclosure: D.K. Gaines: None. C.B. Simone: ; Annals of Palliative Medicine, Proton Collaborative Group (PCG). C. Hadzitheodorou: None. S. Kim: None. B. Osorio: None. J. Malhotra: None. K. Nie: None. W. Zou: None. J. Aisner: None. S.K. Jabbour: Research Grant; Merck.

3082 Impact of Esophageal Motion on Dosimetry and Toxicity for Lung Radiation Therapy H. Gao,1 C.R. Kelsey,1 T. Xie,2 S. Catalano,1 X. Wang,3 and F.F. Yin2; 1 Department of Radiation Oncology, Duke University, Durham, NC, 2Duke University Medical Center, Durham, NC, 3Department of Biostatistics and Bioinformatics, Duke University, Durham, NC Purpose/Objective(s): To investigate intra- and inter- fractional esophageal motion as well as correlate dosimetric changes with observed toxicity grade in a phase 1 dose escalation study of accelerated radiotherapy with concurrent chemotherapy for locally advanced lung cancer. Materials/Methods: As part of a prospective study, patients with locally advanced lung cancer underwent 4DCT imaging for RT treatment planning (CT1) and at 2 (CT2) and 5 (CT3) weeks after starting treatment. All patients were treated with IMRT. Each CT consisted of ten 4D phases in addition to a static 3D scan (either free-breathing or breath-hold). The esophagus was independently contoured on all image datasets including all 4D phases. CT2 and CT3 were rigidly registered with CT1 and the dose was recalculated using original IMRT plan to assess the impact of inter-fractional motion on esophageal dosimetry. Similarly, the 4D phases of CT1 were rigidly registered with the static 3D volume of CT1 to assess the impact of intra-fractional motion. The motion analysis was based on the statistical analysis of slice-by-slice center shifts (after registration) for the upper, middle and lower esophagus respectively; the dosimetric analysis compared V20, V60, max dose, equivalent uniform dose (EUD), and normal tissue complication probability (NTCP) in correlation with toxicity grade. Results: This prospective study enrolled 24 patients. Grade 0-1 esophageal toxicity occurred in 10 patients and grade 2-3 toxicity occurred in 14 patients. The esophageal center intra- (inter-) fractional shift was 0.60.4mm (4.41.7mm), 0.70.7mm (5.52.0mm) and 0.90.7mm (4.92.1mm) for upper, middle and lower portions respectively. It was found that high inter-fractional mean V60 and NTCP correlated positively with high toxicity grade: the mean V60 (NTCP) values for grade-0, grade1, grade-2, and grade-3 were 7.8% (10%), 4.6% (7.5%), 7.5% (8.6%) and 31% (26%) respectively. For example, for one patient developing acute grade 3 esophagitis, the mean inter-fractional shifts between CT1 and CT2/ CT3 were 8mm/23mm, 21mm/26mm and 20mm/21mm for upper, middle and lower esophagus respectively; V60 increased from 10% for CT1 to 37% for CT2 and 50% for CT3 respectively; NTCP increased from 16% for CT1 to 43% for both CT2 and CT3. Conclusion: Inter-fractional esophageal motion is significantly larger than intra-fractional motion. High V60 and NTCP incorporating inter-fractional esophageal motion correlate well with high esophageal toxicity grade. Such dose-limiting toxicity for dose escalation could be further reduced by improved on-board 4D imaging and adaptive planning. Author Disclosure: H. Gao: None. C.R. Kelsey: None. T. Xie: None. S. Catalano: None. X. Wang: None. F. Yin: Patent/License Fees/Copyright; Varian Medical Systems, Inc. The business and affairs of the ISRS will be managed by or under the direction of the Board of Directors, which will may exercise all such powers of the ISRS and take all lawful actions not prohibited by the Bylaws.; The International Stereotactic Radiosurger Society. organize act.

3083 Combined Versus Sequential Radiation and Immunotherapy in Advanced Lung Cancer M. Garrett, T.J.C. Wang, and S.K. Cheng; Department of Radiation Oncology, Columbia University Medical Center, New York, NY Purpose/Objective(s): Several clinical and preclinical reports have demonstrated that combined radiation (RT) and immunotherapy activates

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cytotoxic T-cells and reduces immunosuppression by regulatory cells, encouraging abscopal effects for enhanced systemic tumor control. Given the promising finding that RT potentiates the effects of immunotherapy at distant sites, we tested the hypothesis that this combination would improve the time to progression-of-disease (POD) of the primary tumor and/or metastases in patients with Stage III or IV lung cancer. Materials/Methods: We retrospectively analyzed imaging data and radiology reports of 44 patients with Stage III or IV non-small cell (NSCLC) or small cell (SCLC) lung cancers treated with immunotherapy and either concurrent chest RT, prior chest RT, or no prior RT at our institution between March 2015 and November 2016. Immunotherapy was defined as 1 cycle of monoclonal antibodies against cytotoxic T-lymphocyte antigen-4 (CTLA-4) or against programmed death-1 (PD-1). Combined therapy was defined as overlapping time periods of the two treatment modalities, and sequential therapy was defined as chest RT completed prior to onset of immunotherapy. POD was determined by RECIST-defined tumor progression at any site including lung, and/or radiology reports that subsequently led to a change in management. Results: Of 44 patients, 26 (59%) were female, 35 had NSCLC, and the median age was 68 years (range 39-91). The sequential therapy group had 29 patients, the combined group had 6 patients, and the non-RT group had 9 patients. Our analysis failed to demonstrate a significant association between the treatment modality received and time to POD (pZ0.68 on one-way ANOVA). Overall median time to POD was 70 days, and median follow-up time was 379 days. Log rank test of Kaplan-Meier curves also failed to demonstrate a statistically significant difference in time to POD between the three patient groups (pZ0.48). Linear correlation based on age also did not detect a difference in outcome (rZ0.03, pZ0.84 on Pearson’s). Conclusion: Numerous prospective and retrospective analyses of cancer treatment have provided intriguing yet mixed results in time to POD and overall survival following combined immunotherapy and RT. While this study failed to detect a difference in outcomes between concurrent and sequential therapies at one institution, further evaluation within larger patient populations allowing for more sophisticated stratification is an appropriate next step. Author Disclosure: M. Garrett: None. T.J. Wang: Consultant; Doximity, Merck. Advisory Board; American Cancer Society North Jersey. Travel Expenses; Abbvie. S.K. Cheng: None.

and involved nodes were delineated using a gradient-based method (Mim Software PET Edge). PET metrics were metabolic tumor volume (MTV), total lesion glycolysis (TLG), and maximum SUV. For mid-radiotherapy PET, both absolute value of these metrics and percentage decrease were analyzed. The influence of PET metrics on time to death, local recurrence, and regional/distant recurrence was assessed using Cox regression. Results: 91% of patients had concurrent chemotherapy. Median RT dose was 66 Gy in 33 fractions. Median dose at time of mid-RT PET was 34 Gy. Median follow-up was 14 months, and median overall survival was 23 months. None of the nine PET metrics were associated with overall survival. Three were positively associated with local recurrence: pre-radiotherapy MTV, and mid-radiotherapy MTV and TLG (pZ0.01-0.03). One was positively associated with regional/distant recurrence: ratio of mid- to pre-radiotherapy maximum SUV (pZ0.02). 5/77 mid-radiotherapy scans showed early progression, usually in regional nodes. All of these five patients died, 2-23 months after RT start (median 4 months). Conclusion: Higher pre-radiotherapy MTV and higher mid-radiotherapy MTV and TLG were associated with local recurrence, but not overall survival. The findings relating to local recurrence provide support for the ongoing RTOG 1106 trial and other trials examining adaptive radiation therapy. Patients with progression on mid-radiotherapy PET/CT had poor survival, and the optimal management of such patients remains to be determined. Author Disclosure: M.F. Gensheimer: Research Grant; Varian Medical Systems. J.C. Hong: None. C.N. Chang-Halpenny: None. N. Eclov: None. J. To: None. J.D. Murphy: None. H.A. Wakelee: Research Grant; BMS, Celgene, Clovis, Exelixis, Lilly, Novartis, Pfizer, Pharmacyclics, Roche/Genentech, Xcovery. Consultant; Peregrine. Advisory Board; Gilead, Pfizer. ; International Thymic Malignancies Interest Group. J.W. Neal: Research Grant; Genentech, Merck, Arqule, Exelixis. Honoraria; Clovis, CARET/Physicians Resource Mgmt., Nektar, BI. Q. Le: Research Grant; Amgen. Travel Expenses; BMS. Stock; Aldea. chair of head and neck committee- design clinical trial; RTOG NRG Cooperative group. president elect; American Radium Society. W. Hara: task force member; NCI Metastatic and Recurrent Head & Neck Task Forc. A. Quon: None. P.G. Maxim: None. E.E. Graves: Research Grant; Varian Biosynergy. ; Society of Nuclear Medicine. M.R. Olson: None. M. Diehn: Employee; Kaiser Permanente. Consultant; Roche. Stock; CiberMed. Stock Options; Quanticel Pharmaceuticals. B.W. Loo: Research Grant; RaySearch, Varian Medical Systems Inc. Stock; TibaRay, Inc.. ; American College of Radiology, National Comprehensive Cancer Network, TibaRay, Inc..

3084 Mid-radiation Therapy PET/CT for Prognostication and Detection of Early Progression in Patients With Stage III Nonesmall Cell Lung Cancer M.F. Gensheimer,1 J.C. Hong,2 C.N. Chang-Halpenny,3 N. Eclov,4 J. To,5 J.D. Murphy,6 H.A. Wakelee,1 J.W. Neal,1 Q.T. Le,7 W. Hara,8 A. Quon,9 P.G. Maxim,10 E.E. Graves,11 M.R. Olson,12 M. Diehn,1 and B.W. Loo Jr1; 1 Stanford Cancer Institute, Stanford, CA, 2Duke University Medical Center, Durham, NC, 3Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA, 4Stanford University, Stanford, CA, United States, 5 University of Colorado Denver, Aurora, CO, 6University of California, San Diego, La Jolla, CA, 7Stanford University, Stanford, CA, 8Stanford Radiation Oncology, Stanford, CA, 9University of California Los Angeles, Los Angeles, CA, 10Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, 11Stanford University Department of Radiation Oncology, Stanford, CA, 12Baptist Medical Center, Jacksonville, FL Purpose/Objective(s): Pre- and mid-radiotherapy FDG-PET metrics have been proposed as biomarkers of recurrence and survival in patients treated for stage III non-small cell lung cancer (NSCLC). We evaluated these metrics in patients treated with definitive radiation therapy (RT). We also evaluated outcomes of patients who had progression on mid-radiotherapy PET/CT. Materials/Methods: Seventy-seven patients treated with RT with or without chemotherapy for stage III NSCLC were included in this retrospective study. All patients had pre- and mid-RT PET/CT. Primary tumor

3085 International Collaborative Propensity-Based Matched Pair Analysis of Operable Early Stage Lung Ancer Patients Treated with Stereotactic Body Radiation Therapy Compared to Resection: Differences in Recurrence and Survival with Prolonged Follow-Up I.S. Grills,1 K.C. Lee Jr,2 J. Belderbos,3 A.J. Hope,4 M.E. Giuliani,5 M. Guckenberger,6 F. Mantel,7 M. Werner-Wasik,8 H.M. Peulen,3 J.J. Sonke,9 D. Yan,2 R.V. Hymas Jr,2 A. Caruso,2 N. Abro,2 M.C. Johnson,2 E. Abbott,2 H. Ye,2 and R. Welsh2; 1Department of Radiation Oncology, Beaumont Health System, Royal Oak, MI, 2Beaumont Health, Royal Oak, MI, 3NKI-AvL, Amsterdam 1066 CX, Netherlands, 4 Department of Radiation Oncology, Princess Margaret Cancer Centre/ University of Toronto, Toronto, ON, Canada, 5Princess Margaret Cancer Centre, Toronto, ON, Canada, 6University Hospital Zuerich, Zuerich, Switzerland, 7University Hospital Wuerzberg, Wuerzberg, Germany, 8 Sidney Kimmel Medical College at Thomas Jefferson University, Sidney Kimmel Cancer Center, Philadelphia, PA, 9The Netherlands Cancer Institute (NKI-AVL), Amsterdam, Netherlands Purpose/Objective(s): Compare outcomes for operable patients treated with SBRT to resection. Materials/Methods: An international collaborative pooled 1298 T1-T2N0 NSCLC lung cancers from 5 centers treated with SBRT to a median PTV