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Sequential Versus Concurrent Chemoradiotherapy for Post-Operative pN2-N3 Non–Small Cell Lung Cancer
S106
International Journal of Radiation Oncology Biology Physics
228
Purpose/Objective(s): The most effective sequencing of adjuvant therapies for resected pN2-N3 non-small cell lung cancers (NSCLCs) is controversial. While several feasibility studies have demonstrated safety of concurrent chemoradiotherapy, it remains uncertain whether this approach is superior to sequential treatment with chemotherapy followed by postoperative radiotherapy (PORT). We sought determine the most effective treatment sequence. Materials/Methods: Using the National Cancer Database, we selected a cohort of patients with non-metastatic NSCLC who received at lobectomy with pN2-N3 disease. We excluded patients with grossly positive margins, those who did not receive adjuvant multiagent chemotherapy and radiation, and those who died within 3 months of diagnosis. Patient demographics were compared with Chi-squared analysis. Univariate (UV) and multivariate (MV) Cox regression were used to identify factors associated with overall survival (OS). UVA and MVA logistic regression were used to identify predictors for adjuvant treatment sequence. A propensity score (PS) matched analysis was done to account for confounding covariates. Results: A total of 1,661 patients were included for analysis with a median follow-up of 28.2 months (95% Confidence Interval [CI] Z 6.9 e 81.6 months). Seven-hundred twenty four patients received chemotherapy followed by PORT (C/PORT) and 937 patients received concurrent chemoradiotherapy (CRT). On Cox MV, CRT was associated with worse survival compared to C/PORT (HR 1.3, P<0.01). Additional factors associated with worse survival included increasing age, higher Charlson comorbidity score, increasing primary tumor size, unknown margin status, pN3 disease, and histology coded as NSCLC not otherwise specified. Female gender was associated with improved survival (HR 0.8, P<0.01). The median OS was 47.3 months (95% CI 41.5 e 53.6 months) for C/PORT vs. 33.4 months (95% CI 31.2 e 36.6 months) for CRT (Logrank, P<0.01). On logistic MV, unknown grade was the only predictor for receipt of CRT (OR 3.2, P Z 0.03), while treatment at an academic/ research program (OR 0.6, P Z 0.04) or integrated cancer center (OR 0.3, P<0.01) were predictors for C/PORT. After PS matching, a cohort of 922 patients was analyzed. Sequential C/PORT again was associated with improved OS compared to CRT (Shared frailty, HR 1.3, P Z 0.003). Conclusion: In the setting of post-operative NSCLC patients with pN2-N3 disease without grossly positive margins, sequential C/PORT was associated with improved overall survival compared to concurrent CRT. Author Disclosure: S. Francis: None. A. Orton: None. Y.J. Hitchcock: None. W. Akerley: None. K.E. Kokeny: Consultant; Merit Medical. Speaker’s Bureau; Merit Medical. Stock; Merit Medical, Bard.
Variations in Initiation Dates of Chemotherapy and Radiation Therapy is Associated With Decreases in Overall Survival M.P. Deek,1 S. Kim,1 R. Beck,2 J. Malhotra,1 O.M.E.E. Mahmoud,3 J. Aisner,1 and S.K. Jabbour1; 1Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 2Rutgers Cancer Institute of New Jersey, Department of Radiation Oncology, New Brunswick, NJ, 3Rutgers Newark University Hospital, Newark, NJ Purpose/Objective(s): The standard of care for unresectable Stages II and III non-small cell lung cancer (NSCLC) is concurrent chemoradiation therapy (CRT). In trials evaluating concurrent CRT, the national oncology cooperative group protocols historically have dictated that concurrent CRT begins on the same day. However, logistical barriers sometimes make it difficult for patients to begin CRT simultaneously, which can result in variations in the start dates of each therapy. We hypothesized that differences in initiation of chemotherapy and radiotherapy would show an adverse effect upon overall survival (OS) for NSCLC. Materials/Methods: Cases of Stage II and III NSCLC treated with CRT were obtained from the National Cancer Data Base participant user file from 2003 to 2011. Kaplan-Meier curves were computed for subjects. Curves were stratified to compare those who started CRT within six days of each other versus those who started seven to 13 days of each other. Curves were also stratified to compare those who started therapy within three days of each other versus those who started therapy within four to six days of each other. Survival analysis was carried out with Cox Proportional Hazards models. Propensity score matching was conducted in an attempt to reduce bias. Results: A total of 11,119 patients were available for analysis. Median OS for patients who started dual therapy within six days of each other was 18.3 months (95% CI [17.8 - 18.8]) compared to 16.5 months (95% CI [15.3 17.6]) in those who started dual therapy 7-13 days apart (P Z 0.006). On multivariate analysis, starting dual therapy seven or more days apart remained significantly associated with worse OS. In a propensity matched population, median OS in those who started treatment within six days was 18.3 months (95% CI [17.6 e 19.0]) compared 16.5 months (95% CI [15.4 e 17.6]; P Z 0.028) for those who started treatment within seven to 13 days of each other. Furthermore, patients who started dual therapy on the same day to up to three days apart (18.5 months; 95% CI [17.97 19.03]) had superior survival rates compared to patients starting therapy 4 to 6 days apart (17.4 months; 95% CI [16.13 - 18.73]; P Z 0.032). On multivariate analysis, starting dual therapy within 4-6 days of each other continued to be associated with worse mortality (HR 1.07; 95% CI [0.999, 1.137]; P Z 0.054) compared to starting therapy within 0-3 days. In a matched cohort, the median OS difference between those who started treatment within 0-3 days (18.4 months; 95% CI [17.51 e 19.32]) compared to 4-6 days (17.5 months; 95% CI [16.13 e 18.73 months]) was marginally significant (P Z 0.078). Conclusion: Relatively minor variations in non-simultaneous initiation of both chemotherapy and RT can affect the OS of patients undergoing definitive CRT for NSCLC. Further efforts to understand mitigating factors and barriers that interfere with timely delivery of concurrent CRT are needed. Author Disclosure: M.P. Deek: None. S. Kim: None. R. Beck: None. J. Malhotra: None. O.M. Mahmoud: None. J. Aisner: None. S.K. Jabbour: Research Grant; Merck.
229 Sequential Versus Concurrent Chemoradiotherapy for Post-Operative pN2-N3 NoneSmall Cell Lung Cancer S. Francis,1,2 A. Orton,3 Y.J. Hitchcock,2 W. Akerley,4 and K.E. Kokeny2; 1 Huntsman Cancer Institute, Salt Lake City, UT, 2University of Utah Huntsman Cancer Institute, Salt Lake City, UT, 3Huntsman Cancer Hospital, University of Utah, Salt Lake City, UT, 4Huntsman Cancer Hospital, Salt Lake City, UT
230 Can Robust Optimization for Range Uncertainty in Proton Therapy Act as a Surrogate for Biological Optimization? D. Giantsoudi,1,2 J. Unkelbach,3 P. Botas,1,4 C. Grassberger,2,5 and H. Paganetti2,5; 1Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, 2Harvard Medical School, Boston, MA, 3 University Hospital Zurich, Radiation Oncology, Zurich, Switzerland, 4 Heidelberg University, Heidelberg, Germany, 5Massachusetts General Hospital - Harvard Medical School, Radiation Oncology, Boston, MA Purpose/Objective(s): To investigate how robust optimization (to address range uncertainties) affects the dose and linear energy transfer (LET) distribution in the target and organs at risk (OARs) compared to LET-based inverse optimization (to address relative biological effectiveness - RBE effects) in intensity modulated proton therapy (IMPT). Materials/Methods: A GPU-based Monte Carlo code was used to calculate both physical dose and dose-averaged LET for all pencil beams for IMPT proton plans for previously treated ependymoma patients. The plans were initially optimized based on physical dose constraints. A previously developed LET-based optimization algorithm, using a prioritized optimization scheme, was then applied to modify the LET distribution while constraining the physical dose objectives within 3% of the initial plan. The objective functions for this step were based on the product of LET and physical dose (LETxD) as an approximation of the additional biological
International Journal of Radiation Oncology Biology Physics
228
Purpose/Objective(s): The most effective sequencing of adjuvant therapies for resected pN2-N3 non-small cell lung cancers (NSCLCs) is controversial. While several feasibility studies have demonstrated safety of concurrent chemoradiotherapy, it remains uncertain whether this approach is superior to sequential treatment with chemotherapy followed by postoperative radiotherapy (PORT). We sought determine the most effective treatment sequence. Materials/Methods: Using the National Cancer Database, we selected a cohort of patients with non-metastatic NSCLC who received at lobectomy with pN2-N3 disease. We excluded patients with grossly positive margins, those who did not receive adjuvant multiagent chemotherapy and radiation, and those who died within 3 months of diagnosis. Patient demographics were compared with Chi-squared analysis. Univariate (UV) and multivariate (MV) Cox regression were used to identify factors associated with overall survival (OS). UVA and MVA logistic regression were used to identify predictors for adjuvant treatment sequence. A propensity score (PS) matched analysis was done to account for confounding covariates. Results: A total of 1,661 patients were included for analysis with a median follow-up of 28.2 months (95% Confidence Interval [CI] Z 6.9 e 81.6 months). Seven-hundred twenty four patients received chemotherapy followed by PORT (C/PORT) and 937 patients received concurrent chemoradiotherapy (CRT). On Cox MV, CRT was associated with worse survival compared to C/PORT (HR 1.3, P<0.01). Additional factors associated with worse survival included increasing age, higher Charlson comorbidity score, increasing primary tumor size, unknown margin status, pN3 disease, and histology coded as NSCLC not otherwise specified. Female gender was associated with improved survival (HR 0.8, P<0.01). The median OS was 47.3 months (95% CI 41.5 e 53.6 months) for C/PORT vs. 33.4 months (95% CI 31.2 e 36.6 months) for CRT (Logrank, P<0.01). On logistic MV, unknown grade was the only predictor for receipt of CRT (OR 3.2, P Z 0.03), while treatment at an academic/ research program (OR 0.6, P Z 0.04) or integrated cancer center (OR 0.3, P<0.01) were predictors for C/PORT. After PS matching, a cohort of 922 patients was analyzed. Sequential C/PORT again was associated with improved OS compared to CRT (Shared frailty, HR 1.3, P Z 0.003). Conclusion: In the setting of post-operative NSCLC patients with pN2-N3 disease without grossly positive margins, sequential C/PORT was associated with improved overall survival compared to concurrent CRT. Author Disclosure: S. Francis: None. A. Orton: None. Y.J. Hitchcock: None. W. Akerley: None. K.E. Kokeny: Consultant; Merit Medical. Speaker’s Bureau; Merit Medical. Stock; Merit Medical, Bard.
Variations in Initiation Dates of Chemotherapy and Radiation Therapy is Associated With Decreases in Overall Survival M.P. Deek,1 S. Kim,1 R. Beck,2 J. Malhotra,1 O.M.E.E. Mahmoud,3 J. Aisner,1 and S.K. Jabbour1; 1Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 2Rutgers Cancer Institute of New Jersey, Department of Radiation Oncology, New Brunswick, NJ, 3Rutgers Newark University Hospital, Newark, NJ Purpose/Objective(s): The standard of care for unresectable Stages II and III non-small cell lung cancer (NSCLC) is concurrent chemoradiation therapy (CRT). In trials evaluating concurrent CRT, the national oncology cooperative group protocols historically have dictated that concurrent CRT begins on the same day. However, logistical barriers sometimes make it difficult for patients to begin CRT simultaneously, which can result in variations in the start dates of each therapy. We hypothesized that differences in initiation of chemotherapy and radiotherapy would show an adverse effect upon overall survival (OS) for NSCLC. Materials/Methods: Cases of Stage II and III NSCLC treated with CRT were obtained from the National Cancer Data Base participant user file from 2003 to 2011. Kaplan-Meier curves were computed for subjects. Curves were stratified to compare those who started CRT within six days of each other versus those who started seven to 13 days of each other. Curves were also stratified to compare those who started therapy within three days of each other versus those who started therapy within four to six days of each other. Survival analysis was carried out with Cox Proportional Hazards models. Propensity score matching was conducted in an attempt to reduce bias. Results: A total of 11,119 patients were available for analysis. Median OS for patients who started dual therapy within six days of each other was 18.3 months (95% CI [17.8 - 18.8]) compared to 16.5 months (95% CI [15.3 17.6]) in those who started dual therapy 7-13 days apart (P Z 0.006). On multivariate analysis, starting dual therapy seven or more days apart remained significantly associated with worse OS. In a propensity matched population, median OS in those who started treatment within six days was 18.3 months (95% CI [17.6 e 19.0]) compared 16.5 months (95% CI [15.4 e 17.6]; P Z 0.028) for those who started treatment within seven to 13 days of each other. Furthermore, patients who started dual therapy on the same day to up to three days apart (18.5 months; 95% CI [17.97 19.03]) had superior survival rates compared to patients starting therapy 4 to 6 days apart (17.4 months; 95% CI [16.13 - 18.73]; P Z 0.032). On multivariate analysis, starting dual therapy within 4-6 days of each other continued to be associated with worse mortality (HR 1.07; 95% CI [0.999, 1.137]; P Z 0.054) compared to starting therapy within 0-3 days. In a matched cohort, the median OS difference between those who started treatment within 0-3 days (18.4 months; 95% CI [17.51 e 19.32]) compared to 4-6 days (17.5 months; 95% CI [16.13 e 18.73 months]) was marginally significant (P Z 0.078). Conclusion: Relatively minor variations in non-simultaneous initiation of both chemotherapy and RT can affect the OS of patients undergoing definitive CRT for NSCLC. Further efforts to understand mitigating factors and barriers that interfere with timely delivery of concurrent CRT are needed. Author Disclosure: M.P. Deek: None. S. Kim: None. R. Beck: None. J. Malhotra: None. O.M. Mahmoud: None. J. Aisner: None. S.K. Jabbour: Research Grant; Merck.
229 Sequential Versus Concurrent Chemoradiotherapy for Post-Operative pN2-N3 NoneSmall Cell Lung Cancer S. Francis,1,2 A. Orton,3 Y.J. Hitchcock,2 W. Akerley,4 and K.E. Kokeny2; 1 Huntsman Cancer Institute, Salt Lake City, UT, 2University of Utah Huntsman Cancer Institute, Salt Lake City, UT, 3Huntsman Cancer Hospital, University of Utah, Salt Lake City, UT, 4Huntsman Cancer Hospital, Salt Lake City, UT
230 Can Robust Optimization for Range Uncertainty in Proton Therapy Act as a Surrogate for Biological Optimization? D. Giantsoudi,1,2 J. Unkelbach,3 P. Botas,1,4 C. Grassberger,2,5 and H. Paganetti2,5; 1Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, 2Harvard Medical School, Boston, MA, 3 University Hospital Zurich, Radiation Oncology, Zurich, Switzerland, 4 Heidelberg University, Heidelberg, Germany, 5Massachusetts General Hospital - Harvard Medical School, Radiation Oncology, Boston, MA Purpose/Objective(s): To investigate how robust optimization (to address range uncertainties) affects the dose and linear energy transfer (LET) distribution in the target and organs at risk (OARs) compared to LET-based inverse optimization (to address relative biological effectiveness - RBE effects) in intensity modulated proton therapy (IMPT). Materials/Methods: A GPU-based Monte Carlo code was used to calculate both physical dose and dose-averaged LET for all pencil beams for IMPT proton plans for previously treated ependymoma patients. The plans were initially optimized based on physical dose constraints. A previously developed LET-based optimization algorithm, using a prioritized optimization scheme, was then applied to modify the LET distribution while constraining the physical dose objectives within 3% of the initial plan. The objective functions for this step were based on the product of LET and physical dose (LETxD) as an approximation of the additional biological