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D. Sher



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    O02 - NSCLC - Combined Modality Therapy I (ID 111)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Combined Modality
    • Presentations: 1
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      O02.06 - Predictors of trimodality therapy use and overall survival in patients with stage III non-small cell lung cancer (NSCLC) in the National Cancer Database (ID 1736)

      11:25 - 11:35  |  Author(s): D. Sher

      • Abstract
      • Presentation
      • Slides

      Background
      The optimal locoregional therapy for stage III non-small cell lung cancer is controversial, with definitive chemoradiotherapy (CRT) and trimodality therapy (chemoradiotherapy followed by surgery, TMT) serving as competing strategies. The implementation of TMT and resultant survival outcomes in routine United States clinical practice has not been closely examined. In this study, we used the National Cancer Database (NCDB) to determine predictors of TMT and compare overall survival (OS) among a large cohort of stage III NSCLC patients treated with CRT or TMT.

      Methods
      Patients included were stage III NSCLC patients who received concurrent CRT with or without subsequent surgical resection at Commission on Cancer-accredited programs between 1998 and 2010; survival data were available for patients treated through 2005. High-volume (HV) center was defined as the upper decile. Per NCDB coding, treatment centers were stratified into academic, comprehensive, and non-comprehensive community cancer center (CCC). Logistic regression was used for univariable analyses, and multivariable models were prepared using stepwise selection to determine demographic, clinical and non-clinical predictors of TMT use and overall survival. Propensity score matching was used to estimate treatment effect and to minimize the effect of confounding variables.

      Results
      The overall cohort consisted of 49,534 patients, 25,679 of whom also had available survival data. Trimodality therapy was delivered in 7.8% of patients. Multivariable clinical predictors of TMT included: white race (OR 1.36), younger age (lowest [LQ] vs highest [HQ] quartile, OR 4.31), high school education or higher (HQ vs LQ, OR 1.37), stage IIIA vs IIIB, (OR 3.02) and squamous histology (OR 1.26). Non-clinical variables associated with TMT included: early treatment era (first vs last 3 years, OR 1.30), private insurance (OR 1.53), increasing distance from the treatment center (HQ vs LQ, OR 1.81), geography (Northeast vs. other, OR 1.35), treatment at academic research programs (ARP) over comprehensive CCC or non-comprehensive CCC (OR 1.53 and 2.01, respectively), and HV institution (OR 1.26). The median, 3- and 5-year OS were 12.3 months, 17% and 9.6%, respectively. Univariable comparison between CRT and TMT showed OS benefit with TMT (median 26.1 vs 11.7 months, log rank p<0.001). On MVA, stage IIIA (hazard ratio, HR, 0.85), squamous histology (HR 0.97), young age (HR 0.74) , female gender (HR 0.86), non-white race (HR 0.90), higher income (HQ vs LQ HR 0.76), farther distance from treatment center (HR 0.93), more recent treatment era (HR 0.80 vs. first 2 time periods) and TMT (HR 0.49) were significantly associated with improved OS. ARP was significantly associated with superior OS (HR 0.92 vs. CCP) if TMT was not in the Cox model. After propensity matching, TMT was still associated with improved OS (HR 0.62, p<0.001).

      Conclusion
      The use of TMT was strongly associated with markers of higher socioeconomic status and treatment at high-volume and academic centers. These data further support a significant survival benefit in patients undergoing TMT, and treatment at academic centers may improve OS via increased use of TMT.

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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.06-052 - Biomarkers of phenotypic plasticity associated with clinical outcomes in patients with locally-advanced NSCLC treated with chemoradiation with and without surgery. (ID 3019)

      09:30 - 09:30  |  Author(s): D. Sher

      • Abstract

      Background
      Thoracic chemoradiotherapy (CRT) with or without surgery (S) is the standard-of-care in management of stage III NSCLC. However, it appears that plateau has been reached. New treatment strategies are needed. The objective of this retrospective study was to evaluate the relationships between patient outcomes and expression of biomarkers associated with either the epithelial-to-mesenchymal transition, or EMT ( E-cadherin and vimentin), or a lung cancer “stem-cell” phenotype (CD133), DNA repair enzyme (ERCC1), and cell survival/apoptosis (BCL-2, surviving and PTEN) in attempt to identify new therapeutic strategies.

      Methods
      Stage III NSCLC pts who were treated with chest radiation (40-65Gy) and concurrently with platinum doublet and who had sufficient pretreatment tissue were included in this study. Surgical pts received 40-45 Gy of radiation preoperatively and non-surgical patients received 60-65 Gy. Immunohistochemistry was used to detect nuclear and cytoplasmic expression of ERCC1, bcl-2, survivin, PTEN, vimentin, E-cadherin, and CD133. Scores were calculated using the Allred scoring system. The log-rank tests used to evaluate progression free survival (PFS) and overall survival (OS) with Kaplan-Meier plots used to plot group characteristics.

      Results
      A total of 119 patients receiving chemoradiotherapy with adequate tumor specimens for analysis were enrolled in this study; 61 had definitive chemoradiation whereas 58 had pulmonary resection after chemoradiation. Patients (n=79) with low nuclear survivin immunostaining (score ≤6) had significantly improved PFS as compared to those patients (n=34) with higher expression levels (14.1 vs. 10.5 months, p=0.042). Patients (n=72) with a cytoplasmic vimentin score ≤ 5 had superior PFS than the with higher expression levels (n=33) (13.17 vs. 9.99 months, p=0.045). High nuclear ERCC1 values (n=72) were associated with a worse OS than those patients (n=44) with low immunostaining (22.7 vs. 59.1 months; p=0.023). Patients with low cytoplasmic E-cadherin (n=25) had a significantly better OS than those patients (n=85) with immunostaining scores (62.6 vs. 24.6 months, p=0.036). The cytoplasmic vimentin/ E-cadherin ratio provided the most impressive separation of cohort performance with high V/E ratios being associated with a poor PFS (12.6 vs. 3.1 months; score ratio 10 cutoff; p=0.00073). No significant associations with cytoplasmic CD133 were observed in this cohort for either PFS or OS.

      Conclusion
      The association of inferior overall survival in locally-advanced NSCLC patients whose tumors express high ERCC1, high cytoplasmic E-cadherin (which is associated with mesenchymal phenotype and lower adherence of cells which are able to metastasize easier), and lower progression free survival with high survivin and high vimentin/ E-cadherin ratio suggests that combining inhibitors of survivin, DNA repair, EMT pathways might improve outcomes in molecularly defined subset of stage III NSCLC patients.