Y. Zhuang

Improved survival outcomes with the incidental use of beta-blockers among patients with non-small-cell lung cancer treated with definitive radiation therapy

BACKGROUND Preclinical studies have shown that norepinephrine can directly stimulate tumor cell migration and that this effect is mediated by the beta-adrenergic receptor. PATIENTS AND METHODS We retrospectively reviewed 722 patients with non-small-cell lung cancer (NSCLC) who received definitive radiotherapy (RT). A Cox proportional hazard model was utilized to determine the association between beta-blocker intake and locoregional progression-free survival (LRPFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS). RESULTS In univariate analysis, patients taking beta-blockers (n = 155) had improved DMFS (P < 0.01), DFS (P < 0.01), and OS (P = 0.01), but not LRPFS (P = 0.33) compared with patients not taking beta-blockers (n = 567). In multivariate analysis, beta-blocker intake was associated with a significantly better DMFS [hazard ratio (HR), 0.67; P = 0.01], DFS (HR, 0.74; P = 0.02), and OS (HR, 0.78; P = 0.02) with adjustment for age, Karnofsky performance score, stage, histology type, concurrent chemotherapy, radiation dose, gross tumor volume, hypertension, chronic obstructive pulmonary disease and the use of aspirin. There was no association of beta-blocker use with LRPFS (HR = 0.91, P = 0.63). CONCLUSION Beta-blocker use is associated with improved DMFS, DFS, and OS in this large cohort of NSCLC patients. Future prospective trials can validate these retrospective findings and determine whether the length and timing of beta-blocker use influence survival outcomes.

Risk factors for local and regional recurrence in patients with resected N0–N1 non-small-cell lung cancer, with implications for patient selection for adjuvant radiation therapy

BACKGROUND The purpose of this study was to evaluate the actuarial risk of local and regional failure in patients with completely resected non-small-cell lung cancer (NSCLC), and to assess surgical and pathological factors affecting this risk. PATIENTS AND METHODS Between January 1998 and December 2009, 1402 consecutive stage I-III (N0-N1) NSCLC patients underwent complete resection without adjuvant radiation therapy. The median follow-up was 42 months. RESULTS Local-regional recurrence was identified in 9% of patients, with local failure alone in 3% of patients, regional failure alone in 4% of patients, and both local and regional failure simultaneously in 2% of patients. Patients who had local failure were found to be at increased risk of mortality. By multivariate analyses, three variables were shown to be independently significant risk factors for local [surgical procedure (single/multiple wedges+segmentectomy versus lobectomy+bilobectomy+pneumonectomy), tumor size>2.7 cm, and visceral pleural invasion] and regional (pathologic N1 stage, visceral pleural invasion, and lymphovascular space invasion, LVI) recurrence, respectively. CONCLUSION Patients with N0-N1 disease have low rates of locoregional recurrence after surgical resection. However, several prognostic factors can be identified that increase this risk and identify patients who may benefit from adjuvant treatment.

Predictors of Site-Specific Distant Metastasis After Definitive Radiation Therapy in Non-Small Cell Lung Cancer and the Impact of Metastatic Location on Survival

Purpose/Objective(s): Systemic lymphocyte count has been established as prognostic in numerous cancer types. Of relevance is the ability of low dose radiation therapy (RT) to induce death in circulating lymphocytes despite the mitotic inactivity of this cell type. We sought to investigate the potential causes of RT-induced lymphopenia and its associations with patient outcomes in non-small cell lung cancer (NSCLC). Materials/Methods: Subjects were 711 patients who had received definitive RT for NSCLC with 2 lymphocyte measurements during RT. A lymphocyte nadir was defined as the minimum systemic lymphocyte value during RT. Associations between gross tumor volumes (GTVs) and lung dose-volume histogram (DVH) parameters with lymphocyte nadirs were assessed with Spearman’s correlations. Relationships between lymphocyte nadirs with overall survival (OS) and event free survival (EFS) were evaluated with Kaplan-Meier analysis and log-rank tests. Stepwise multivariate regression was conducted with linear and Cox regressions. All variables were analyzed as continuous if possible. Results: Analyses of lung DVH parameters revealed significant correlation with lymphocyte nadir at lower doses (lung v5-10: P 0.05). Lung v5 were lower in patients receiving proton therapy (Median: 30.4%) compared with 3D conformal (Median: 55.6%, P<0.0001) and intensity modulated (Median: 55.4%, P<0.0001) RT. Similarly, larger GTVs were correlated with lower lymphocyte nadirs regardless of concurrent chemotherapy receipt (with concurrent: r Z –0.26, P<0.0001; without: r Z –0.48, P<0.0001). GTV and lung DVH parameters were not associated with other treatment nadirs in other hematopoietic populations (total leukocyte, neutrophil, or monocyte) nor were they associated with pre-RT lymphocyte count. Multivariate analysis revealed GTV (P<0.0001), lung v5 (P<0.0001), receipt of concurrent chemotherapy (P Z 0.001), and twice-daily fractionation (P Z 0.0002) to be associated with lower lymphocyte nadirs. With regard to patient outcomes, univariate analyses revealed lower lymphocyte nadirs to be associated with worse OS (hazard ratio [HR] Z 1.96 per 10 lymphocytes/mL, P Z 0.01) and EFS (HR Z 2.17 per 10 lymphocytes/mL, P<0.0001). Differences held on multivariate analyses controlling for disease and treatment characteristics including GTV. Conclusions: GTV and Lung v5 were associated with lower lymphocyte nadirs, while lower lymphocyte nadirs were predictive of worse patient outcomes. If validated, further investigations should focus on techniques that minimize this “low dose bath.” Author Disclosure: C. Tang: None. Z. Liao: None. D. Gomez: None. L. Levy: None. Z. Yan: None. X. Ting: None. Q. Nguyen: None. R. Komaki: None. J. Welsh: None.

Prognostic Factors for Overall Survival in Stage IIIA/IIIB Non-small Cell Lung Cancer After Definitive (Chemo)radiation Therapy

frequently develop acute esophageal toxicity (AET). Studies investigating the dose-effect relationship with qualitative AET scores have resulted in a wide range of dosimetric predictive parameters, while the underlying biological processes and local dose-effect relation have not been investigated. The purpose of this study was to correlate the planned dose distribution to post-CRT local esophageal FDG-PET uptake as a surrogate for local inflammation, and subsequently utilize the derived local dose-effect for AET prediction. Material/Methods: Patients treated with 24 x 2.75 Gy IMRT plus daily low dose Cisplatin and having a post-RT PET (PETpost) scan acquired within 3 months after cCRT were retrospectively selected. The outer wall of the esophagus was delineated on the planning CT and propagated to the PETpost-CT through deformable registration. The value of PETpost in relation to AET was evaluated by comparing the mean esophageal SUVof the highest 50% (SUV50%) between gr 50 Gy were associated with elevated FDG uptake, when the PETpost was acquired within 4 weeks after cCRT. After 4 weeks no dose effect was observed. The derived local dose effect model parameters, based on data acquired within 4 weeks (nZ47), were D50 Z 93 Gy and k Z 9.4. The SUV50% was significantly higher for gr 2 AET (2.2 vs. 2.7, pZ0.008). The average DPET was 54.1 Gy (1SDZ11.3) for gr<2, and 60.3 Gy (1SDZ4.3) for gr 2 AET (pZ0.001). DPET based prediction of AET gr 2 had the highest likelihood compared to Dmean (pZ0.06), V35 (pZ0.05) and V60 (pZ0.29). Conclusions: Esophageal uptake of FDG post-cCRT is associated with acute esophageal toxicity, and was only observed for RT dose above 50Gy. Predictability of grade 2 AET was improved by using the derived local relation between RT dose and PETpost SUV. With this biological response model, planning constraints onand predictability of AET can be done more accurately. Author Disclosure: J. Nijkamp: None. M. Rossi: None. J. Belderbos: None. W. Uyterlinde: None. M. Kwint: None. M. van den Heuvel: None. W. Vogel: None. J. Sonke: None.