Xu Wei Cai

Combining Physical and Biologic Parameters to Predict Radiation-Induced Lung Toxicity in Patients With Non-Small-Cell Lung Cancer Treated With Definitive Radiation Therapy

PURPOSE To investigate the plasma dynamics of 5 proinflammatory/fibrogenic cytokines, including interleukin-1beta (IL-1β), IL-6, IL-8, tumor necrosis factor alpha (TNF-α), and transforming growth factor beta1 (TGF-β1) to ascertain their value in predicting radiation-induced lung toxicity (RILT), both individually and in combination with physical dosimetric parameters. METHODS AND MATERIALS Treatments of patients receiving definitive conventionally fractionated radiation therapy (RT) on clinical trial for inoperable stages I-III lung cancer were prospectively evaluated. Circulating cytokine levels were measured prior to and at weeks 2 and 4 during RT. The primary endpoint was symptomatic RILT, defined as grade 2 and higher radiation pneumonitis or symptomatic pulmonary fibrosis. Minimum follow-up was 18 months. RESULTS Of 58 eligible patients, 10 (17.2%) patients developed RILT. Lower pretreatment IL-8 levels were significantly correlated with development of RILT, while radiation-induced elevations of TGF-ß1 were weakly correlated with RILT. Significant correlations were not found for any of the remaining 3 cytokines or for any clinical or dosimetric parameters. Using receiver operator characteristic curves for predictive risk assessment modeling, we found both individual cytokines and dosimetric parameters were poor independent predictors of RILT. However, combining IL-8, TGF-ß1, and mean lung dose into a single model yielded an improved predictive ability (P<.001) compared to either variable alone. CONCLUSIONS Combining inflammatory cytokines with physical dosimetric factors may provide a more accurate model for RILT prediction. Future study with a larger number of cases and events is needed to validate such findings.

Plasma Proteomic Analysis May Identify New Markers for Radiation-Induced Lung Toxicity in Patients With Non–Small-Cell Lung Cancer

PURPOSE To study whether radiation induces differential changes in plasma proteomics in patients with and without radiation-induced lung toxicity (RILT) of Grade >/=2 (RILT2). METHODS AND MATERIALS A total of 57 patients with NSCLC received radiation therapy (RT) were eligible. Twenty patients, 6 with RILT2 with tumor stage matched to 14 without RILT2, were enrolled for this analysis. Platelet-poor plasma was obtained before RT, at 2, 4, 6 weeks during RT, and 1 and 3 months after RT. Plasma proteomes were compared using a multiplexed quantitative proteomics approach involving ExacTag labeling, reverse-phase high-performance liquid chromatography and nano-LC electrospray tandem mass spectrometry. Variance components models were used to identify the differential protein expression between patients with and without RILT2. RESULTS More than 100 proteins were identified and quantified. After excluding proteins for which there were not at least 2 subjects with data for at least two time points, 76 proteins remained for this preliminary analysis. C4b-binding protein alpha chain, Complement C3, and Vitronectin had significantly higher expression levels in patients with RILT2 compared with patients without RILT2, based on both the data sets of RT start to 3 months post-RT (p < 0.01) and RT start to the end of RT (p < 0.01). The expression ratios of patients with RILT2 vs. without RILT2 were 1.60, 1.36, 1.46, and 1.66, 1.34, 1.46, for the above three proteins, respectively. CONCLUSIONS This proteomic approach identified new plasma protein markers for future studies on RILT prediction.

Comparative survival in patients with postresection recurrent versus newly diagnosed non-small-cell lung cancer treated with radiotherapy.

PURPOSE To compare the survival of postresection recurrent vs. newly diagnosed non-small-cell lung cancer (NSCLC) patients treated with radiotherapy or chemoradiotherapy. METHODS AND MATERIALS The study population consisted of 661 consecutive patients with NSCLC registered in the radiation oncology databases at two medical centers in the United States between 1992 and 2004. Of the 661 patients, 54 had postresection recurrent NSCLC and 607 had newly diagnosed NSCLC. Kaplan-Meier and Cox regression models were used for the survival analyses. RESULTS The distribution of relevant clinical factors between these two groups was similar. The median survival time and 5-year overall survival rates were 19.8 months (95% confidence interval [CI], 13.9-25.7) and 14.8% (95% confidence interval, 5.4-24.2%) vs. 12.2 months (95% CI, 10.8-13.6) and 11.0% (95% CI, 8.5-13.5%) for recurrent vs. newly diagnosed patients, respectively (p = .037). For Stage I-III patients, no significant difference was observed in the 5-year overall survival (p = .297) or progression-free survival (p = .935) between recurrent and newly diagnosed patients. For the 46 patients with Stage I-III recurrent disease, multivariate analysis showed that chemotherapy was a significant prognostic factor for 5-year progression-free survival (hazard ratio, 0.45; 95% CI, 0.224-0.914; p = .027). CONCLUSION Our institutional data have shown that patients with postresection recurrent NSCLC achieved survival comparable to that of newly diagnosed NSCLC patients when they were both treated with radiotherapy or chemoradiotherapy. These findings suggest that patients with postresection recurrent NSCLC should be treated as aggressively as those with newly diagnosed disease.

Baseline Plasma Proteomic Analysis to Identify Biomarkers that Predict Radiation-Induced Lung Toxicity in Patients Receiving Radiation for Non-small Cell Lung Cancer

Purpose: To identify new plasma proteomic markers before radiotherapy start to predict later grade ≥2 radiation-induced lung toxicity (RILT2). Methods: Fifty-seven patients with non-small cell lung cancer received radiotherapy (RT) were eligible. Forty-eight patients with minimum follow-up of 1 year, nine with RILT2 with tumor stage matched to 39 without RILT2, were enrolled for this analysis. Platelet-poor plasma was obtained within 2 weeks before radiotherapy. The plasma proteomes were compared using a multiplexed quantitative proteomics approach involving ExacTag labeling, reverse-phase high-performance liquid chromatography, and nano liquid chromatography electrospray ionization tandem mass spectrometry. Z scores and Bonferroni-adjusted p values for the two-sample mean comparison were used to identify the differential protein expression between patients with and without RILT2. Results: More than 200 proteins were identified and quantified. After excluding proteins that were not detected in at least 40% of the 48 patient samples, C4b-binding protein alpha chain and vitronectin had significantly higher (p < 0.001 and p = 0.02) expression levels in patients with RILT2 compared with patients without RILT2. These two proteins were validated by Western blot. Ingenuity pathway analysis revealed that they both play important roles in the inflammatory response and are associated with the known pathways of radiation-induced lung damage. Conclusions: This proteomic approach demonstrates new plasma protein biomarkers before treatment for future studies on RILT2 prediction.

Semiquantification and Classification of Local Pulmonary Function by V/Q Single Photon Emission Computed Tomography in Patients with Non-small Cell Lung Cancer: Potential Indication for Radiotherapy Planning

Introduction: Perfusion (Q) single photon emission computed tomography (SPECT) has been used to divert dose away from higher-functioning lung during radiation therapy (RT) planning. This study aimed to (1) study regional lung function through coregistered pulmonary ventilation/perfusion (V/Q)-SPECT-CT and (2) classify these defects for its potential value in radiation planning in patients with non-small cell lung cancer (NSCLC). Methods: Patients with stages I to III NSCLC requiring radiation-based therapy were eligible for this prospective study. V/Q-SPECT performed within 2 weeks before the start of radiation was interpreted by nuclear medicine physicians and then measured by a semiquantitative score. The potential mechanism of V and Q defects was analyzed; the potential impact of V/Q-SPECT over Q-SPECT alone was completed through classified applications (high-dose RT versus RT avoidance) during planning. Results: Images of 51 consecutive patients were analyzed. The V and Q defects were matched, reverse mismatched (V defect > Q defect), and mismatched (Q defect > V defect) in 61, 31, and 8% of patients, respectively. Tumor was the leading cause of the defects of ipsilateral lung in 73% of patients. The defect scores of the ipsilateral lung were greater in patients with central primaries than those with peripheral primaries for both V-SPECT (2.3 ± 1.1 versus 1.5 ± 0.8, p = 0.017) and Q-SPECT (2.2 ± 0.8 versus 1.4 ± 0.6, p = 0.000). The patients with chronic obstructive pulmonary disease had greater defect scores in contralateral lung for both V-SPECT (1.5 ± 0.7 versus 1.0 ± 0.8, p = 0.006) and Q-SPECT (1.4 ± 0.6 versus 1.0 ± 0.4, p = 0.010). On assessing the potential value of SPECT on RT plan, 39% of patients could have their RT plan when applying V/Q-SPECT rather than Q-SPECT alone. Conclusions: V/Q-SPECT provides a more comprehensive functional assessment, may provide additional value over Q-SPECT alone in assessing local pulmonary function, and guide RT plan decisions in patients with NSCLC.