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F.(. Kong



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    MO25 - NSCLC - Combined Modality Therapy II (ID 112)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
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      MO25.10 - A Phase II trial of mid-treatment FDG-PET adaptive, individualized radiation therapy plus concurrent chemotherapy in patients with inoperable non-small cell lung cancer (NSCLC) (ID 3461)

      11:25 - 11:30  |  Author(s): F.(. Kong

      • Abstract
      • Presentation
      • Slides

      Background
      We hypothesized that individualized radiation treatment targeting to the FDG-avid tumor identified mid-treatment would improve local tumor control.

      Methods
      This is a phase II trial for patients with inoperable/unresectable NSCLC. Conformal radiotherapy (RT) was given in 30 daily fractions. RT dose was individualized to a fixed rate of grade >2 lung toxicity and adaptively escalated to the residual tumor on mid-tx FDG-PET upto a total dose of 86 Gy. Patients were given concurrent weekly followed by consolidation carboplatin/paclitaxel. The primary endpoint was local-regional tumor control (LRTC) and local-regional progression free survival (LRPFS) at 2 years.

      Results
      42 patients were enrolled: median age 63 years (range 45-83); 28 (67%) male; 39 (93%) smokers; 38 (92%) stage III; and 45% squamous cell. Median physical dose reached was 83 Gy (range 63-86 Gy), equivalent to 90 Gy in 2 Gy fractions (biological effective dose 107 Gy). Minimum and median follow-up were 9 and 27 months, respectively. The 2-year rates of in-field LRTC, overall LRTC, and LR-PFS were 84% (62-94%), 61% (39-77%), and 37% (22-52%), respectively. 15 patients progressed: 2 (13%) at primary tumor alone; 4 (27%) first at distant sites alone; 2 (13%) at nodal regions alone; 5 (33%) at both distant sites and nodal regions; 1 (7%) at both distant site and primary tumor; 1 (7%) at both nodal region and primary tumor. Median overall survival was 22 months (10-33 months) and 2-year overall survival rate was 49% (32-63%). These results compared favorably to stage-matched patients treated with standard-dose RT in our center 2-year overall survival 23% (8-41%) during the same time period.

      Conclusion
      Adapting RT by targeting high dose radiation to the FDG avid region detected mid-treatment provides outstanding 2-year local-regional tumor control. RTOG 1106 is currently testing this regimen in a randomized fashion.

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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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      P1.06-045 - Serum microRNA as a predictive marker for radiation pneumonitis in patients with inoperable/unresectablenon-small cell lung cancer (NSCLC) (ID 2795)

      09:30 - 09:30  |  Author(s): F.(. Kong

      • Abstract

      Background
      Radiation pneumonitis (RP) is a major dose-limiting toxicity after thoracic radiotherapy (RT), with no good models available to accurately predict the individual risk.MicroRNAs (miRNAs) are found to be stable in serum and other body fluids,with exciting potential as novel non-invasive biomarkers. This study is to investigate serum microRNAs associated with RP grade ≥ 2 in inoperable/unresectable NSCLC patients treated with definitive RT.

      Methods
      134 patients with inoperable/unresectable NSCLC treated with definitive RT (18-month minimum follow-up) were eligible. Serum samples were collected prospectively before treatment. 100 patients who had enough serum and reliable miRNA profile quality were included in this study. MiRNA profiling was performed using real-time PCR-based array, containing a panel of 84 miRNAs detectable in human bodily fluids. Spiked-in cel-miR-39 was used for normalization. The primary endpoint was symptomatic RP (grade 2 and higher). 2-sample mean comparisons were used between the RP and non-RP subgroups.Stepwise Logistic regression model building was used to build a miRNA signature. Receiver operator characteristic (ROC) analysis was used to assess the predictive ability of single-marker and signature of RP.

      Results
      Of 100 patients enrolled, 17 (17.0%) patients developed symptomatic RP. Patients received a median of 70 Gy (34-85.6Gy) of RT with a mean lung dose (MLD) of 16.9 Gy (2.1-25.5 Gy). Serum miRNA profiling identified pre-treatment expressions of 9miRNAs were significantly associated with risk of RP (p<0.05). Significant correlations were not found for any clinical or dosimetric parameters including age, gender, stage, MLD (p>0.05). Stepwise regression modeling identified only has-miR-191 as significant predictors of symptomatic RP (HR=4.94, 95%CI:1.46-16.66, p=0.01). Using ROC curves, we found has-miR-191 was independent predictors of symptomatic RP (p=0.01). A model of combining has-miR-191 and MLD had AUC of 0.72 (p=0.004) comparing to 0.64 of MLD alone (p=0.08).

      Conclusion
      In our preliminary analysis, baseline serum has-miR-191 may help predictingsymptomaticRP. However, analysis on larger and independent datasets will be required to verify our findings.

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    P2.19 - Poster Session 2 - Imaging (ID 180)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Imaging, Staging & Screening
    • Presentations: 1
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      P2.19-012 - Inter-method Comparison of 18F-FDG PET Metabolic Response Assessment in Non-small Cell Lung Cancer (ID 2670)

      09:30 - 09:30  |  Author(s): F.(. Kong

      • Abstract

      Background
      This study aimed to: 1) compare qualitative and semi-quantitative assessment of [18]F-fluorodeoxyglucose PET based categorical metabolic response in patients with NSCLC and determine their value for prognosis prediction; 2) investigate the relationship between semi-quantitative assessments of post-treatment change of metabolic activity and survival and explore an optimal cutoff to distinguish a subset of responders with more favorable outcome.

      Methods
      This is a secondary analysis of prospective studies with IRB approval. Enrolled patients with NSCLC underwent PET/CT imaging within 2 weeks prior to (pre-RT PET/CT), at 4 weeks during and after radiation treatment (post-RT PET/CT). Post-RT metabolic therapeutic response was assessed using 1) visual assessment and 2) semi-quantitative measurement based on reduction in tumor FDG uptake; SUVmax normalized to mediastinal blood pool (NSUV-A). Interpretation of PET/CT scans was performed by three nuclear medicine physicians, blinded to clinical information. The three physicians did independent reads of the patients, performing a single read for each patient’s set of PET studies. Kappa coefficient was used to evaluate the agreement between categorical variables. Survival analysis and Cox proportional hazard regression model were adopted to analyze the effect of various response criteria on overall survival (OS) and progression free survival (PFS).

      Results
      Forty-four patients (36 male: 8 female) were eligible for analysis. The median interval between end of RT and post-RT PET/CT scan was 93 days. A poor agreement was observed between visual and semi-quantitative responses (Kappa coefficient = 0.393). Categorical responses were significantly correlated with both OS and PFS independent of employed response assessment criteria (either visual or semi-quantitative, p < 0.001) and patients with complete metabolic response (CMR) obtained the longest survival. As a continuous variable, reduction percentage of NSUV-A showed significant correlations with OS (hazard ratio, HR = 0.980, p < 0.001) and PFS (HR=0.984, p < 0.001). Analysis of OS and PFS consistently recommended NSUV-A reduction of sixty percent (60%) as another discriminative cutoff to distinguish patients with different outcome (p < 0.01).

      Conclusion
      There is a great discrepancy in metabolic response rates between qualitative and semi-quantitative methods. Categorical metabolic response criteria, either from qualitative visual assessment or a semi-quantitative method, demonstrate significant association with overall survival and progression free survival. Visual method offers a simpler approach that provides good information with regard to predicting OS and PFS, while the semi-quantitative method provides ordinal value that correlates with prolonged OS. As a continuum, the numerical percentage reduction in the normalized SUV is positively correlated with longer overall survival, reinforcing the prognostic value of metabolic change on FDG PET/CT. A sixty percent reduction of SUV may be the optimal cutoff for metabolic response to identify subsets of the PMR population with distinct outcomes, pending validation by an independent population.

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-041 - Serum miRNA signature predicts survival in patients with unresectable/inoperable non-small cell lung cancer treated with definitive radiation therapy (ID 2785)

      09:30 - 09:30  |  Author(s): F.(. Kong

      • Abstract

      Background
      The expression profiles of serum micro RNAs (miRNAs) are known to predict overall survival (OS) of metastatic and operable non-small cell lung cancer (NSCLC). We hypothesized that circulating miRNAs is also correlated with survival in unresectable/inoperable NSCLC treated with radiation therapy (RT).

      Methods
      134 patients with inoperable/unresectable NSCLC treated with definitive RT (18-month minimum follow-up) were eligible. Serum samples were collected prospectively before RT commencement. 100 patients with enough serum and reliable miRNA profile quality were randomly divided into training and validation sets (50 patients each). MiRNA profiling was performed using real-time PCR-based array, containing a panel of 84 miRNAs detectable in human bodily fluids. Spiked-in cel-miR-39 was used for normalization. Stepwise regression Cox model building was used to build a miRNA signature on the training set, which was then assessed on the validation set both alone and with clinical factors.

      Results
      The median age was 67 years; 76% were stages III and 79% received chemoradiation; the median physical dose was 70 Gy. Stepwise regression modeling identified five miRNAs as jointly significant predictors. Using coefficients from Cox model fit, the miRNA signature was 0.53*log(hsa-miR-15b)+0.21*log(hsa-miR-34a)-0.27*log(hsa-miR-221)-0.27*log(hsa-miR-224) -0.07*log(hsa-miR-130b). This signature was a significant predictor of OS in the validation set (p=0.011). It retained statistical significance in a model also containing terms for GTV Volume and KPS, the only two significant clinical factors in univariate analysis in the validation set (p=0.012). Using computational methods (TargetScan6.2) for miRNA target prediction, the putative targets of these five miRNAs are known to modulate apoptosis, cell cycle control, DNA damage response and repair process (including nucleotide excision repair and DNA translesion synthesis), angiogenesis and epithelial-mesenchymal transition.

      Conclusion
      In this study, we developed a prognostic miRNA signature consisting of five miRNAs and validated in an independent dataset for unresectable/inoperable NSCLC treated with RT. This circulating miRNA signature may be used as a non-invasive biomarker, which may have prognostic or therapeutic implications for the future management of locally advance NSCLC patients. Larger sample size studies are needed to further validate our findings.