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L. Le



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    O10 - Stereotactic Ablative Body Radiotherapy (ID 104)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      O10.06 - Inter-Rater Reliability of the Categorization of Late Radiographic Changes after Lung Stereotactic Body Radiation Therapy (SBRT) (ID 1901)

      16:15 - 17:45  |  Author(s): L. Le

      • Abstract
      • Presentation
      • Slides

      Background
      Radiographic changes following lung SBRT have been previously categorized into 4 groups: modified conventional pattern (A), mass-like fibrosis (B), scar-like fibrosis (C) and no evidence of increased density (D) (Dahele et al.).The purpose of this study was to assess the inter-rater reliability of this categorization in patients with early stage non-small cell lung cancer.

      Methods
      79 patients treated with SBRT for early stage NSCLC at a single institution who had a minimum follow-up of 6 months were included in this study. Serial post-treatment CT images were presented to expert clinicians (up to 6) familiar with post-SBRT radiographic changes and were scored by each individual in a blinded fashion according to the published categorization of A, B, C or D. The proportion of patients categorized as A, B, C or D at each interval was determined. Krippendorff's alpha (KA) was used to establish inter-rater reliability at each time point. A leave-one-out analysis was performed at each time point on each rater to determine the sensitivity of the KA score to an individual rater. To explore if a training effect existed the KA of the first and last 20 patients scored by the raters was determined.

      Results
      There were 351 ratings on 67 patients at 12mo, 250 ratings on 49 patients at 24mo, 169ratings on 31 patients at 36mo and 80 ratings on 14 patients at 48mo. The proportion of patients scored in each category of A,B,C &D is reported in Table 1. Table 1: Scale Category by Time-Point

      A (Modified-Conventional) B (Mass-like Fibrosis) C (Scar-like Fibrosis) D (No Evidence of Increased Density)
      6 months 43% 9% 6% 42%
      12 months 50% 16% 11% 23%
      18 months 46% 18% 16% 20%
      24 months 46% 22% 17% 15%
      36 months 40% 24% 21% 15%
      48 months 29% 24% 31% 16%
      Category A was the most common at all time points except 48 months when category C was the most common. KA was 0.28, 0.27, 0.18 and 0.27 at 12, 24, 36 and 48 months respectively. The range of KA in the leave-one-out analysis was 0.25-0.31, 0.24-0.27, 0.15-0.22 and 0.24-0.31 at 12, 24, 36 and 48 months respectively. The KA of the first 20 patients vs the last 20 patients was 0.34 vs 0.47 at 12 months.

      Conclusion
      The predominant pattern of post SBRT radiographic changes evolves over time. In this study categorization of late post-SBRT radiographic changes has moderate inter-rater agreement. There is a suggestion of a training effect with more experience. However, categorization of late radiographic changes following SBRT is challenging and may require specific training.

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    P1.08 - Poster Session 1 - Radiotherapy (ID 195)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      P1.08-019 - Late Radiographic Changes After Lung Stereotactic Body Radiotherapy: Piloting a Recurrence Scale and a Synoptic Reporting Scale (ID 2209)

      09:30 - 16:30  |  Author(s): L. Le

      • Abstract

      Background
      Radiographic lung changes after Stereotactic Body Radiotherapy (SBRT) for non-small cell lung cancer (NSCLC) are difficult to interpret. The reliability of previous scoring systems and their relationship to local failure has not been assessed. The purpose of this study was to design a synoptic radiographic scale for characterizing late radiographic changes after SBRT and to determine the inter-rater reliability of the scale.

      Methods
      A Recurrence Scale (RS) was developed among lung radiation oncology/SBRT experts at a single institution, and a Synoptic Radiographic Scale (SRS) was designed in collaboration with an expert thoracic radiologist. For the RS, the suspicion for local recurrence on CT images was scored on a 5 point scale: 1) complete response, no recurrence; 2) fibrosis, not suspicious for recurrence; 3) fibrosis/mass, indeterminate for recurrence; 4) fibrosis/mass, suspicious for recurrence and 5) biopsy proven recurrence. On the SRS, CT changes were scored as ‘increasing’, ‘stable’, ‘decreasing’, ‘no change’ or ‘obscured’, along five dimensions: changes in the primary tumor site, involved lobe, consolidation, ground-glass opacity, and volume loss. Early stage NSCLC patients treated with SBRT at the institution with a minimum follow-up of 6 months were included. Serial post-treatment CT images at 12, 18, 24, 36, and 48 months were presented to the expert group (up to 6) who scored both scales in a blinded fashion. Krippendorff's alpha (KA) was used to assess inter-rater reliability. The association between RS score and known local failure was compared using Fisher’s Exact Test. The association between ‘growing tumor’ on the SRS and known local failure was compared using Fisher’s Exact Test.

      Results
      79 patients were scored; 7 of them had documented local failures. Experts did 11243 scorings in total, ranging from 2351 at 6 months to 480 at 48 months. For the RS, the KA was 0.27, 0.36, 0.23 and 0.45 at 12, 24, 36 and 48 months respectively. For the SRS, KA was 0.22, 0.14 and 0.11 for the treated tumor at 12, 24 and 48 months and 0.33, 0.36 and 0.22 for consolidation at 12, 24 and 36 months. The tumor was scored as obscured in 40% of patients by 24 months. Of patients with local failure, 71% were at least once scored as ‘suspicious for recurrence’ by at least one rater, compared to 28% in patients without failure (p = 0.03). 86% of patients with failure were scored at least once as increased opacity in tumor site by at least one of raters, compared to 35% in patients without failure (p = 0.01).

      Conclusion
      The RS has a significant relationship with local failure, and there is fair inter-agreement among experts on the suspicion of recurrence following SBRT. The SRS has low inter-rater reliability. Among its categories, only an increase in the opacity of treated tumor site is significantly related to failure. With future refinement of SRS categories, it can be a useful tool to standardize post-SBRT radiology reporting.

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    P2.08 - Poster Session 2 - Radiotherapy (ID 198)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      P2.08-005 - 4D-PET/CT-based adaptive dose escalated radiotherapy (RT) in locally advanced non-small cell lung cancer (LA-NSCLC) (ID 1171)

      09:30 - 16:30  |  Author(s): L. Le

      • Abstract

      Background
      There has been recent interest in dose escalation in LA-NSCLC, with the aim to improve both loco-regional control and overall survival. Attempts to dose escalate CT-defined volumes for radiotherapy (RT) for LA-NSCLC have been limited due to organ at risk (OAR) toxicity. We investigated the potential for adaptive dose-escalation to PET-defined volumes, using 4DPET/CT scans acquired prior to and during a course of radical chemo/RT (CRT).

      Methods
      This single institution study prospectively enrolled patients with NSCLC receiving CRT to a dose ≥60Gy, delivered in daily 2Gy treatments. 4DPET/CT scans were acquired prior to (week 0) and at weeks 2 and 4 during RT. RT was delivered using the intensity modulated RT (IMRT) plan developed from the week 0 scans. Three alternative dose escalated IMRT plans were developed offline based on the week 0, 2 and 4 scans. The PET avid primary (PET-T) and nodal disease (PET-N) volumes were auto-contoured using the 50%SUV~max~ metric. PET-T and PET-N were dose escalated to as high as possible while respecting OAR constraints and ensuring coverage of the clinical plan PTV. The D95% and D~max~ of the PET-T and PET-N were calculated and compared between week 0-2-4.

      Results
      Thirty-two patients were recruited, with 27 completing all scans. Sixteen patients were stage IIIA (60%), 9 were IIIB (33%) and 2 were IIA (7%). Eight patients (30%) had been prescribed a clinical dose of 60 Gy, 17 (63%) had 66 Gy, 1 patient 70Gy and 1 patient 74Gy. 25 patients (93%) were boosted successfully above the clinical plan doses at week 0; this reduced to 23 (85%) at week 2 and 20 (74%) at week 4. For all weeks combined, the D95 for PET-T was higher than that delivered to clinical PTV by a median of 16.2 Gy (4.2-37.4Gy). The D95 for PET-N exceeded that delivered to clinical PTV by 13.4Gy (6.8-29.7Gy). The median D95% to the PET-T at week 0, 2 and 4 were 74.4 Gy, 75.3Gy and 74.1Gy respectively. The median D~max~ to PET-T at week 0, 2 and 4 were 85.9Gy, 83.8Gy and 81.2Gy. The median D95% to PET-N at week 0, 2 and 4 was 74.3Gy, 71.0Gy and 69.5Gy. The median D~max~ to PET-N at week 0, 2 and 4 were 82.7Gy, 82.5Gy and 78.9Gy.

      Conclusion
      Using 4DPET/CT derived volumes, it is feasible to dose escalate a majority of patients, either at the onset or during RT. Though the PET-T was able to be escalated to higher doses than PET-N, nodal disease can still be boosted to significant doses. More patients were able to be dose escalated at the onset of RT; however mid-RT dose escalation allows the additional potential for adaptation.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-044 - Clinical impact of EGFR mutation fraction and tumour cellularity in EGFR mutation positive NSCLC (ID 2982)

      09:30 - 16:30  |  Author(s): L. Le

      • Abstract

      Background
      We investigated the impact of mutation fraction, tumour sample cellularity, and diagnostic specimen type on EGFR TKI response, time to treatment failure (TTF) and overall survival (OS), as well as patterns of treatment in a population-based cohort of advanced EGFR mutation positive NSCLC patients.

      Methods
      From March 2010 to May 2012, EGFR testing in the province of Ontario (Canada) was conducted at a single centre, using fragment analysis for exon 19 deletion and Sau961 restriction enzyme digest for exon 21 mutations. Patients with EGFR mutation positive samples were identified and tumour sample cellularity, mutation fraction (percent of tumour cells mutated), demographic, treatment and outcome data were collected. Regression analysis was undertaken to assess the association between demographic variables, mutation fraction, tumour sample cellularity and sample type on clinical outcomes.

      Results
      Among 293 patients identified with EGFR mutation positive NSCLC, 253 received EGFR TKIs and are included in this analysis. Most are female (72%), never smokers (59%), have exon 19 deletions (53%; 47% exon21 L858R), and median age 65 years (range 26 to 96). Tumour specimens tested include resection (32%), cytology (30%), and core biopsies (38%). Median EGFR mutation fraction is 30% (range 0.4% to 96%); 24% had a low (≤10%) mutation fraction, and 13% had a mutation fraction ≤5%. Responses (any tumour reduction) were seen in 62%, mixed response or stable disease in 25%, and progression as the best response in 13%. Median TTF from the start of EGFR TKI therapy is 13.2 months (range 0-43.7 months). Median OS from TKI start is 22.3 months (95% CI: 19.5-28.2 months), with 1-, 2- and 3-year survival rates of 72%, 49% and 37%. In multivariable analysis, factors associated with TTF included female sex (HR 0.69, p=0.03) and sample type (resection HR 0.56, cytology HR 0.82, core biopsy as reference, p=0.01). Age at metastatic diagnosis (p=0.01), sample cellularity (p=0.01) and sample type were significantly associated with OS, (resection HR 0.51, cytology HR 0.70, core biopsy as reference, p=0.04). Proportional odds logistic regression identified that mutation frequency and age at metastatic diagnosis were significantly associated with the odds of response, (p=0.047, p=0.04 respectively). Responses were seen even in those with lower EGFR mutation fraction, 48% (24/50) at a mutation frequency of ≤10% and 33% (9/27) at a mutation frequency of ≤5%. The average cellularity in the high (>10%) mutation fraction group was 53% (95%CI 50– 56%), and 36% (95%CI 29 – 43%) in those with a low mutation fraction (p<.0001).

      Conclusion
      Pathologic features may be relevant to clinical outcomes in EGFR mutation positive NSCLC, including mutation fraction, sample cellularity, and specimen tested. The clinical relevance of sample tumour cellularity and sample type tested remains unclear. In particular, initial stage and prognosis may be confounders in the association between resected specimens and favourable outcomes. Given that those with mutation fractions ≤5% may have significant response from EGFR TKI therapy, treatment should not be withheld on the basis of mutation frequency alone.