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J.M.A. Daniels

Moderator of

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    E01 - LDCT Screening (ID 1)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Imaging, Staging & Screening
    • Presentations: 4
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      E01.1 - Risk Stratification for Lung Cancer Screening Studies (ID 372)

      14:05 - 14:25  |  Author(s): M. Tammemagi

      • Abstract
      • Slides

      Abstract

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      E01.2 - Volumetrics for Nodule Assessment (ID 373)

      14:25 - 14:45  |  Author(s): M. Oudkerk, M. Heuvelmans

      • Abstract
      • Presentation
      • Slides

      Abstract
      Introduction Lung cancer is a major health problem with no improvement in survival over the last decades. At time of diagnosis, lung cancer is often already in advanced stage, with 5-year survival of no more than 15%. Currently, several lung cancer screening trials investigating whether early detection of lung cancer in high-risk individuals will reduce lung cancer mortality are ongoing. In 2011, the National Lung Screening Trial (NLST), was the first and to date only reporting a 20% decrease in lung cancer mortality when three rounds of annual low-dose computed tomography (CT) were compared with three annual rounds of chest X-ray screening. A major challenge, however, is the high rate of positive test results reported by the NLST (24.2%). No less than 96.2% of these comprised false-positive test results, causing unnecessary patient anxiety, radiation exposure and cost. The Dutch-Belgian lung cancer screening trial (Dutch acronym: NELSON study) was launched in September 2003. The NELSON study is an ongoing multicentre randomized controlled multi-detector low-dose CT lung cancer screening trial. The primary object is to investigate whether chest CT screening in year 1, 2, 4 and 6.5 will decrease lung cancer mortality by at least 25% in high-risk (ex-)smokers between 50 and 75 years of age compared to a control group receiving no screening. The NELSON study is the first lung cancer screening trial in which nodule management is based on nodule volume, instead of transverse cross-sectional nodule diameter for new nodules, and nodule growth in terms of volume doubling time (VDT) for existing ones. In this presentation, different aspects of nodule management in the NELSON study will be discussed. Volume detection thresholds Sensitive pulmonary nodule detection is crucial not to miss any lung cancer in a screening setting. The sensitivity of nodule detection was investigated by scanning a Lungman phantom according to the standard NELSON protocol. Nodules of five different volumes (range 14–905mm[3]) were randomly positioned in the phantom. A sensitivity of 100% was found for nodules with a volume equal to or larger than 65mm[3] (5mm), and a sensitivity of 60–80% was found for solid nodules with a volume of 14mm[3] (3mm). Since the lung cancer probability of lung nodules smaller than 50mm[3] or 4mm is neglectable, the sensitivity of nodule detection using the NELSON protocol is sufficient for accurate detection of malignant lung nodules. Measurement reproducibility For accurate decision making in serial CT studies, nodule measurement reproducibility is essential. A sub-study of the NELSON trial showed a difference in repeatability among three reconstruction settings, demonstrating that the use of consistent reconstruction parameters is important. Volume measurements of pulmonary nodules obtained at 1mm section thickness combined with a soft kernel were found to be most repeatable. Another sub-study showed that variability on volume measurements is related to nodule size, morphology and location. Besides image reproducibility, interobserver variability in performing semi-automated volume measurements is of major importance in the classification of lung nodules. Gietema et al. found that interobserver correlation was very high (r=0.99) in small-to-intermediate size (15-500mm[3]) nodules. Volume criteria for nodule stratification For solid nodules, and solid components of part-solid nodules, volume was calculated by 3-dimensional volumetric computer assessment, using LungCare software (version Somaris/5:VA70C-W; Siemens Medical Solutions). The final screen result was based on the nodule with largest volume or fasted growth. In the NELSON study, nodules were classified as negative if volume was <50mm[3] (4.6mm diameter if the nodule would have been perfectly spherical), leading to an invitation for the regular next-round CT, as positive if nodule volume was >500mm[3] (>9.8mm diameter), leading to direct referral to a pulmonologist for further workup, and as indeterminate in case of volume of 50-500mm[3]. Indeterminate nodules underwent a 6-week to 3-month follow-up low-dose CT for growth assessment. Volumetric growth assessment of pulmonary nodules After a nodule has been selected by a radiologist, the LungCare software automatically calculates nodule volume. Information is saved in the NELSON Management System (NMS), which calculates the growth in case of a pre-existing nodule. Growth is defined as a change in volume of ≥25% between two subsequent scans according to the formula: Percentage volume change (%) = (V2-V1)/V1)*100 V2 = volume at last CT, and V1 = volume at previous examination. Determination of the volume-doubling time For solid nodules, or solid components of partial-solid nodules with PVC≥25%, the VDT is semi-automatically calculated by the NMS according to the formula: VDT (days) = (ln(2)*Δt)/(ln(V2/V1)) The VDT is used to distinguish between positive screens (VDT<400days), requiring additional diagnostic procedures, indeterminate screens (VDT 400-600days), requiring an extra follow-up CT 12 months after the regular round CT and negative screens (VDT>600days). Using this two-step approach of volume and growth assessment, 2.6% of NELSON baseline screens were positive, and compared to other screening trials, a higher proportion (34.6% at baseline) were true-positive. The NELSON study reported a baseline screen sensitivity of 94.6% and a negative predictive value of 99.9%. Comparison between volumetric and diameter assessment of pulmonary nodules For determining pulmonary nodule size, the use of volume measurements has been found to be more reliable than diameter measurements. In the previously mentioned phantom study, measurements of the manually measured maximal transverse diameter and semi-automated measurements of diameter and nodule volume were compared with actual properties. In both methods, diameter and volume of the spherical nodules were significantly underestimated. In diameter evaluation, the overall underestimation for solid nodules was about 10% using the manual method, compared with less than 4% using the semi-automated method. In volumetry, the overall underestimation for solid nodules was about 25% (translates into 8% diameter underestimation) using the manual method, compared with less than 8% (translates into 2.5% diameter underestimation) using the semi-automated method. It is important to keep in mind that a small change in diameter already corresponds to a considerably higher change in volume. Thus, in lung cancer screening we suggest nodule measurements by semi-automated volumetry should be used. Differences between volume and diameter based nodule management protocol in terms of early lung cancer detection, morbidity, mortality, radiation exposure and costs remain to be demonstrated.

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      E01.3 - Molecular Pathology / Profiling of CT Detected Nodules (ID 374)

      14:45 - 15:05  |  Author(s): W. Lam

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      E01.4 - Implementing Screening: Recommendations From the IASLC (ID 375)

      15:05 - 15:25  |  Author(s): J.K. Field

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    P1.17 - Poster Session 1 - Bronchoscopy, Endoscopy (ID 182)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pulmonology + Endoscopy/Pulmonary
    • Presentations: 3
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      P1.17-006 - Early Bronchoscopic Interventional Strategy in Highly at Risk Morbid Ageing Cohort (ID 2322)

      09:30 - 09:30  |  Author(s): J.M.A. Daniels

      • Abstract

      Background
      We retrospectively reviewed our longitudinal data (1992 - 2012) with regard to early interventional techniques using advancements of non- and minimally invasive techniques (NiMiT) as alternatives for early intervention in squamous carcinogenesis in highly at risk -including frail elderly individuals. >50% lung cancer develops in >70 years age cohort and cancer and ageing are becoming an important health care issue in our society.

      Methods
      So far, 159 surgically non-resectable candidates with various comorbidities (Previous LC/ENT primaries, COPD, etc.) have been closely monitored using autofluorescence bronchoscopy for suspicious endobronchial lesions (e.g. dysplasia, carcinoma in situ and microinvasive squamous cancer). End points were the development of squamous cancer and its outcome with the use NiMiT (Chest 2001;120:1327; Respiration 2004;71:391

      Results
      Patient characteristics and outcome are shown in the table. Cohort analyses of age ≤70 years versus over, showed a significant longer time of survival in the elderly cohort (35.9 vs 18.5 months; p = 0.01). Lung cancer specific mortality was low ,respectively 15% and 22%. Table: Longitudinal carcinogenesis study in cohorts highly at risk to develop (subsequent) squamous cancer primaries and its outcome.

      Age cohort (years) n patients <70 112 >70 47 p-value
      Gender - Male - Female 93 (83%) 19 (17%) 39 (83%) 8 (17%) NS
      Mean age years (range) 60(42-70) 74(70-83)
      Indication for close surveillance: - Previous LC /ENT cancer - Suspicion occult lung cancer 55 (49%) 57 (51%) 19 (40%) 28 (60%) NS
      Mean pack-years smoked (range) 44(4-120) 49(20-137) NS
      COPD Non-COPD Unknown 72 (64%) 32 (29%) 8 (7%) 29 (62%) 10 (21%) 8 (17%) NS
      Interval to (subsequent) primaries (months) 69(0-198) 54(1-184) NS
      Acquiring (subsequent) squamous ca. Recurrences of previous primaries 41 (37%) 4 (4%) 12 (26%) 2 (4%) NS NS
      Death due to lung cancer Other causes 25 (22%) 31 (28%) 7 (15%) 17 (36%) NS NS
      Survival after curative treatment (months) 19 (0-110) 36 (0-106) 0,01

      Conclusion
      In contrast to the undocumented belief about less aggressive cancer, the need for less aggressive treatment, potential toxicities in the co-morbid elderly and their expected shorter life span, the outcome shows that early interventional strategy is warranted. LC mortality is relatively low despite the highly negative selection bias, especially in the frail – ageing – subcohort. This warrants further studies to increase the cost-effectiveness of NiMiT in our ageing population.

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      P1.17-007 - A proposal for a new clinical strategy and follow-up in patients with bronchial carcinoids initially treated bronchoscopically. (ID 2468)

      09:30 - 09:30  |  Author(s): J.M.A. Daniels

      • Abstract

      Background
      Bronchial carcinoids (BC) belong to the wide spectrum of neuroendocrine tumors; ranging from tumorlets, typical carcinoid (TC), intermediate-grade atypical carcinoid (AC), to highly malignant large cell neuroendocrine and small cell carcinoma. The Travis classification (Am J SurgPathol 1998; 22:934) seems essential for choosing the best treatment strategy based on retrospective analyses of surgically resected specimens. We implemented an initial bronchoscopic treatment (IBT) strategy and its long term outcome have been reported with update of the final analysis (J Thorac Cardiovasc Surg. 2007 Apr;133(4):973; Abstract IASLC Sydney submitted). The long-term outcome seems to justify IBT and the histological differentiation between typical versus atypical seems to matter much less, while conservation of normal lung parenchyma is optimal. We question how optimal the close surveillance strategy of IBT protocol should be, i.e. in performing regular high resolution CT (HRCT) and/or bronchoscopy after the initial success of bronchoscopic treatment.

      Methods
      In the IBT protocol, HRCT and bronchoscopy were performed 6-monthly in the first two years and annually until the fifth year. Thereafter a yearly check-up was advised to the referring pulmonologists. We analyzed retrospectively the value of HRCT and/or bronchoscopy in this IBT cohort for early detection of local recurrences, that require surgical salvage.

      Results
      So far, IBT was successful in 57 of the 133 patients (43%). Sixty-seven patients (50%) could be immediately identified to be surgical candidates without further delay due to obvious extraluminal tumor growth. Four patients (3%) developed extraluminal tumor recurrence and surgical salvage was performed at 47, 104, 115, 192 months. In all four cases follow-up HRCT suggested local extraluminal tumor growth, which were confirmed by bronchoscopy. The surgical outcome was radical and did not lead to more extensive resections than initially anticipated. Detailed treatment results are shown in table 1. Table 1. Initial bronchoscopic treatment strategy in patients with bronchial carcinoids

      BT Completion Surgery Remark
      Number of patients 62 71
      Histology TC AC 56 (90%) 6 (10%) 43 (61%) 28 (39%)
      Follow up (median) in months 87.5 (2-223) 87 (12-264)
      Completely resected 57 (92%) 64 (90%)
      Residual after CT/recurrences Additional treatment bronchoscopy Additional treatment surgery 3 4 0 0 Interval in months: 10,13,63 47,104,115,192
      Alive with disease 5 0 2 unfit for surgery 3 refused surgery
      Alive with metastatic disease 0 1 40 months
      Carcinoid related mortalities 0 2 Pulmonary metastases
      Treatment related mortalities 0 1
      Non-carcinoid related mortalities 8 3

      Conclusion
      Initial bronchoscopic treatment strategy in patients with bronchial carcinoids is justifiable. Local regrowth after successful bronchoscopic removal was infrequent (3%) and was timely detected by HRCT. HRCT can be performed much less frequent and regular bronchoscopy was redundant if IBT attempt was successful. The significance of an iceberg phenomenon is questionable.

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      P1.17-008 - Results of a close surveillance strategy for subjects with pre-invasive endobronchial squamous lesions (ID 2678)

      09:30 - 09:30  |  Author(s): J.M.A. Daniels

      • Abstract

      Background
      The dismal overall 5-year survival of non-small cell lung cancer (NSCLC) patients is mainly due to advanced stage of disease at time of initial diagnosis in most and the inability to cure metastatic disease in all patients. In contrast, the prognoses of in situ mucosal and small parenchymal lesions are excellent. Early detection strategies might result in the identification of early-stage, (pre-)invasive lesions that are still eligible for curative treatment. The present study was set out to characterize the risk of lung cancer development in a cohort of high-risk subjects harboring pre-invasive endobronchial lesions and to assess the results of surveillance using autofluorescence bronchoscopy (AFB) and computed tomography (CT) scan.

      Methods
      Between November 1995 and December 2012, one hundred and sixty-four at risk individuals with pre-invasive endobronchial lesions were monitored by repeated AFB and CT. During the course of surveillance, progression of lesions to cancer (in situ), recurrences and second primary cancers were treated with different modalities (e.g. endobronchial techniques, surgery, radiotherapy), depending on tumor stage and location. Log-rank tests were performed to examine the relation between baseline characteristics and progression-free and overall survival (PFS and OS, respectively). Cox regression was used for multivariate survival analysis.

      Results
      Demographical and clinical variables of the cohort are shown (Table). At inclusion, 80 individuals were identified with one or more high-grade pre-invasive lesions (severe dysplasia or CIS; HGD), whereas 84 subjects were identified solely with lower grade pre-invasive lesions (LGD). During close surveillance (median follow-up (FU) of 30 months, range 4-152), sixty-one lung cancers were detected (26 CT-detected, 35 AFB-detected cancers) in 55 individuals within a median time to event of 16.5 months. Mean PFS was similar between individuals with radiographically occult lesions vs. FU after surgery for early-stage NSCLC/ENT ca (122.3 vs. 126.9 months, p=0.237) and COPD vs. non-COPD (118.8 vs. 136.8 months, p=0.162). There was a relatively large difference in PFS between LGD and HGD groups (142.6 vs. 93.7 months, p=0.057). Independent risk determinants for OS were indication for surveillance (FU after surgery for early-stage NSCLC/ENT ca vs. radiographically occult lesions, p=0.008) and COPD-status (COPD vs. non-COPD, p<0.001).

      Referral for radiographically occult lesion Follow-up after surgery for early-stage NSCLC / ENT ca
      total
      individuals, n 164 92 72
      Gender
      male 134 72 62
      female 30 20 10
      Age at baseline
      years, mean (range) 64.2 (42-83) 64.8 (42-81) 64.0 (43-82)
      Smoking status
      current smoker 75 44 31
      former smoker 74 36 38
      unknown 15 12 3
      Smoking history
      Pack-years, mean (range) 45 (4-137) 45 (4-120) 40 (15-137)
      COPD-status
      COPD 100 56 44
      non-COPD 45 22 23
      unknown 19 14 5
      AF Bronchoscopies
      Number, mean (range) 7 (1-27) 5 (2-27) 6 (1-18)
      CT-scans
      Number, mean (range) 3 (0-20) 2 (0-20) 3 (0-18)
      No. of detected lung cancers
      During surveillance period 61 29 32
      Parenchymal cancer 21 12 9
      Site-specific lesion progression 24 13 11
      Interval cancer 10 4 6
      Recurrences previous primaries 6 0 6
      Patient outcome
      alive 80 56 24
      died of lung cancer 33 13 20
      died of other/unknown cause 51 23 28

      Conclusion
      Our findings demonstrate that individuals with pre-invasive endobronchial lesions are at high risk of developing (second primary) lung cancers. Combined surveillance using AFB in addition to CT screening facilitated early detection and early (endobronchial) intervention in most patients. Future clinical trials are warranted to determine whether the current approach improves patient outcome.

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    P2.17 - Poster Session 2 - Bronchoscopy, Endoscopy (ID 183)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pulmonology + Endoscopy/Pulmonary
    • Presentations: 1
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      P2.17-006 - Long term outcome of initial bronchoscopic treatment strategy in patients with bronchial carcinoids (ID 2447)

      09:30 - 09:30  |  Author(s): J.M.A. Daniels

      • Abstract

      Background
      Bronchial carcinoids are considered low-grade malignancies and, traditionally, are treated surgically. Tumor biology and advances in diagnostic and therapeutic techniques, however, enable a less invasive approach such as surgical bronchoplasty can preserve normal lung parenchyma. We previously reported favourable outcome for initial bronchoscopic treatment (BT) strategy in patients with intraluminally located bronchial carcinoids. We now present our long term results.

      Methods
      In patients presenting with a bronchial carcinoid, an initial diagnostic therapeutic bronchoscopy is attempted for complete tumor eradication for sampling sufficient tissue for the proper differentiation between typical (TC) and atypical (AC) histologic type apart from to optimally improve pre-surgical condition. A high resolution computed tomography is performed six weeks later, to determine intra- versus extraluminal tumor growth. In case of intraluminal growth of TC bronchoscopic removal attempt can be repeated. We perform surgical resection in case of extraluminal disease, or failure to bronchoscopic radical resection (i.e. recurrence or persistent residual tumor). Complete bronchoscopic resection of AC histological type is currently not followed by surgical resection.

      Results
      So far, 133 patients have been treated; 76 females, 67 males, median age 46 (range 16 – 85 years). Median follow up was 87 (range 2 – 264) months. Ninety-nine patients (84%) had TC, and 34 (26%) had AC. Bronchoscopic eradication was successful in 57 (43%) patients (51 TC, 6 AC). Detailed treatment results are shown in table 1. Table 1. Initial bronchoscopic treatment strategy in patients with bronchial carcinoids

      BT Completion Surgery Remark
      Number of patients 62 71
      Histology TC AC 56 (90%) 6 (10%) 43 (61%) 28 (39%)
      Follow up (median) in months 87.5 (2-223) 87 (12-264)
      Completely resected 57 (92%) 64 (90%)
      Residual after CT/recurrences Additional treatment bronchoscopy Additional treatment surgery 3 4 0 0 Interval in months: 10,13,63 47,104,115,192
      Alive with disease 5 0 2 unfit for surgery 3 refused surgery
      Alive with metastatic disease 0 1 40 months
      Carcinoid related mortalities 0 2 Pulmonary metastases
      Treatment related mortalities 0 1
      Non-carcinoid related mortalities 8 3

      Conclusion
      Initial bronchoscopic treatment strategy in patients with bronchial carcinoids is justifiable with excellent long term outcome. It should be implemented in the standard algorithm for patients with bronchial carcinoids.

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    P2.20 - Poster Session 2 - Early Detection and Screening (ID 173)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Imaging, Staging & Screening
    • Presentations: 1
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      P2.20-004 - DNA copy number aberrations in endobronchial lesions: a validated predictor for cancer (ID 1166)

      09:30 - 09:30  |  Author(s): J.M.A. Daniels

      • Abstract

      Background
      Individuals who present with squamous metaplastic and dysplastic lesions are considered at high risk of lung cancer. However, these lesions behave erratically and only a minority progresses towards lung cancer. Therefore, biomarkers need to be discovered that can aid in assessing an individual’s risk for subsequent cancer. We recently identified a DNA copy number aberration (CNA)-classifier, including changes at 3p26.3-p11.1, 3q26.2-29, and 6p25.3-24.3, as a risk predictor for cancer in individuals presenting with endobronchial squamous metaplasia (van Boerdonk et al, AJRCCM, 2011). The current study was set out to validate this classifier in an independent series of endobronchial squamous metaplastic and dysplastic lesions.

      Methods
      DNA copy number profiles (i.e., chromosomal gains and losses) were determined in a set of endobronchial lesions (8 squamous metaplasia (SqM), and 28 dysplasias (Dys) of various grades), identified and biopsied during autofluorescence bronchoscopy, of 36 high-risk subjects using a nested case-control design. Of the 36 patients, 12 cases had a carcinoma in situ or invasive carcinoma at the same site at follow-up (median 11 months, range 4-24), while 24 controls remained cancer-free (median 78 months, range 21-142). DNA copy number profiles were related to lesion outcome. The prediction accuracy of the predefined CNA-based classifier to predict endobronchial carcinoma (in situ) in this series was determined.

      Results
      All SqM and Dys lesions of controls showed no or a relatively low number of CNAs (i.e., quiescent profile with on average 0.2% altered probe features, range 0.0 – 2.4%), while the majority of lesions of cases showed multiple CNAs (i.e. highly aberrant profile with on average 38.8% altered probe features, range 0.0 – 76.7%). The previously defined CNA-classifier demonstrated 92% accuracy for cancer (in situ) prediction in the current series. All nine subjects with CNA-classifier-positive endobronchial lesions at baseline had cancer as final outcome (i.e., a positive predictive value of 100%). The negative predictive value of the classifier was 89%, i.e., all 24 controls and 3 cases were classified as being low-risk.

      Conclusion
      CNAs are a highly accurate biomarker for assessing the progression risk of endobronchial squamous metaplastic and dysplastic lesions. This classifier could assist in selecting subjects with endobronchial lesions who might benefit from more aggressive therapeutic interventions.