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O.T. Brustugun

Moderator of

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    MS 20 - Joint Imaging/Therapy Conference (ID 38)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Treatment of Locoregional Disease – NSCLC
    • Presentations: 4
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      MS20.01 - Imaging for Surgical Treatment Decision and Planning (ID 1937)

      14:20 - 14:40  |  Author(s): H. Hoffmann, C.P. Heussel

      • Abstract
      • Presentation

      Abstract:
      When patients with early-stage non-small cell lung cancer (NSCLC) are accurately staged inappropriate surgery is avoided and on the other hand potentially curative surgical resection is not refused. The clinical algorithms using imaging studies for staging lung cancer patients with regard to surgical treatment decision and planning as recommended by current guidelines will be presented and discussed. Low-dose CT screening is now recommended for asymptomatic select patients who are at high risk for lung cancer and an increasing number of patients may come to clinical attention during screening. CT findings suggestive of malignancy in a patient with a solitary pulmonary nodule include larger lesion size, irregular or spiculated borders, upper lobe location, thick-walled cavitation, presence or development of a solid component within a ground glass lesion, and detection of growth by follow-up imaging. The general approach to patients suspected of having lung cancer begins with a thorough history and physical examination (1). Following that, essentially every patient suspected of having lung cancer should undergo a contrast-enhanced diagnostic CT scan of the chest. The diagnostic chest CT scan is an important first step, not only to help define the clinical diagnosis, but to structure the subsequent staging and diagnostic evaluation (1). In patients in whom lung cancer has been demonstrated, consideration must turn toward determining the extent of the disease to identify patients with stage IA, IB, IIA, and IIB disease who can benefit from surgical resection. **Extrathoracic (M) Staging** The purpose of extra thoracic imaging in NSCLC is to detect metastatic disease. Current literature continues to demonstrate that PET and PET-CT scans are superior to conventional staging tests (bone scan and abdominal CT scan) in terms of performance characteristics (1). Recent data confirm the superiority of the performance characteristics of PET and PET-CT scans compared with conventional scans in the evaluation of metastatic disease in key specific distant sites (1). Recommendation (1): In patients with a normal clinical evaluation and no suspicious extra thoracic abnormalities on chest CT being considered for curative-intent treatment, PET imaging (where available) is recommended to evaluate for metastases (except the brain) (Grade 1B). However, positive PET/CT scan findings for distant disease need pathologic or other radiologic confirmation (e.g., MRI of bone) (2). Brain MRI (to rule out asymptomatic brain metastases) is recommended for patients with stage II and higher (2). Patients with stage IB NSCLC are less likely to have brain metastases; therefore, brain MRI is only a category 2B recommendation in this setting (2). **Mediastinal Nodal (N) Staging** Mediastinal lymph node staging in NSCLC is particularly important, because in many cases, the nodal status actually determines whether there is surgically resectable disease. If the contrast-enhanced CT scan shows nodal mediastinal infiltration that encircles the vessels and airways, so that discrete lymph nodes can no longer be discerned or measured, non-resectable disease is evident and no further imaging studies are required to determine the exact N status (1). In patients with discrete mediastinal node enlargement further evaluation is recommended (1, 2). The NCCN Panel assessed studies that examined the sensitivity and specificity of chest CT scans for mediastinal lymph node staging. Depending on the clinical scenario, a sensitivity of 40% to 65% and a specificity of 45% to 90% were reported. PET/CT scans may be more sensitive than CT scans (2). However, in patients with discrete mediastinal node enlargement, the risks of false positive test results from either CT scanning and/or PET scanning are too high to rely on imaging alone to determine the mediastinal stage of the patient, and tissue confirmation is necessary (1). Transesophageal EUS-FNA and EBUS-TBNA have proven useful to stage patients or to diagnose mediastinal lesions; these techniques can be used instead of invasive staging procedures in select patients. When compared with CT and PET, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has a high sensitivity and specificity for staging mediastinal and hilar lymph nodes in patients with lung cancer. In patients with positive nodes on CT or PET, EBUS-TNBA can be used to clarify the results. In patients with negative findings on EBUS-TNBA, conventional mediastinoscopy can be done to confirm the results. **Thoracic Tumor (T) Staging** The size of the tumor, its location and invasion of adjacent structures as reflected in the T status determines resectablity and - in cases with given resectablity - the extent of resection. In patients with T3 tumors or centrally located tumors that may necessitate a pneumonectomy, additional functional evaluation of the patient may be required to determine operability. Contrast-enhanced CT scan is the most commonly used imaging modality for T staging and can provide all the information needed. In select cases (e.g. Pancoast-Tumors) MRI may be useful to diagnose involvement of the brachial plexus and extension into the neural foramina and the spinal canal (3). Infiltration of the mediastinal great vessels, esophagus, trachea, and vertebral body is staged as T4 and usually defines unresectability. Findings on CT scan like obliteration of fat plane between the tumor and the mediastinum, circumference of contact between the tumor and the aorta, and the length of anatomical contact between the tumor and the mediastinum are not definitive signs for invasion. Both CT scan and MRI have similar diagnostic accuracy (56-89% for CT and 50-93% for MRI) in predicting mediastinal invasion, with no modality being considered to be distinctly superior (3). References: 1. Silvestri GA, et al. Methods for Staging Non-small Cell Lung Cancer. Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST 2013; 143(5)(Suppl):e211S–e250S 2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Non-Small Cell Lung Cancer, Version 7.2015, NCCN.org 3. Nilendu C Purandare and Venkatesh Rangarajan.Imaging of lung cancer: Implications on staging and management. Indian J Radiol Imaging. 2015 Apr-Jun; 25(2): 109–120.

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      MS20.02 - Imaging for Radiation Therapy Planning (ID 1938)

      14:40 - 15:00  |  Author(s): J. Bogart

      • Abstract
      • Presentation
      • Slides

      Abstract:
      This session reviews considerations of imaging for radiotherapy planning and delivery with particular focus on available completed and active prospective clinical research. State - of - the - art (intensive) treatment approaches, including definitive concurrent radiotherapy and chemotherapy for locally advanced lung cancer, and stereotactic body radiotherapy for treating early stage lung cancer, depend on the ability to precisely identify sites of gross tumor and surrounding critical normal structures. As such, the incorporation of optimal anatomic and functional imaging studies, both three-dimensional (3D) and four-dimensional (4D), in the radiation planning process has become increasing critical. Prospective trials initiated in the late 1990's were the first studies assessing three-dimensional conformal radiotherapy based on computed tomography simulation. These trials directly assessed the ability to adequately dose 3D targets and permitted implementation of tissue heterogeneity dose correction. The routine inclusion of mediastinal lymph node stations that were not pathologically enlarged was also questioned in the design of these studies, and while the initial prospective study from the University of North Carolina mandated elective nodal irradiation (ENI), subsequent studies performed by the RTOG and NCCTG did not include ENI. These single arm prospective studies suggested improved survival in stage III disease with delivery of high dose conventionally fractionated radiotherapy. Somewhat surprisingly, the landmark RTOG 0617 phase III trial did not confirm these results, but perhaps refinement of target volumes through improved imaging (and treatment planning/delivery) would lead to a different result. Functional imaging with FDG-PET (/CT) has had a profound overall impact on the staging and ultimate therapy for patients with lung cancer, and radiotherapy plans are frequently altered by including FDG-PET imaging data in addition to cross sectional imaging. Moreover, while the treatment volume may be increased, such as inclusion of PET avid mediastinal lymph nodes not enlarged on CT, the radiation target volume may also be reduced particularly in instances with atelectasis or tumor obstruction. Prospective studies in the US and Europe have prospectively assessed the impact of PET on radiotherapy planning. For example, RTOG 0515 reported that PET/CT-derived tumor volumes were smaller than those derived by CT alone and that PET/CT changed nodal GTV contours in most patients. Techniques to determine the gross target volume using PET images vary and include simple visualization and a variety of software / hardware based methods including automated solutions. This remains an area of active investigtion and an understanding of potential pitfalls of PET fusion with CT simulation is necessary in defining target volumes. Retrospective series suggest a correlation between the pre-treatment standardized uptake value (SUV) and survival in patients with non-small cell lung cancer. Though the primary objective of ACRIN 6668 / RTOG 0235 was to assess post-treatment SUV for patients receiving radiotherapy as part of their treatment for stage III NSCLC, pre-treatment FDG-PET SUV (mean and max) were also assessed. While pre-treatment FDG-PET SUV did not predict outcomes, active research is assessing the delivery of differential dosing (via IMRT dose painting) based on variation in PET activity. Understanding the impact of tumor and organ motion during respiration is essential when utilizing highly conformal techniques in treating lung cancer. This is a key component of the simulation process and AAPM Task Group 76 describes various options for tumor motion management in detail. Four-dimensional CT-simulation 4D CT is accomplished by correlating the motion of an external surrogate device to the time signature of CT scans. Multiple scans are acquired during each phase of respiration and should provide sufficient motion detail to properly define the internal target volume (ITV). These phase calibrated images can then be processed into average or maximal intensity projections (MIP), or used directly as a cinema image of the tumor motion. In order to incorporate the extent of tumor motion from breathing during SBRT, contouring on the MIP, as opposed to helical or average intensity images, may be optimal. Tumor motion seen on the 4D CT is only representative of the motion at the time of simulation, so further assessment is needed to ensure this will be representative of tumor motion during the actual treatment. Real-time confirmation of tumor location during treatment, whether using the ITV method, respiratory gating, or tumor tracking may be provided by use of “cine” mode or fluoroscopy. Routine real-time imaging should be performed given the potential for variability in breathing and tumor motion over the treatment course. Image guided radiotherapy (IGRT), particularly KV cone-beam CT (CBCT) or MV – CT, is essential for ensuring accurate tumor targeting during radiotherapy. For example, image guidance capable of confirming the position of the target with each treatment was required for the RTOG 0236 trial.While the majority of clinical experience is based on 3D CBCT, 4D (respiration correlated) CBCT is now commercially available and reduces motion artifact and may have additional advantages over 3D CBCT in the treatment of lung tumors. IGRT also allows for routine assessment of tumor response and anatomic changes over time and facilitates implementation of adaptive radiotherapy approaches. Several experiences have detailed changes in tumor volume during the radiotherapy course and the (potential) impact of revising the radiotherapy plan during therapy. An ongoing prospective randomized phase II trial, RTOG 1106, is studying adaptive radiotherapy in stage III non-small cell lung cancer by incorporating changes in both functional and anatomic imaging. Repeat PET/CT and CT simulation in the midst of RT is performed for all patients on study with the “boost” volume in the experimental arm defined by the repeat PET/CT. The total dose for each patient in the experimental arm is dictated by the boost volume and predicted NTCP toxicity. The RTOG 1106 trial includes evaluation of [18]F-fluoromisonidazole (FMiso) PET imaging, which may help identify areas of hypoxia, in a subset of patients. Magnetic resonance imaging (MRI) traditionally has been reserved for assessment of select lung tumors (potentially) invading soft tissue structures such as chest wall, mediastinum, lung apex in proximity to the brachial plexus (pancoast tumors), and lesions in proximity to the spinal cord. The recent development of a commercial hybrid radiotherapy /MRI unit may expand the role of MRI and permits IGRT (without the need for additional patient exposure to ionizing radiation) while also facilitating soft tisse tracking and adaptive radiotherapy.

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      MS20.03 - Optimal Monitoring After Combined Modality Treatment (Imaging and Markers) (ID 1939)

      15:00 - 15:20  |  Author(s): M. Macmanus

      • Abstract
      • Presentation

      Abstract:
      When response assessment is carried out after definitive high-dose radiation therapy (RT) or chemoRT for patients with locally-advanced non-small cell lung cancer (NSCLC), it should give an early indication of the likely prognosis of the patient. Ideally it should identify those patients most likely to experience long term freedom from progression, who require no further therapy, and it should further identify patients with persistent or progressive disease who could benefit from additional therapy or who may be candidates for clinical trials of investigational treatments designed to improve their poor prognosis. In usual clinical practice, response assessment in NSCLC involves the use of structural imaging with computed tomography (CT), to assess the effect of treatment on tumor volumes. The initial dimensions of tumor sites are compared with their dimensions after treatment, either on a single occasion or with serial images acquired over time. Potential sites of distant disease progression are also sought within the field of view of the restaging CT scan although this is a relatively insensitive test for small volume metastatic tumour. Another possible approach to response assessment is to employ a global measure of the success of therapy, typically by analysing serial blood samples for a tumor-specific biomarker. A sensitive blood-based assay could potentially detect the presence of very small amounts of persistent tumor, beyond the resolution of currently available imaging modalities. A disadvantage of a blood test compared to imaging in a locoregionally confined rather than a metastatic cancer is the absence of any indication of the likely location of persistent or recurrent disease, making it impossible to implement any local salvage therapies without additional information. However, a combination of a sensitive biomarker and state of the art imaging could potentially provide detailed and clinically useful prognostic information after therapy. The use of both local and global approaches to response assessment will be discussed.Using Imaging to assess local Treatment Response in NSCLCStructural Imaging Traditionally, serial imaging with CT has been used to assess treatment response in NSCLC. Serial tumor measurements are compared with specific response assessment criteria, enshrined in systems such as the Response Evaluation Criteria In Solid Tumors (RECIST) [1]. Patients are categorized by RECIST as having either; Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started, or Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Although these categories have prognostic significance, they can be an unreliable predictor of ultimate survival in individual cases. Tumor masses are often slow to resolve after RT and their margins may be obscured by fibrotic or consolidated lung, making accurate measurements impossible. The very concept of remission is hard to define after RT in NSCLC because of the changes in the thorax that occur due to a combination of invasion and destruction of parenchyma by tumor and of the morphological changes that result from atelectasis, radiation pneumonitis and radaition induced pulmonary fibrosis. Fibrotic masses may persist indefinitely even in cured cases. Regions of dense fibrosis can harbor persistent tumor that only becomes apparent when regrowth occurs months or years after treatment is complete. The CR category, with disappearance of all lesions, may be especially hard to define on CT imaging. CT scanning, although it is the standard response assessment modality in clinical trials, has very significant limitations when used for this purpose.Functional Imaging with PET Some of the limitations of CT can be transcended by the use of molecular imaging. The advent of positron emission tomography (PET), using [18]F-fluoro-deoxyglucose (FDG) as the tracer, has provided a means of “seeing inside” areas of fibrosis and persistent mass lesions and identifying focal areas of persistent tumor. Furthermore PET imaging compensates for another major limitation of CT, that of its poor sensitivity and specificity for assessing the true status of mediastinal nodes. Unlike CT, PET can detect tumor in small (<1cm short axis) mediastinal nodes and correctly defines enlarged reactive nodes as non-malignant in the great majority of cases. Several meta-analyses have confirmed the superiority of PET-based mediastinal staging in this regard, making it a logical choice for re-staging the mediastinum after therapy. Prospective data have shown the superiority of PET-based response assessment compared to CT-based response assessment after RT in NSCLC. Our group developed FDG-PET response criteria based on visual assessment and used them prospectively in patients treated with RT/chemoRT [2]. Patients were classified into four metabolic response categories groups, namely; 1) Complete Metabolic Response (CMR): tumor FDG uptake absent or less than mediastinal blood pool. 2) Partial Metabolic Response (PMR): appreciable reduction in the intensity of tumor FDG uptake or tumor volume. 3) Stable Metabolic Disease (SMD): no appreciable change in intensity of tumor FDG uptake or volume. 4) Progressive Metabolic Disease (SMD); any new sites of disease, and/or an appreciable increase in intensity of tumour FDG uptake or volume in known tumor sites. In 73 patients, PET response was evaluated at a median of 70 days post-treatment. PET and CT responses were the same in only 40% of cases and PET response predicted survival much better than CT response. There were many more complete responders on FDG criteria (n=34) compared to CT (N=10), and no patients were inevaluable by PET on compared to 6 on CT. In this study, PET was clearly far superior to CT and in an expanded cohort it was clear that a poor PET response was strongly associated with distant metastasis [3]. Without standardization, the use of visual response criteria may be limited by interobserver variability. The Deauville criteria were developed specifically for use in lymphoma in an effort to standardise visual response assessment by comparing residual tumor FDG uptake with uptake in the liver and mediastinum [4]. Another way to reduce interobserver variability is to use a semi-quantitative method of response assessment, such as by comparing pre- and post treatment standardized uptake values (SUV). Although this is an attractive approach, accuracy may be affected by differences technique on different scanning occasions and by the fact that after treatment, uptake of FDG in radiation penumonitis is often within the range associated with the presence of tumor. This is especially so after high dose hypofractionated stereotactic body radiotherapy (SBRT). It is inappropriate therefore to consider a particular SUV cut-off as being diagnostic of persistent disease. Uptake in lung affected by radiation pneumonitis can also hamper visual response assessment but on a qualitative reading of the scan, pattern recognition can take this into account and still provide valuable prognostic information [5]. Despite the apparent superiority of PET for response assessment, no large prospective studies have yet helped refine how this information might be used. The ideal time for imaging is undecided. A longer interval between treatment and imaging is likely to be associated with greater accuracy but less clinical utility. The use of PET imaging during RT is being actively explored by several groups but remains investigational. In anecdotal cases, patients with resectable PET-detected residual disease have undergone successful salvage surgery after RT but large prospective trials are required to validate this approach.Use of circulating biomarkers to measure global treatment response in NSCLC In some cancers, the use of biomarkers in the blood to monitor disease status is a well established part of standard management. Commonly used circulating biomarkers include paraproteins in multiple myeloma, prostate specific antigen in prostate cancer and alpha-fetoprotein and human chorionic gonadotrophin in germ cell tumors. These markers can be highly specific and sensitive and can be used to guide therapy. However, in NSCLC, the search for a practical circulating biomarker with wide application has been hampered by the extreme heterogeneity of this group of diseases. Two of the most intensely investigated tumor biomarkers in NSCLC have been carcinoemryonic antigen (CEA), which is commonly detected in adenocarcinoma and CYFRA21-1 which can be detected in squamous carcinoma. In a review of the literature in 2012, Grunnet and Sorensen analysed the level of CEA as a prognostic marker in NSCLC in 23 studies of serum and two of plasma [6]. In 18 studies CEA was found to be a prognostic marker for either overall survival OS, recurrence after surgery and/or progression free survival (PFS) in NSCLC patients. The remaining 7 studies contained an excess of patients with squamous carcinoma. One study found that a tumor marker index (TMI), based on preoperative CEA and CYFRA21-1 serum levels was useful as a prognostic marker for OS. Six studies evaluated the use of CEA as a predictive marker. Four of these studies found, that serial CEA measurement had some potential as a predictive marker for recurrence and death. Although a combination of CEA and CYFRA21-1 markers have some value in a proportion of patients with NSCLC the heterogeneity of their expression limits their role in response assessment after RT [7]. Measurement of circulating tumor (ct)DNA has shown promise as a "liquid biopsy" for assessing cancer burden but ctDNA detection methods have to date been insensitive or lacked the broad coverage needed to permit clinical application in NSCLC where genetic variation is extreme. Because background circulating DNA is present in healthy individuals, tumour derived ctDNA can be detected and quantified only if it contains a tumour specific sequence. Diehn and colleagues at Stanford reported a breakthrough in ctDNA in NSCLC, which they called “Cancer Personalized Profiling by Deep Sequencing” (CAPP-Seq) [8]. This is an ultrasensitive method for quantifying ctDNA with clinical applicability. CAPP-Seq was implemented in NSCLC patients with a design covering multiple classes of somatic alterations that identified mutations in >95% of tumours. The method detected ctDNA in 100% of patients with stage II–IV NSCLC and in 50% of patients with stage I disease, with 96% specificity for mutant allele fractions down to ~0.02%. At least one, and on average 4, mutations were covered in >95% of patients. Levels of ctDNA detected by CAPP-Seq were highly correlated with tumour volume and helped distinguish between residual disease and treatment-related imaging changes in several cases. A large clinical trial is being planned to establish the utility of ctDNA for monitoring disease status after RT in NSCLC.Conclusions Structural imaging with CT gives useful prognostic information after RT in NSCLC but is inferior to FDG-PET. Of all of the blood based methods for estimating global tumour burden, ctDNA analysis seems the most promising at present. A combination of PET and ctDNA could potentially provide prognostic information of previously unattainable accuracy and utility.References1. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205-216.2. Mac Manus MP, Hicks RJ, Matthews JP, et al. Positron emission tomography is superior to computed tomography scanning for response-assessment after radical radiotherapy or chemoradiotherapy in patients with non-small-cell lung cancer. J Clin Oncol 2003;21:1285-1292.3. Mac Manus MP, Hicks RJ, Matthews JP, Wirth A, Rischin D, Ball DL. Metabolic (FDG-PET) response after radical radiotherapy/chemoradiotherapy for non-small cell lung cancer correlates with patterns of failure. Lung Cancer 2005;49:95-108.4. Gallamini A, Barrington SF, Biggi A, et al. The predictive role of interim positron emission tomography for Hodgkin lymphoma treatment outcome is confirmed using the interpretation criteria of the Deauville five-point scale. Haematologica 2014;99:1107-1113.5. Hicks RJ, Mac Manus MP, Matthews JP, et al. Early FDG-PET imaging after radical radiotherapy for non-small-cell lung cancer: inflammatory changes in normal tissues correlate with tumor response and do not confound therapeutic response evaluation. Int J Radiat Oncol Biol Phys 2004;60:412-418.6. Grunnet M, Sorensen JB. Carcinoembryonic antigen (CEA) as tumor marker in lung cancer. Lung Cancer 2012;76:138-143.7. Okamura K, Takayama K, Izumi M, Harada T, Furuyama K, Nakanishi Y. Diagnostic value of CEA and CYFRA 21-1 tumor markers in primary lung cancer. Lung Cancer 2013;80:45-49.8. Newman AM, Bratman SV, To J, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med 2014;20:548-554.

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      MS20.04 - Prevention, Diagnosis and Treatment of Radiation Pneumonitis (ID 1940)

      15:20 - 15:40  |  Author(s): L. Gaspar

      • Abstract
      • Presentation

      Abstract not provided

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Author of

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    MINI 06 - Quality/Prognosis/Survival (ID 111)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Localized Disease - NSCLC
    • Presentations: 1
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      MINI06.10 - Discussant for MINI06.06, MINI06.07, MINI06.08, MINI06.09 (ID 3545)

      17:35 - 17:45  |  Author(s): O.T. Brustugun

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    ORAL 06 - Next Generation Sequencing and Testing Implications (ID 90)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      ORAL06.01 - Genomic Characterization of Large-Cell Neuroendocrine Lung Tumors (ID 1667)

      11:05 - 11:16  |  Author(s): O.T. Brustugun

      • Abstract
      • Slides

      Background:
      Neuroendocrine lung tumours account for 25% of all lung cancer cases, and they range from low-aggressive pulmonary carcinoids (PCA) to highly malignant small-cell lung cancer (SCLC) and large-cell neuroendocrine lung carcinoma (LCNEC). The last two are strongly associated with heavy smoking and are typically detected at a clinically advanced stage, having a poor survival. Comprehensive genomic analyses in lung neuroendocrine tumours are difficult because of limited availability of tissue. While more effort has been done in the context of SCLC, the detailed molecular features of LCNEC remain largely unknown.

      Methods:
      We conducted 6.0 SNP array analyses of 60 LCNEC tumours, exome sequencing of 55 tumor-normal pairs, genome sequencing of 11 tumour-normal pairs, transcriptome sequencing of 69 tumours, and expression arrays on 60 tumors. Data analyses were performed using in house developed and published pipelines.

      Results:
      Analyses of chromosomal gene copy number revealed amplifications of MYCL1, FGFR1, MYC, IRS2 and TTF1. We also observed deletions of CDKN2A and PTPRD. TTF1 amplifications are characteristic of lung adenocarcinoma (AD); CDKN2A deletions are frequent alterations in both AD and squamous-cell lung carcinoma (SQ); FGFR1 amplifications are found in SQ and, less frequently, in SCLC; and MYCL1 and IRS2 amplifications are frequent events in SCLC. Similar to the copy number data, we found patterns of mutations characteristic of other lung cancer subtypes: TP53 was the most frequently mutated gene (75%) followed by RB1 (27%), and inactivation of both TP53 and RB1, which is the hallmark of SCLC, occurred in 20% of the cases. Mutations in STK11 and KEAP1-NFE2L2 (frequently seen in AD and SQ) were found in 23% and 22% of the specimens, respectively. Interestingly, mutations in RB1 and STK11/KEAP1 occurred in a mutually exclusive fashion (p-value=0.016). Despite the heterogeneity observed at the mutation level, analysis of the pattern of expression of LCNEC in comparison with the other lung cancer subtypes (AD, SQ, SCLC, and PCA) points to LCNEC as being an independent entity. An average mutation rate of 10.7 mutations per megabase was detected in LCNEC, which is in line with the rate observed in other lung tumours associated with smoking. We found that, similar to SCLC, the mutation signatures associated with APOBEC family of cytidine deaminases, smoking, and age (based on Alexandrov et al 2013) were the predominant ones in LCNEC. However, the contribution of the individual SCLC and LCNEC samples to these three signatures was quite different, and we are currently exploring it.

      Conclusion:
      Taking into account somatic copy number and mutation data, we distinguished two well-defined groups of LCNEC: an SCLC-like group, carrying alterations in MYCL1, ISR2, and in both RB1 and TP53; and a group resembling AD and SQ, with alterations in CDKN2A, TTF1, KEAP1-NFE2L2, and STK11. Although these results suggest that LCNEC might be a mix of different lung cancer subtypes, mutation clonality and expression analyses show that they are likely to be a separate entity, sharing molecular characteristics with the other lung cancer subtypes. Their heterogeneity suggests that LCNEC might represent an evolutionary trunk that can branch to SCLC or AD/SQ.

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    ORAL 19 - Radiation for Localized Lung Cancer (ID 126)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Localized Disease - NSCLC
    • Presentations: 1
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      ORAL19.01 - The SPACE Study: A Randomized Phase II Trial Comparing SBRT and 3DCRT in Stage I NSCLC Patients; Final Analysis including HRQL (ID 923)

      10:45 - 10:56  |  Author(s): O.T. Brustugun

      • Abstract
      • Presentation
      • Slides

      Background:
      Stereotactic body radiotherapy (SBRT) for NSCLC patients with T1-T2 tumors has been intensively studied the last decades and is widely used due to excellent results in terms of local control and survival in combination with the convenient and fast treatment procedure. This radiation technique has however never been compared to standard radiotherapy in a randomized manner, and consequently the Swedish lung cancer study group launched the SPACE study in 2007 (Stereotactic Precision And Conventional radiotherapy Evaluation).

      Methods:
      Patients with stage I medically inoperable histologically confirmed NSCLC or PET-positive tumors with progression (non-centrally located with a maximum size < 5 cm) were randomized in 9 Scandinavian centers to receive SBRT to 66 Gy in 3 fractions in one week or conventionally fractionated 3DCRT to 70 Gy in 7 weeks. Patients were followed with regard to treatment efficacy, toxicity and HRQL.

      Results:
      Between January 2007 and July 2011 102 patients were randomized (49 SBRT, 53 3DCRT). Mean age 74 (57-86), 60% women and the vast majority (92%) had COPD or cardiovascular comorbidity. The mean FEV1 and mean CO-diffusion capacity were 1.4 L and 55% respectively. Seventy-four percent had a histopathologic diagnose where the majority were adenocarcinomas and 65% had T1 tumors and 35% T2. The two treatment groups differed somewhat in terms of tumor size and gender where the SBRT arm included more patients with T2 tumors and of male gender. The median follow-up is 37 months with a 1- 2- and 3 year PFS of: SBRT: 89%, 70%, 62% and 3DCRT: 88%, 66% 58% with no difference between the groups and no difference regarding OS. At the end of study 72% were without progression among the SBRT patients compared to 59% in the conventional arm. Toxicity was generally low, grade ≥ 3 of any toxicity was observed in 19% in SBRT patients and 15% in the 3DCRT group with no grade 5 toxicities. Pneumonitis of any grade was observed in 19% (SBRT) and 36% (3DCRT), and any grade esophagitis in 8% and 30% respectively. HRQL was evaluated with the EORTC QLQ 30 and LC14 module and patients treated with 3DCRT experienced worse dyspnea, cough and chest pain compared to the SBRT patients.

      Conclusion:
      NSCLC stage I patients treated with SBRT had the same PFS and OS as the conventionally treated patients despite an imbalance of prognostic factors with regards to more T2 tumors and males in the SBRT group. There was a tendency to improved disease control rate in the SBRT patients and in addition they experienced higher QoL values regarding dyspnea, cough and chest pain. SBRT should be considered standard therapy for this patient group.

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    P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P1.04-060 - Pathways Involved in Lung Adenocarcinomas, - Integrated Analyses on Methylation and mRNA Data (ID 2699)

      09:30 - 09:30  |  Author(s): O.T. Brustugun

      • Abstract
      • Slides

      Background:
      Lung cancer is one of the biggest cancer killers in the world. Despite certain recent advances, mortality is still high. Targeted therapy has increased the time to death for metastastic lung cancer, but such therapy is not available for all lung cancer patients. Targeted therapy is more often available for never smokers, due to presence of druggable driver mutations. In order to search for new putative targets of therapy, we seek to identify pathways involved different subgroups of patients and in patients with early relapse.

      Methods:
      A total of 190 patients undergoing surgery for lung cancer were included in the study (154 EGFR positive, 23 EGFR negative, 170 smokers and 20 non-smokers). Lung cancer tissue and clinical information was available for all patients and normal lung tissue was available for 30 of the patients. Whole genome expression array analysis (Agilent) was performed using mRNA isolated from all samples and DNA-methylation was analysed for 168 tumours and 21 matched normal lung tissue samples. R was used for statistical analyses; annHeatmap (from Heatplus) for hierarchical clustering, limma to identify differentially expressed genes, SPIA for pathway analysis and canonical correlation of methylation and mRNA-expression was performed with the CCA function from the PMA package. Pathways with an FDR<0.1 were considered significant. DAVID was used for gene ontology analysis.

      Results:
      Based on correlation of mRNA and methylation, different pathways were identified as predominant in specific subgroups of lung adenocarcinomas. Preliminary results indicate that genes involved in the KEGG-pathways cell cycle are more highly expressed in EGFR positive than in EGFR negative tumours in smokers. In the EGFR-negative tumours, several pathways are up-regulated: Oocyte meiosis, progesterone-mediated oocyte maturation, HTLV-1 infection, p53 signalling pathway and small cell lung cancer. For non-smoking patients, four pathways were up-regulated in EGFR-positive tumours: ECM-receptor interaction, TGF-beta signalling pathway, bile secretion and cocaine addiction. There were no pathways up-regulated in EGFR-negative compared with EGFR-positive never-smokers. This may partly be due to small numbers. Similarly, pathways dominating the tumours of patients with early relapse will be identified. Genes whose expression and methylation status were correlated were identified within smokers and non-smokers separately.

      Conclusion:
      Based on correlation between mRNA and methylation, specific pathways were identified activated in subgroups of lung adenocarcinomas. There are significant differences between ever-smokers and never-smokers. Survival analyses are ongoing.

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    P1.07 - Poster Session/ Small Cell Lung Cancer (ID 221)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Small Cell Lung Cancer
    • Presentations: 1
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      P1.07-001 - Preoperative Serum proGRP as a Predictor for Lung Tumor Histology (ID 2561)

      09:30 - 09:30  |  Author(s): O.T. Brustugun

      • Abstract
      • Slides

      Background:
      Progastrin-releasing peptide (proGRP) is the stable precursor of gastrin-releasing peptide, a hormone secreted by neuroendocrine cells. Serum measurements of proGRP are helpful to detect relapses of small cell carcinoma during follow up, but its usefulness as a preoperative marker to distinguish between different lung tumors is unclear.

      Methods:
      Preoperative serum proGRP was determined in 116 patients with primary pulmonary tumors. 31% of the tumors displayed endocrine features (19 carcinoids, 8 small cell carcinoma, 9 large cell carcinomas) whilst the remainder were non-small cell carcinomas (40 adenocarcinomas and 40 squamous cell carcinomas). The presence of proGRP in tumors with possible endocrine features was evaluated by immunohistochemistry using two in-house anti-proGRP monoclonal antibodies (mAb M16 and mAb E149]. Tumors with less than 2 % positive cells were considered negative for proGRP expression. Serum levels of proGRP above 70 ng/L were considered elevated.

      Results:
      Mean serum proGRP (s-proGRP) was 267 ng/L (median: 96.5 ng/L, [range 25 – 2080 ng/L] for the neuroendocrine tumors, while adenocarcinomas and squamous cell carcinomas had mean values of 50 and 60 ng/L respectively [19,137] and median values 53.5 ng/L and 59.6 ng/L respectively (table 1). Among the tumors with possible endocrine features, serum levels of proGRP reflected the IHC score (Wilcoxon rank-sum test, p<0.0005). We did not find any relationship between tumor size and s-proGRP levels, but values >70 ng/L were predictive of either carcinoid tumor or small cell carcinoma. Table 1: Tumor characteristics

      Histology ProGRP IHC positives (n/total) S-proGRP (median) S-proGRP (mean) Mean tumor size (mm)
      Carcinoid 9/19 127 424 26.1
      Small cell carcinoma 5/8 75.5 145 30.2
      Large cell carcinoma 3/9 46 72.8 42.2
      Squamous cell carcinoma NA 59.6 60 NA
      Adenocarcinma NA 53.5 50 NA


      Conclusion:
      The correlation between s-proGRP and IHC scores suggest that the elevated s-proGRP results from proGRP produced by the tumor. The lack of correlation between s-proGRP and tumor size might be explained by variations in number of proGRP producing cells within the different tumors and/or to the amount proGRP secreted by different tumors. For lung tumors with unclear preoperative histology or cytology, s-proGRP-levels can be helpful as an adjuvant diagnostic marker to differentiate between tumors with and without endocrine features, but the test is not robust enough for final decision making.

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    P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P2.04-011 - Whole-Genome Copy Number Analyses of NSCLC Tumors Reveal Aberrations Associated With EGFR Mutations and May Have Prognostic Impact (ID 1504)

      09:30 - 09:30  |  Author(s): O.T. Brustugun

      • Abstract
      • Slides

      Background:
      Knowledge about genetic alterations in Non-Small Cell Lung Cancer (NSCLC) has given us a significant insight in the biology of these tumors. It is of great clinical importance with consequences for the patients, and DNA mutations and translocations are currently targets for therapy. Aberrations in DNA copy number are frequent events in NSCLC tumors and important in tumorogenesis. In this present study we want to investigate how the copy number changes varies between different subgroups of NSCLC tumors based on the patients’ smoking status, histology or EGFR-, KRAS- and TP53 mutations. The DNA copy number data will be integrated with global mRNA expression to study the cis-associated mRNA expression changes. Last, we want to investigate whether genomic events, like specific copy number changes or the complex arm-wise aberration index (CAAI), have prognostic impact in patients with NSCLC.

      Methods:
      In this study we have included 200 patients with operable NSCLC tumors. Copy number data were obtained by using the Affimetrix Genome-wide human SNP array 6.0. Histopathological information, EGFR-, KRAS- and TP53 mutation status were determined and clinical information and follow-up data was obtained for all patients. The mRNA expression was determined by the Agilent 60K mRNA expression array on a subset of 117 patients. The data was analyzed by using bioinformatic tools like ASCAT and integration of the mRNA data and the survival analyses are on-going.

      Results:
      Preliminary results have shown that copy number aberrations are frequent events in NSCLC tumors, consistent with previous reports. We have identified that the copy number patterns differ between adenocarcinomas and squamous cell carcinomas, and between tumors from patients with different smoking history. However, the largest differences were found between the EGFR-mutated adenocarcinomas compared with EGFR wildtype tumors, where we identified a specific pattern of copy number changes in the tumors that harbour EGFR mutation. These changes were mainly located at chromosome arm 1p, 2p, 3q, 5q, 7, 12 and 13. Preliminary analyses have also identified specific copy number aberrations with prognostic significance.

      Conclusion:
      Copy number aberrations are frequent in NSCLC tumors and may have great impact on gene expression and give us valuable prognostic information. EGFR-mutated adenocarcinomas have a specific pattern of copy number changes, which provides new insight of the biology of these tumors.

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    P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 4
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      P3.04-030 - Are Experienced Physicians More Likely to Acquire Adequate Tissue Material for EGFR-Testing? (ID 2405)

      09:30 - 09:30  |  Author(s): O.T. Brustugun

      • Abstract
      • Slides

      Background:
      Epidermal Growth Factor Receptor (EGFR) mutation testing is now recommended practice for non-squamous non-small cell lung cancer. The patients with activating EGFR mutations are eligible for targeted personalized treatment offering better survival and quality of life, often with low toxicity. However, little is known about how the physician’s level of experience influences the quality of samples taken for EGFR-analysis and if complicated interventions result in more inadequate samples. We therefore performed a retrospective analysis on correlation between doctors’ experience and tissue quality at a moderately-sized community hospital.

      Methods:
      The Norwegian Lung Cancer Group (NLCG) recommended EGFR- testing of all patients with non-small cell lung carcinoma from June 2010. In March 2013 squamous cell carcinomas were excluded. Basic demographic data, sample type, test results and procedure related complications were recorded for the period June 2010 to December 2013, and the level of experience (measured as inexperienced physicians having less than 10 procedures per year) of the involved physicians was recorded.

      Results:
      Material was sent for EGFR analysis for 256 of the 304 eligible patients diagnosed in the period. For a total of 34 patients (13%) the first biopsy was not analyzed at department of molecular pathology due to inadequate tumor material. The tissue collected by experienced physicians was sufficient for EGFR analyses in 91-97.2% (median 93%), compared to 50-90% (median 86.7%) for the less experienced physicians. For image supervised biopsies, non-analyzable samples were more frequent when puncturing small (<3 cm) peripheral tumors than when taken from large central tumors. Of 14 image guided biopsies that were returned because of inadequate tumor tissue, only two had complications: one with bleeding and the other with pneumothorax. Both tumors were peripheral. Of three bronchoscopical biopsies that were returned due to inadequate tumor tissue, one was complicated by major bleeding, in another the patient was very restless during the procedure. The last was uncomplicated.

      Conclusion:
      Our results show that the quality of image guided biopsies taken by more experienced physicians is better than those taken by doctors with less experience. For small peripheral tumors, the frequency of non-analyzable samples were higher than for large central tumors taken by image guided biopsy.

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      P3.04-056 - Some Lung Cancer Patients End up without an EGFR-Mutation Analysis (ID 2394)

      09:30 - 09:30  |  Author(s): O.T. Brustugun

      • Abstract
      • Slides

      Background:
      Lung cancer patients with activating mutations in the EGFR-gene are eligible for targeted therapy with tyrosine kinase inhibitors, and clinicians strive for acquiring enough tumor tissue for the needed diagnostic analyses. However, not all patients have an EGFR-test, and little is known about the subsequent steps for patients with inadequate first biopsy.

      Methods:
      Data on the diagnostic work-up on all NSCLC patients eligible for EGFR-testing was collected at a medium-sized Norwegian hospital for the period June 2010 to December 2013. For samples without successful EGFR-mutation results, we recorded possible explanations.

      Results:
      Material was sent for EGFR analysis for 256 of the 304 eligible patients diagnosed in the period. For a total of 34 patients (13%) the first biopsy was not analyzed at the department of molecular pathology due to inadequate tumor material. Of these 34 patients, 23 (65%) had no new sample submitted for analysis. 13 of the 23 (57%) were in stage IV, and of these, three did not want active treatment and one was not a candidate for active treatment because of poor general condition. One patient was not ​​re-biopsied due to rapid disease progression. Eigth patients were for no obvious reason never considered for re-biopsies, including a younger patient who had brain metastases at the time of diagnosis, but who lived for 19 months after diagnosis. One of the 11 sent was diagnosed with activating EGFR mutation in the second sample sent for analyses. For patients with rejected samples, EGFR results were available after 17 - 69 days (median 38) from rejection of the first sampling.

      Conclusion:
      For 65% of the rejected samples, no new samples were submitted for analysis. 57% of the patients with no new sample taken, were in stage IV. When a new biopsy was planned, our study shows that EGFR results from the new sampling were available after median 38 days. For this patient group, with poor prognosis and often rapid disease progression, one should strive for a new sampling and a quicker turn-around time.

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      P3.04-087 - NUT Expression in Surgically Treated Small Cell, Non-Small Cell and Carcinoid Tumors of the Lung (ID 451)

      09:30 - 09:30  |  Author(s): O.T. Brustugun

      • Abstract
      • Slides

      Background:
      NUT midline carcinoma (NMT) is a rare, highly aggressive carcinoma defined by rearrangement of nuclear protein gene in testis (NUT) on chromosome 15; in most cases to bromodomain-containing protein 4 (BRD4) on chromosome 19. Although the majority of cases occur in midline structures above the diaphragm there are reports regarding cases in non-midline solid organs. There is an increased need to identify tumors with targetable mutations, and NUT-BRD4 translocations are potential goals for bromodomain and extra terminal (BET) inhibitors. The putative incidence among lung carcinomas low, but the true incidence is unknown.

      Methods:
      In a tissue micro array (TMA) set we investigated samples from 483 surgically resected lung tumors for the expression of the NUT protein using immunohistochemistry with monoclonal anti-NUT antibody (clone C52B1, Cell Signaling). 278 were adenocarcinomas, 140 squamous cell carcinomas, 30 large cell carcinomas, 7 small cell carcinoma, 18 carcinoid tumours and 10 carcinoma not otherwise specified. The median age were 66.3 [33.9 – 87.0], 247 were males and 236 were females. Testis and two previously confirmed NMT served as positive controls. Lymph nodes and normal lung tissue served as negative controls.

      Results:
      The positive controls had distinct nuclear staining without any unspecific background. The negative controls and all tumours were completely negative for the anti-NUT staining.

      Conclusion:
      We did not find any NUT expression in the investigated set of tumors. The golden standard for showing NUT rearrangement are fluorescence in situ hybridization (FISH), but the sensitivity and specificity for immunohistochemistry are high, 87% and 100% respectively (Haack et al. Am J Surg Pathol 2010). Although we cannot exclude a minority to be false negative, NUT translocations does not seem to be a relevant differential diagnostic issue in unselected early stage lung carcinomas.

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      P3.04-125 - Cytokine Profiles in Non-Small Cell Lung Cancer Patients Undergoing Palliative Thoracic Radiotherapy; Predictor of Response? (ID 2588)

      09:30 - 09:30  |  Author(s): O.T. Brustugun

      • Abstract
      • Slides

      Background:
      A majority of patients with non-small cell lung cancer are diagnosed in later stages of disease where no curative treatment is currently available. The prognosis for these patients is poor. Median survival from diagnosis in stage IV is approximately 9 months. Many patients will benefit from external radiotherapy to the thorax for alleviation of symptoms due to advanced lung cancer. Despite adequate radiotherapy, however, many tumors progress locally in the radiation field. Here, we investigate whether the kinetics of cytokines in serum can be utilized as predictors for tumor response to radiotherapy and/or predictors of lung toxicity.

      Methods:
      Patients with histologically confirmed non-small cell lung cancer, eligible for palliative radiotherapy to the hilus-mediastinum, were included in a randomized phase II clinical trial; the ThoRaT-study. Patients were randomised to 1 of 2 study arms undergoing thoracic radiotherapy, 3 Gy x 10, with or without the addition of erlotinib concomitant with radiotherapy treatment. Side effects were recorded and graded according to CTC version 4.0. Clinical response in the radiation field was evaluated by CT or PET-CT scans. Blood serum was sampled at different time points; prior to treatment, at mid-therapy, at the end of therapy and 6 week following treatment completion. Multiplex immunoassays were used to measure serum concentration of 52 cytokines and 9 MMPs on all collected samples. Serum samples from COPD patients were included as controls.

      Results:
      Cytokine analyses of serum samples are ongoing and have to date been performed on 43 non-small cell lung cancer patients. Pre-treatment and follow up CT/PET-CT scans are currently under revision. Preliminary investigations show considerable variation in cytokine patterns between the patients and between different time points for some of the cytokines. Analyses of possible predictors for radiotherapy response and toxicity, as well as comparison with normal controls are currently ongoing and will be presented.

      Conclusion:
      We hypothesize that pre-treatment cytokine values and/or kinetics of concentration changes may provide information on the probability of clinical response and side effects from radiotherapy.

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    P3.06 - Poster Session/ Screening and Early Detection (ID 220)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Screening and Early Detection
    • Presentations: 1
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      P3.06-011 - Unique Combination of 6 Circulating microRNAs for Early Detection of Lung Cancer (ID 2130)

      09:30 - 09:30  |  Author(s): O.T. Brustugun

      • Abstract
      • Slides

      Background:
      Worlwide, lung cancer is the primary cause of cancer death. Today 75% of patients are diagnosed in a locally advanced or metastatic inoperable stage, and a new tool for early detection of lung cancer is urgently needed in order to improve the outcome. Circulating microRNAs have emerged as stable, non-invasive and promising biomarkers for diagnosis, prognostication and prediction in cancer. The purpose of this study was to identify circulating microRNAs for detection of early stage lung cancer, capable of discriminating lung cancer patients from those with chronic obstructive pulmonary disease (COPD) and healthy normal individuals.

      Methods:
      We profiled the expression of 756 unique microRNAs in sera from 38 patients with NSCLC, 16 patients suffering from COPD and 16 healthy volunteers, to explore the potential of the microRNAs as diagnostic biomarkers. For validation of our results, we analyzed serum from an independent cohort of high-risk individuals enrolled in the IELCAP screening trial (n=161) using RT-qPCR

      Results:
      Focusing on microRNAs upregulated in sera from lung cancer patients, we identified a unique set of 6 microRNAs with significantly higher abundance compared with sera from COPD patients and healthy normals. Validation of the 6-miR signature demonstrated a sensitivity of 86% and specificity of 79.3%

      Conclusion:
      Considering their accessibility and stability, circulating microRNAs can be a diagnostic tool for clinicians in the future, and may lead to increased fraction of lung cancers diagnosed in an early curative stage. The 6-miR signature may be a basis for a screening study and can easily be implemented in the clinic to identify those who should be further examined for lung cancer

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    P3.07 - Poster Session/ Small Cell Lung Cancer (ID 223)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Small Cell Lung Cancer
    • Presentations: 2
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      P3.07-014 - Associations between Comorbidity, Treatment Toxicity and Overall Survival in Limited Disease Small-Cell Lung Cancer (LD-SCLC) (ID 2739)

      09:30 - 09:30  |  Author(s): O.T. Brustugun

      • Abstract
      • Slides

      Background:
      Concurrent chemotherapy and thoracic radiotherapy (TRT) is the recommended treatment of LD-SCLC. The treatment often causes severe toxicity. Many patients have comorbidity due to old age and smoking, and it is unclear whether these patients tolerate and benefit from the treatment as much as more fit patients. Studies have shown that comorbidity is a negative prognostic factor in many cancers (including lung cancer), but this has not been investigated in LD-SCLC patients receiving chemo-radiotherapy. We investigated whether comorbidity was a prognostic factor or associated with severe toxicity in a randomized trial comparing two schedules of TRT in LD-SCLC (n=157).

      Methods:
      Patients received four courses of cisplatin plus etoposide and were randomized to receive concurrent TRT of either 45 Gy/30 fractions (twice daily) or 42 Gy/15 fractions (once daily). Responders were offered prophylactic cranial irradiation of 30 Gy/15 fractions. The Charlson Comorbidity Index (CCI) was used to assess comorbidity from hospital medical records. The CCI rates common conditions associated with increased 1-year mortality with scores of 1, 2, 3 or 6 based on severity - and a total score (“CCI-score”) is calculated. Toxicity was assessed using the CTCAE v3.0. We adjusted for treatment arm and established baseline prognostic factors in lung cancer (gender, stage of disease, appetite loss, weight-loss, age and performance status (PS) in the multivariate analyses.

      Results:
      157 patients were analyzed (100%). Median age was 63 years, 52% were men, 16% had PS 2, 72% stage III, 30% weight-loss >5% last 3 months and 46% received twice-daily TRT. The most common grade 3-4 toxicities were pneumonitis (n=4; 3%); esophagitis (n=50; 32%) and neutropenic infections (n=64; 41%). 4 patients (3%) died from pneumonitis. 63 patients (40%) had CCI-score 0; 54 (34%) CCI-score 1; 23 (15%) CCI-score 2; 13 (8%) CCI-score 3; 3 (2%) CCI-score 4 and 1 patient had CCI-score 5 (1%). Most common comorbidities were chronic obstructive pulmonary disease (n=60, 38%), peptic ulcer disease (n=19, 12%), previous myocardial infarction (n=17, 11%) and diabetes (n=17, 11%). Median overall survival (OS) for the whole population was 22.7 months. There were no significant associations between CCI-score and median OS in univariate (CCI-score 0: 30.6 months; CCI-score 1: 15.1 months; CCI-score 2: 23.0 months; CCI-score 3: 23.0 months and CCI-score 4-5: 9.3 months, p=0.18) or multivariate analyses (HR: 0.97; 95% CI 0.79 – 1.18, p=0.74). Patients with comorbidity had a shorter survival than others in the univariate (CCI-score 0: 30.6 months, CCI-score ≥1: 18.8 months, p=0.047), but not in the multivariate analysis (HR: 1.27; 95% CI 0.82–1.98, p=0.29). Patients with comorbidity did not experience significantly more grade 3-4 pneumonitis (CCI-score 0: 3%, CCI-score ≥1: 2%, p=1.0), esophagitis (CCI-score 0: 38%, CCI-score ≥1: 28%, p=0.17), neutropenic infections (CCI-score 0: 41%, CCI-score ≥1: 40%, p=0.92) or deaths from pneumonitis (CCI-score 0: 2%, CCI-score ≥1: 3%, p=0.65). There were no other significant associations between CCI-scores and overall survival or toxicity.

      Conclusion:
      LD-SCLC patients with comorbidity had similar survival and toxicity as others, suggesting that they should be offered similar treatment as those without comorbidity.

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      P3.07-016 - Survival of Patients with N3 Lymph Node Disease in a Cohort with Limited Disease Small-Cell Lung Cancer Receiving Concurrent Chemoradiotherapy (ID 1134)

      09:30 - 09:30  |  Author(s): O.T. Brustugun

      • Abstract
      • Slides

      Background:
      Treatment of small-cell lung cancer depends on the extent of disease. Concurrent chemotherapy and thoracic radiotherapy (TRT) is recommended if all lesions can be included in a radiotherapy field (limited disease – “LD”), while patients with more advanced disease (extensive disease – “ED”) receive chemotherapy alone. LD is defined as confined to one hemithorax, but some have excluded patients with contralateral hilar and supraclavicular lymph node metastases (LNM). When the latest revision of TNM was published, it was recommended that N3-disease should be considered as LD with the possible exception of supraclavicular LNM – and that TNM-stage should be reported in clinical trials of LD SCLC to further explore this. We assessed extent of disease according to TNM v7 in patients from a randomized phase II trial comparing two schedules of TRT in LD SCLC (n=157) and investigated whether N3-disease was a negative prognostic factor; and whether there were survival-differences between the different N3-subcategories.

      Methods:
      Patients received four courses of cisplatin plus etoposide and were randomized to receive concurrent thoracic radiotherapy of either 45 Gy/30 fractions (twice-daily) or 42 Gy/15 fractions (once daily). Responders were offered prophylactic cranial irradiation of 30 Gy/15 fractions. Extent of disease was assessed from CT scans obtained three weeks before chemotherapy commenced. N3-disease was categorized according to contralateral supraclavicular, ipsilateral supraclavicular, contralateral hilar and contralateral mediastinal LNM. Weight loss was defined as weight loss >5% the last 3 months prior to enrolment.

      Results:
      150/157 patients were analysed (96%). Median age was 63 (40-85); 51% were men; 15% had PS 2 and 46% received twice-daily TRT. 1% had stage I disease; 14% stage II; and 84% stage III. Median overall survival (OS) for stage I: not reached, stage II: 41.1 months, and stage III: 20.9 months (p=0.022). 17% had N0-disease; 5% N1-disease; 30% N2-disease; and 47% had N3-disease. Among those with N3-involvement, 40 % had contralateral mediastinal LNM, 16% contralateral hilar LNM, and 17% supraclavicular LNM (13% ipsilateral and 7% contralateral supraclavicular LNM). 43% had LNM to more than one N3-station. Patients with N3-disease had inferior survival compared with N0-2 disease (18.0 vs. 33.7 months; p<0.001). All subcategories of N3 had inferior median OS compared with N0-2 disease (median 33.7 months): contralateral mediastinal LNM (18.0 months; p=0.022), contralateral hilar (19.8 months; p=0.021), supraclavicular LNM (15.1; p=0.003) [ipsilateral supraclavicular LNM (15.1 months; p=0.009) and contralateral supraclavicular LNM (13.8 months; p=0.007)]. There were no significant differences in median OS between the different N3-categories (p=0.84). Multivariate analyses adjusting for established prognostic factors in lung cancer (gender, age, PS, weight-loss and appetite loss) and treatment showed that N3-disease (HR 2.30; 95% CI=1.51-3.48; p<0.001), supraclavicular LNM (HR 1.67; 95% CI=1.01-2.77; p=0.046) and contralateral mediastinal LNM (HR 2.34; 95 % CI = 1.55-3.51; p<0.001) remained significant prognostic factors.

      Conclusion:
      Patients with N3-disease had inferior OS to those with N0-2 disease. All subcategories of N3 had inferior OS in the univariate analyses, while supraclavicular and contralateral mediastinal LNM remained significant in the multivariate analyses. Patients with supraclavicular LNM had similar OS as other N3 subcategories.

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