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C. Bai
Moderator of
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CALC - Chinese Alliance Against Lung Cancer Session (ID 79)
- Event: WCLC 2013
- Type: Other Sessions
- Track: Other Topics
- Presentations: 14
- Moderators:C. Bai, Y. Wu, D.C. Lam
- Coordinates: 10/27/2013, 07:30 - 12:00, Parkside Auditorium, Level 1
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- Abstract
Abstract
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CALC.02 - Keynote: Epidemiology and Burden of Smoking Related Diseases in China (ID 3866)
07:40 - 08:30 | Author(s): C. Bai
- Abstract
Abstract
Epidemiology and Burden of Smoking Related Diseases in China Prevalence of Smoking in China Being the largest producer and consumer of tobacco across the globe, China produces one-third (2.66 million tons/year) of the global tobacco leaves [1] and consumes 30% of the world’s cigarettes [2]. According to the Global Adult Tobacco Survey (GATS) Collaborative Group, China had the highest number of tobacco users (300.8 million) and a low quit ratio compared to 16 countries [3]. The International Collaborative Study of Cardiovascular Disease in Asia showed that 147,358,000 Chinese male and 15,895,000 Chinese female aged 35–74 years had been current cigarette smokers [4]. Regardless of gender difference, such prevalence was higher in the rural population compared to the urban population (male 61.6% vs 54.5% P <0.001; female 7.8% vs. 3.4% P<0.001) [4]. A growing prevalence of smoking was also observed in women [5], adolescents and young adults [2,6-8]. Even among non-smokers, the threat of tobacco smoke remained because airborne nicotine had been detected in 91% of the 273 public locations sampled in rural and urban China [9]. Specifically, an estimated 50-72% of Chinese non-smokers had been exposed to secondhand tobacco smoke [10,11]. Considering active and passive smoking altogether, 72% of the Chinese population were tobacco exposed [12]. Such common exposure has aggravated tobacco-related morbidity and mortality which create a direct economic burden accounting for 42.31 billion yuan [13]. By increasing mortality from cancer, respiratory disease and cardiovascular disease [14-18], smoking currently costs over 1 million Chinese lives per year. If the trend continues, a predicted sum of 2 million Chinese may die of tobacco-related diseases in 2025 [19]. COPD and Smoking Chronic obstructive pulmonary disease (COPD) had an estimated prevalence of 8.2% (>43 million) in the Chinese population > 40 years old [20] and was ranked the fourth/third leading cause of death in urban/rural area respectively [21]. Prompted by the causative roles of active [22-24] and passive smoking [25], a yet increasing prevalence of COPD would be expected in the Chinese population. In the meantime, the expensive treatments and compromised productivity of COPD patients had already created an enormous economic burden equaling to 110% and 34% of the annual incomes in rural areas and urban areas respectively [26]. Even so, the situation might have been undermined due to premature mortality and impaired working capabilities within affected families. Anti-smoking measures could be the best solution since the absolute risks of COPD would fall by 56% in Chinese male and 63% in Chinese female 5 years after smoking cessation [27]. Lung Cancer and Smoking Smoking is the main risk factor for lung cancer regardless of smoking experience (ever, current and ex smoking), tobacco product variety (pipes, cigars and cigarettes) and histological subtypes [28].\\Lee et al. demonstrated the dose-response relationship between smoking and lung cancer pathogenesis [28]. Specifically, risk of lung cancer decreased with duration of smoking cessation but increased with an earlier age of smoking and elevations in (i) the amount and fraction of smoking; (ii) duration of smoking; and (iii) tar level. Analyzing data from10 cancer registries, the crude incidence rate of lung cancer in China was estimated to be 49.35 per 100,000 population (63.7 per 100,000 men and 35.0 per 100,000 women) in 2005 [29]. Compared to lifelong non-smokers, the mortality rate of lung cancer was found to be approximately 23 times and 13 times higher in current male smokers and current female smokers respectively [30]. As prevalence of smoking rose during the past 3 decades, lung cancer mortality also increased by 464.84% [31]. Since 2008, lung cancer has surpassed other malignant tumors to become the most common cause of death in Chinese cancer patients [32]. At present, the mortality rate of lung cancer is 600,000 per year [33]. If the current trend continues, it may reach 1 million by 2025 [33]. With an increased prevalence of lung cancer and more advanced technology, the total number of lung cancer inpatients increased from 174,066 to 364,484 while medical costs increased from 2.16 billion yuan to 6.33 billion yuan between 1999 to 2005 as illustrated in the China Statistical Yearbook. Nonetheless, such dedication did not effectively prove its worth since the 5-year survival rate of lung cancer remained relatively low (10% - 14%) [34]. To relieve the socioeconomic burden, measures should be taken to reduce the incidence of lung cancer and relevant medical costs. CAD and Smoking Smoking has been associated with increased risk of coronary artery disease (CAD). In China, the reported crude odd ratio varied between 1.37 - 5.19 in former and current smokers [35-38]. In a study about risk ratio for CAD mortality, former smokers and current smokers had a risk ratio of 0.68 and 1.81 respectively when compared to never smokers [37]. Nonetheless, such figures bore no significant difference if stratified by co-morbidity of diabetes. Perhaps not surprisingly, passive smoking was verified to independently increase the risk of cardiovascular heart disease (CHD) by 25% - 30% [39,40]. While the prevalence of coronary artery disease (CAD) have fallen in developed countries through control of preventable risk factors, China witnessed an opposite trend as CAD climbed from the fifth most common heart disease in 1948-1957 to the most common in 1980-1989 [41]. As reported, CAD caused 51.4% and 32.8% of mortality related to cardiovascular disease (CVD) in urban and rural areas respectively. Projected from 1990, 72.7 million Chinese male and 72.1 million Chinese female will have been diagnosed with CAD in 2020 [42]. Smoking, one of the modifiable risk factors of CAD, should be tightly controlled in China if the socioeconomic burden has to be alleviated. Conclusion COPD, lung cancer and CAD are common smoking related chronic diseases which occupy a large share of medical resources yet cost a massive number of lives in China. In order to improve the current situation, smoking cessation should be reinforced in China through introduction of effective measures supported by favorable policy. Reference 1. Wang H. Tobacco control in China: the dilemma between economic development and health improvement. Salud Publica Mex. 2006; 48(Suppl. 1): S140–7. -
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CALC.03 - Pathogenesis and Pathology of Never Smoking Lung Cancer (ID 3867)
08:30 - 08:50 | Author(s): A.F. Gazdar, C. Zhou
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Abstract
Lung cancer (LC) is the leading cause of cancer deaths in the world. While smoking is universally accepted as the major cause of lung cancer in tobacco users, lung cancer in lifetime never smokers (LCNS) is among the 10 major causes of cancer deaths. LCNS is a very different disease than LC arising in ever smokers (LCES), and these differences are discussed in this Abstract. Because LCNS is highly influenced by gender and ethnicity, we put special emphasis on LCNS arising in East Asians. The reader is referred to several recent review articles on this subject [1-5] Etiology: Unlike LCES, the etiology of LCNS is not fully elucidated. The suspected factors include exposure to environmental tobacco smoke (ETS), exposure to industrial or domestic carcinogens including coal smoke and volatile cooking oils, radon exposure, viruses including HPV, and genetic factors. While these factors may individually or in combination contribute to the pathogenesis of LCNS, none of them is likely to be the major causative factor. Further investigation of causation is required. Clinico-patholgoical differences. While adenocarcinoma is the predominant form of NSCLC, the vast majority of LCNS are of adenocarcinoma histology, or large cell carcinomas (which may represent poorly differentiated adenocarcinomas). Squamous cell histology is rare and small cell carcinomas almost never occur. A retrospective study from Singapore identified significantly better performance status, younger age at diagnosis, and higher proportion of females (68.5% vs. 12-13%) and more advanced stage at diagnosis in never smokers compared with current and former smokers [6]. The disease stage variation at diagnosis might be explained by late presentation of symptoms and delayed diagnosis by physicians. The survival outcome of never smokers was significantly better than smokers, with the 5-year overall survival rate of LCES, respectively [6]. The differences in the treatment response and survival outcome between never smokers and smokers with lung cancer may be attributed to the differences in molecular pathogenesis and tumor biology (see below). Genetics: While lung cancer prone families have been well described, the risk of affected subjects is greatly increased after smoke exposure. Recently the interest has focused on single nucleotide polymorphisms (SNPs). Genome wide association studies (GWAS) identified a locus in chromosome region 15q25 that was strongly associated with lung cancer. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits [7]. Such subunits are expressed in neurons and other tissues, including alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to potential lung carcinogens. Thus variants in this region undoubtedly code for increased susceptibility to smoke and are unlikely to be associated with LCNS. Not unexpectedly, GWAS studies indicate different patterns of susceptibility for Asians and never smokers and possibly related to gender [8, 9]. Molecular differences: The molecular differences between LCES and LCNS show marked differences and characteristic patterns. While TP53 mutations are common to all types of lung cancer, the mutational spectra are very different [10]. KRAS mutations are largely limited to LCES, and, along with TP53, show the typical smoking associated characteristic G to T transversions. In addition, the total numbers of non-synonymous and synonymous mutations in LCES tumors are much higher than that in LCNS, indicating that tobacco exposure results in in widespread genomic instability. Paradoxically, some of the most responsive currently available or potential molecular targets for precision medicine are more frequent in never smokers, including EGFR, BRAF and HER2 mutations and ALK translocations. Therapeutic options and precision medicine: While the overall treatment strategy is the same for LCES and LCNS, the differences in molecular profiles dictate differences in precision medicine and, response to targeted agents and overall survival. These factors are also influenced by gender and ethnicity. For instance, one study found that the frequency of driver mutations (EGFR, HER2, ALK, KRAS, or BRAF) in lung adenocarcinoma from female never-smokers in China was over 87% [11]. Summary: The differences between LCES and LCNS are major, and cover etiologic factors, clinic-pathological changes, genetic susceptibility genes, mutational and molecular changes and precision medicine. These differences are vast enough so that we can regard lung cancers arising in ever and never smokers as two different diseases. References: 1. Rudin CM, Avila-Tang E, Harris CC, et al. Lung cancer in never smokers: molecular profiles and therapeutic implications. Clin Cancer Res 2009;15(18):5646-61. 2. Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers - a different disease. Nat Rev Cancer 2007;7(10):778-90. 3. StatBite lung adenocarcinoma in smoker vs. never smokers. J Natl Cancer Inst 2010;102(10):674. 4. Lee YJ, Kim JH, Kim SK, et al. Lung cancer in never smokers: change of a mindset in the molecular era. Lung Cancer 2011;72(1):9-15. 5. Subramanian J, Govindan R. Lung cancer in never smokers: a review. J Clin Oncol 2007;25(5):561-70. 6. Toh CK, Gao F, Lim WT, et al. Never-smokers with lung cancer: epidemiologic evidence of a distinct disease entity. J Clin Oncol 2006;24(15):2245-51. 7. Hung RJ, McKay JD, Gaborieau V, et al. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 2008;452(7187):633-7. 8. Shiraishi K, Kunitoh H, Daigo Y, et al. A genome-wide association study identifies two new susceptibility loci for lung adenocarcinoma in the Japanese population. Nat Genet 2012;44(8):900-3. 9. Lan Q, Hsiung CA, Matsuo K, et al. Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia. Nat Genet 2012;44(12):1330-5. 10. Pfeifer GP, Besaratinia A. Mutational spectra of human cancer. Hum Genet 2009;125(5-6):493-506. 11. Zhang Y, Sun Y, Pan Y, et al. Frequency of driver mutations in lung adenocarcinoma from female never-smokers varies with histologic subtypes and age at diagnosis. Clin Cancer Res 2012;18(7):1947-53 -
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Abstract
Approximately 20% of patients with NSCLC present with early stage diseases. While with the advances in imaging and the success in low-dose CT screening in high risk patients, the proportion of patients diagnosed of stage I disease may increase. Radical surgery has been well established as the primary treatment for localized disease. However, a substantial number are ineligible for resection because of comorbidities that are associated inoperable medical condition or advanced age. Conventional fractionated therapy has had disappointing outcomes for stage I NSCLC, with reported local failure rates as high as 60–70% in some series, likely due of inadequate doses. Prior dose escalation study suggested that 70 Gy in 2 Gy fractionation would predict a local-progression free survival of only 24% at 30 months, while dose of 80 to 90 Gy were needed to achieve a recurrence-free survival rate of 50%. Utilizing the advances in radiotherapy planning and tumor targeting techniques, stereotactic body radiation therapy (SBRT) using ablative-range daily doses of 7.5–30 Gy (1-8 fractions), has achieved a biologically effective dose above 100 Gy. This biological unique treatment is associated with notable increases in tumoricidal effect. Reported local control rates have been repeatedly around 90% at 3 years. There is some uncertainty equating SBRT doses and fractionations. In a recent systemic review involving 1076 patients with stage I NSCLC with a follow up of at least 30 months (15 studies), no positive dose–response relationship for tumor control was revealed within different schemes. Current dose to eradicate stage I disease might thus be overestimated. Treating central lesions with hypo-fractionated radiotherapy or SBRT at lower biologically effective doses may be justified. Survival after SBRT is, in general, worse than that after surgery in indirect comparisons, probably because of the frail nature of the patients who receive SBRT. In a population-based study, SEER data showed that even though lobectomy were associated with the best long term outcomes in fit patients with early-stage NSCLC, the survival after SBRT was similar to that after lobectomy in the propensity-score matched analysis, suggesting comparable efficacy with in select populations. Further, the introduction of SBRT reduced the proportion of stage I NSCLC patients who received no local therapy. In north Netherlands population, the application of SBRT corresponded to a 16% absolute increase in the proportion of patients receiving radiotherapy, and this shift was associated with a 6-month median survival improvement SBRT is characterized by both high conformality of the ablative dose delivered to the target, and a sharp dose gradient at the edge of the target volume. This enables possibility for the physician to minimize treatment toxicity. Rate of symptomatic pneumonitis is usually less than 20%. Common, self-limited toxicities were revealed in approximately up to 40% of patients including fatigue, cough, dyspnea and chest pain. Hemoptysis and rib fracture can occur, whereas life-threatening complications are rare. Dose constraints have been investigated for SBRT, though the basic data are now being accrued. Nevertheless, clinical factors like gender, smoking history, and larger gross PTV may equally important or even overweight dosimetric metrics. Further research is required to better understand the tolerance of normal tissues and the long term quality of life after SBRT. -
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CALC.05 - COPD and Lung Cancer (ID 3869)
09:10 - 09:25 | Author(s): I.A. Yang
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Abstract
Lung cancer and COPD frequently occur together in smokers, and COPD increases the risk of developing lung cancer in at-risk individuals. Exposure to cigarette smoke is clearly the most important causative factor. Other biological mechanisms for susceptibility to both lung cancer and COPD may involve inflammation, abnormal repair, oxidative stress, cellular proliferation, and epithelial-mesenchymal transition. In addition, genomic and epigenomic changes - such as single nucleotide polymorphisms, copy number variation, promoter hypermethylation and microRNAs - could alter biological pathways and enhance susceptibility to lung cancer and COPD. Approaches of studying genomics, epigenomics and gene-environment interaction will yield greater insight into the shared pathogenesis of lung cancer and COPD, leading to new diagnostic and therapeutic modalities. In addition to smoking cessation and preventing smoking initiation, understanding shared mechanisms in these smoking-related lung diseases is critical, in order to develop new methods of prevention, diagnosis and treatment of lung cancer and COPD. -
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CALC.06 - Diagnosis of Lung Nodules by CT-Guided Lung Biopsy (ID 3873)
09:55 - 10:05 | Author(s): Y. Song
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Abstract
CT-guided percutaneous needle biopsy(CT-guided PTNB) of the lung, with its high sensitivity, specificity, and accuracy, is an important diagnostic tool in the evaluation of pulmonary lesion, especially in malignant disease . And it’s specificity can reach 95 percent to 100 percent in malignant disease. Although PTNB of the lung is a mature technique, careful case selection is necessary to increase diagnostic yield and avoid unnecessary complications. It is indicated for indeterminate pulmonary nodules or masses, particularly those that will likely require chemotherapy or radiation rather than surgery. Pneumothorax and pulmonary hemorrhage are the most common complications of PTNB, whereas air embolism and tumor seeding are extremely rare. Attention to biopsy planning and technique and postprocedural care help to prevent or minimize most potential complications. A retrospective investigation of patients with CT-guided PTNB in Jinling Hospital between January 2000 to October 2010 was performed. The risk factors for complications were determined by multivariate analysis of variables related to patients’ demographics, lung lesions, biopsy procedures, and individual radiological features.1014 biopsy prcedures were enrolled. The total complication rate was 18.5 percent with pneumothorax 12.9 percent (131/1014), hemoptysis 5.6 percent (57/1014), and with no mortality. The diagnosis was cofirmed by PTNB in 961 patients (94.8 percent) with 639 patients as malignant disease (63 percent) and 322 patients as benign diease (31.8 percent). Taken into all the evidence, CT-guided percutaneous needle biopsy is a safe and effective means in the diagnosis of pulmonary occupying lesions. -
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CALC.07 - Molecular Signatures for the Accurate Classification of NSCLC and Neuroendocrine Tumors and Cell Lines (ID 3874)
10:05 - 10:25 | Author(s): A.F. Gazdar, L. Girard
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Abstract
Until recently the oncologist was only interested to know whether a lung cancer was SCLC or NSCLC. However, recent changes, particularly during this century, require more precise classification of lung cancer, and, in some cases, for subclassification [1]. The different classes of lung cancer respond differently to conventional therapy and to precision medicine. The patterns of driver mutations are highly tumor type dependent, with very little overlap between classes. Thus mutation testing depends of accurate classification. Other reasons for accurate classification include: 1) Adenocarcinoma histology is a strong predictor of response to pemetrexed therapy in patients with advanced disease; and 2) Serious hemorrhagic complications after bevacizumab therapy have been reported in patients with squamous histologies. With the development and application of newer agents for precision medicine, the need for accurate classification will only increase. Complicating the increased need for accurate classification is the fact that currently 70% of lung cancers are diagnosed from small biopsies or cytological samples. Thus more accurate diagnoses are demanded from smaller amounts of materials [1, 2]. A further complication is that large international clinical trials often require that tumor materials be reserved for entry requirements or various tests. In routine pathology practice, immunostains are often used to classify poorly differentiated lung carcinomas. While many immunostains have been proposed, a simple algorithm utilizing TTF1 and Napsin A for adenocarcinoma and p63 (or its isoform p40) and high molecular weight keratins have is effective [3]. However, even with excellent pathology practices, over 10% of cases will be incorrectly classified or be unclassified (undifferentiated large cell carcinoma or NSCLC-not other wise specified (NSCLC-NOS). Pathology practices and quality may vary from institution to institution or country to country. The SEER data on cancer incidence indicates that over 20% of lung cancer cases in the USA are not further classified. For these reasons we developed highly specific and sensitive RNA expression signatures as an adjunct test for routine pathological classification. The signatures not only classify the smaples, but provide a numeric scor ranging from 0-1.0, indicating the degree of differentiation. We utilized expression arrays from multiple public and private sources including The Tumor Cell Genome Atlas (TCGA), which used several platforms including Illumina, Affymetrix and RNA-Seq. For complete identification, four signatures had to be developed and validated and can be utilized independently or in combination. These signatures are: 1) Adenocarcinoma-squamous cell carcinoma discrimination, 2) lung specific neuroendocrine (NE)-non neuroendocrine lung cancer discrimination, 3) Non-malignant lung- lung carcinoma discrimination and 4) lung respiratory cell-lung carcinoma cell discrimination. The adenocarcinoma signature includesTTF1, the squamous cell carcinoma signature includes p63 and several high molecular weight keratins, and the NE cell signature includes chromgranin A, synaptophysin and dopa decarboxyase, adding credence to the signatures. These signatures have <10% discrepancy rates with expert pathology review and have helped n the correct classification of NSCLC, large cell and NSCLC-NOS carcinomas, NE lung tumors and lung cancer cell lines. John Minna and Alex Augustyn, in collaboration with us, have utilized their modification of the NE cell signature, and have identified two potential major clinical applications. These include identification of the full NE expression signature in a subset (5-10%) of NSCLC. While some of these may represent misclassified large cell neuroendocrine carcinomas, others appear to be typical adenocarcinomas. In addition, they have identified that BCL2 is one of the downstream targets of ASCL1, the driving force for NE differentiation in the lung, and that inhibition of BCL2 results in apoptosis of SCLC and NSCLC-NE tumors. Practical application of our signatures requires modification to a more practical platform such as Nanostring technology, and application to formalin fixed paraffin embedded small biopsies. These are currently in development. We are grateful to Drs. William Travis and Natasha Rehktman, members of the TCGA pathology panel and Ignacio Wistuba, John Minna and Alex Augustyn for their invaluable assistance. References 1. Gazdar AF. The evolving role of the pathologist in the management of lung cancer. Lung Cancer Management 2012;1(4):1-9. 2. Travis WD, Brambilla E, Noguchi M, et al. Diagnosis of Lung Cancer in Small Biopsies and Cytology: Implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society Classification. Arch Pathol Lab Med 2012. 3. Travis WD, Rekhtman N. Pathological diagnosis and classification of lung cancer in small biopsies and cytology: strategic management of tissue for molecular testing. Semin Respir Crit Care Med 2011;32(1):22-31. -
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CALC.08 - Targeted Therapies for Adenocarcinoma, Now and Future (ID 3875)
10:25 - 10:45 | Author(s): C. Zhou
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Abstract
Lung cancer remains as the most fatal disease world-wide.Non-small cell lung cancer (NSCLC) accounts for about 80% of all lung cancers. Incidence of pulmonary adenocarcinoma has been increasing in most countries and becomes a major histology. We had, up to the recent past, treated patients with chemotherapy without any clinical or biological selection. Unfortunately, the improvement in overall survival (OS) with platinum-based doublets is modest, although statistically significant when compared to best supportive care. We now, however, understand that adenocarcinoma could be divided into several subsets according to oncogenic drivers and each subset of adenocarcinoma has a different biology. So, targeted therapies against these drivers have been extensively studied and will play more and more important roles in treatment of advanced adenocaricnoma of the lung. Oncogenic drivers Adenocarcinoma is different in oncogenic drivers between East Asian and Caucasian patients. East Asian patients have more frequent epidermal growth factor receptor (EGFR) mutation but less frequent KRAS mutation. Incidence of EGFR mutation is about 50% - 78.8% but of KRAS mutation about 1.9% to 12%. Other oncogenic drivers include ALK or ROS1 rearrangement, BRAF mutation, HER2 amplification or mutation, c-MET amplification, etc, and arecomparable in their incidencesbetween Asian and Caucasian patients. These oncogenic drivers are mutually exclusive in majority cases. EGFR TKI Several phase II/III studies have investigated the efficacy of EGFR tyrosine kinase inhibitors (TKI) as front-line therapy of patients with advanced NSCLC. EGFR TKI is not appropriate for front-line therapy in unselected populations, in those without EGFR mutation, or those with unknown EGFR mutation status. Improvement in PFS with EGFR TKI is confined to those with EGFR mutation. In fact, first-line EGFR TKI seems to have a detrimental effect in those without an EGFR mutation. Clinical characteristics alone are not sufficient to correctly predict benefit from EGFR TKIs. Treatment with EGFR TKI in EGFR mutant NSCLC patients has also been found to be associated with improvement of progression-free survival (PFS) and quality of life and less toxicity profile. Both first-generation and second-generation EGFR TKIs are effective. Treatment of patients with acquired resistance to EGFR-TKI is wildly being studied. Switching to standard chemotherapy, continuation of an EGFR TKI beyond disease progression and/or plus local therapy, afatinib plus cetuximab are some options of treatment. ALK inhibitors Crizotinib proves effective in adenocarcinoma with ALKorRos1 rearrangement. Several studies (Profile 1001, 1005 and 1007) investigated crizotinib in advanced NSCLC with ALK rearrangement. Tumor response is about 51-61% and PFS 41.9-48.1 weeks. Second-line crizotinib was found more effective than chemotherapy in terms of tumor response rate and PFS. The compound was also found to be effective in those with ROS1 rearrangement. Among 35 patients, its tumor response rate was 60% and PFS was not reached. LDK 387 is a second-generation ALK inhibitor. Phase I study showed its promising efficacy in the patients with ALK rearrangement. It could overcome acquired resistance of NSCLC to crizotinib. Antiangiogenicagents Bevacizumab is approved to be combined with doublet chemotherapy as 1[st] line treatment of non-squamous NSCLC. The combination significantly improves tumor response, PFS and OS. But up to now, there is no biomarker for selection of non-squamous NSCLC patients to receive bevacizumab therapy. Many small molecular anti-angiogenicinhibitors plus standard chemotherapy have been investigated but failed in improvement of OS. Recently, LUME-Lung 1 trials suggested ninetedanib plus docetaxelsignificantly improved PFS and OS of patients with advanced adenocarcinoma of the lung in second line setting compared with docetaxel + placebo. KRAS inhibitors Some compounds are being investigated in those with KRAS mutation. Selumetinib, MKE1/2 inhibitor, combined with docetaxel significantly improved tumor response (37% vs 0%) and PFS (5.2 months vs 2.1 months, HR 0.58), compared with docetaxel alone.Trametinib plus second line chemotherapy produced about 12 to 28% of tumor response rate and 2.9 to 4.1 months of PFS. BRAF inhibitor Dabrafenib has been approved for treatment of melanoma harboringBRAF V600E mutation. Incidence of BRAF V600E mutation is about 1% in NSCLC. A phase II study investigated dabrafenib in adenocarcinoma of the lung withBRAF V600E mutation. Preliminary results in 20 patients showed 40% of tumor response rate and 60% of disease control rate with the compound. c-MET inhibitors c-METamplification is one of major mechanisms for acquire resistance of NSCLC to EGFR TKI. Several small molecular inhibitors of cMET and monoclonal antibodies against cMET are under clinical development. METmab plus erlotinib significantly improved PFS than erlotinib in those with MET high patients in the phase II trial. Crizotinib led to tumor shrinkage in a patient with MET amplification. HER2 inhibitors HER2 mutation and amplification are not frequently observed in adenocarcinoma of the lung. Mazieres and the colleagues reported that HER2-targeted therapies in additional lines of treatment produced 50% of overall response rate, 82% of disease control rate and 5.1 months of PFS. The disease control rate was 96% with trastuzumab-based therapies and 100% with afatinib monotherapy. The relative efficacy of these compounds deserves prospective evaluation in larger international clinical trials. Inhibitors of other oncogenic drivers Many inhibitors of other drivers including PDGFR, FGFR, RET rearrangement, PI3K, mTOR, MEK, AKT, STAT3, etc are under clinical development. We are just waiting for their results of clinical trials. In summary, EGFR TKI and ALK inhibitors are important agents for EGFR mutant and ALK or ROS1 rearranged adenocarcinoma of the lung, respectively. They become standard 1[st] line therapy for these patients. Bevacizumab plus doublet chemotherapy could be 1[st] line therapy for those with advanced adenocarcinoma harboring no oncogenic drivers. Many inhibitors of other oncogenic drivers are under clinical development and will become standard therapy for these patients in near future. -
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CALC.09 - Targeted Therapies for SCC, Now and Future (ID 3876)
10:45 - 11:05 | Author(s): T. Mok
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Abstract not provided
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CALC.10 - Second Line Treatment of NSCLC: Needed to Detect Driven Gene Mutation Status (ID 3877)
11:05 - 11:15 | Author(s): B. Han
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Abstract
Despite progressive advances in biomarker-driven personalised therapeutic approaches to non-small cell lung cancer (NSCLC) in recent years, the efficacy of first-line treatment remains suboptimal. Most chemotherapy-treated patients experience disease progression within 3–6 months[1,2] and even those who initially benefit from tyrosine kinase inhibitor (TKI) therapy inevitably progress after 10–14 months.[3–6] However, 40–50% of patients have a good performance status at progression and are suitable for subsequent therapy.[7,8] Thus, improving second-line treatment has the potential to significantly impact patient outcomes. The success of several molecularly targeted therapies in the first-line setting in clinical trials has stimulated research interest in similar applications in the second-line setting. Data from the DELTA[9] and CTONG0806[10] studies presented at ASCO 2013 corroborate findings from the TAILOR[11] study which suggest that chemotherapy may be a marginally better option than epidermal growth factor receptor (EGFR)-TKI for EGFR wild-type patients beyond the first-line setting. It is now clear that treatment response varies widely between patients with different biomarker profiles and this underscores the increasing importance of biomarker testing prior to second-line therapy. For patients with unknown mutation status in the first-line setting, biomarker analysis upon progression is essential to guide second-line treatment decisions to optimise treatment response, both for targeted therapies and chemotherapy. In the pivotal BR.21 trial of erlotinib versus placebo in the second-line setting, response to erlotinib increased from 8.9% in the unselected population to 27.0% in the EGFR mutation-positive sub-population. Similarly, overall survival (OS) increased from 6.7 months to 10.9 months when the EGFR genotype was known.[12,13] In patients with anaplastic lymphoma kinase (ALK)-positive tumours, crizotinib has demonstrated superiority to chemotherapy in the second-line setting with improved progression-free survival (PFS; 7.7 vs. 3.0 months; p<0.001) and quality of life, an important second-line outcome.[14] Although improvements in chemotherapy efficacy seem to have reached a plateau, the use of molecular testing to identify patients who will benefit most from chemotherapy is being actively investigated. A recent study exploring the predictive role of BRCA1 and ERRC1 genes in patients receiving second-line platinum-based chemotherapy showed that low mRNA levels of both genes correlated with increased OS (16.0 vs. 5.4 months; p<0.001) and PFS (4.1 vs. 2.0 months; p=0.002) compared with high levels.[15] Although clinically validated biomarkers have not been identified for most therapies, they remain a critical focus of research and currently available information offers clinicians new insights into second-line management. For patients with known mutation status who experience disease progression following first-line therapy, biomarker testing prior to therapy allows identification of mechanisms of acquired resistance to enable clinicians to tailor subsequent treatment strategies. The most common mechanism of acquired resistance to EGFR-TKIs is the T790M mutation, which has been reported in up to 60% of patients with acquired EGFR-TKI resistance.[16–19] Oxnard et al. demonstrated favourable prognosis and more indolent disease progression in patients with T790M-mediated acquired resistance compared with other mechanisms of acquired resistance, and customised subsequent treatment based on these findings. Over 80% of T790M-positive patients were maintained on TKI therapy, along with chemotherapy, to help maintain the indolent characteristics of T790M-associated progression.[17] A re-response phenomenon has also been described in T790M-positive patients in whom TKI-sensitive cells repopulate upon cessation of TKI therapy, allowing the tumour to regain sensitivity to EGFR-TKI. Thus, re-treatment with EGFR-TKI and chemotherapy may be well suited to target both sensitive and resistant cell populations.[20] Other mechanisms of acquired EGFR-TKI resistance include secondary c-MET overexpression/amplification via HER3/erbB3 or KRAS activation (5–19%), AXL upregulation (20–25%) and phosphatidylinositol-3-kinase mutations (5%).[21,22] Similarly, secondary genetic alterations have been demonstrated in crizotinib-resistant ALK-positive tumours.[23,24] For patients with known mutation status who are still on first-line treatment, biomarker testing provides real-time information to monitor for the development of mutations and to uncover additional targetable tumour characteristics that may impact treatment response and warrant a change in therapy. Tumour characteristics may evolve following first-line treatment as tumour heterogeneity may exist at both genomic and morphological levels. Bai et al. investigated the impact of chemotherapy on EGFR mutation in advanced NSCLC patients who received first-line chemotherapy and patients with stage IIb–IIIb disease who received neoadjuvant chemotherapy, and found that mutation-positive rates were lower post-chemotherapy in both cohorts (p<0.01 and p=0.13, respectively). Importantly, patients who lost EGFR mutation positivity post-chemotherapy had a better partial response than patients with a reverse change (p=0.037).[25] Morphological tumour heterogeneity following first-line therapy has been increasingly reported in the literature. EGFR mutation-positive adenocarcinomas have been reported to transform to small cell histology with maintained EGFR mutation following progression.[16,18] In a study by Sequist et al., these observations allowed investigators to switch patients to small cell lung cancer chemotherapy regimens, with 75% responding to treatment.[18] Epithelial-mesenchymal transitions have also been reported.[18,26] Biomarker testing in the second-line setting is important to detect any changes in tumour characteristics before significant clinical deterioration when alterations to regimens might be most effective. The growing number of biomarker-targeted treatment options may create a need for biopsy or re‑biopsy during treatment. Recent guidelines by the College of American Pathologists, the International Association for the Study of Lung Cancer and the Association for Molecular Pathology recommends re-biopsies for EGFR and ALK mutation analysis to guide treatment decisions beyond the first-line setting.[27] Although re-biopsy may be challenging due to patients’ and/or clinicians’ reluctance, it has shown to be feasible and provides sufficient material for mutation analysis in most patients. High-sensitivity sequencing methods can detect T790M mutation in up to 68% of re-biopsy samples from patients with acquired resistance.[16,17,28,29] Nevertheless, promising surrogates for tumour tissue DNA, such as circulating blood biomarkers, are being investigated and may represent a less invasive approach. The BATTLE-1 trial, which employed real-time biopsies to match patients to targeted therapies, proved that a biomarker-driven treatment approach is feasible.[30] BATTLE-2, which involves more drug combinations, and real-time selection and validation of predictive biomarkers, is currently ongoing;[31] the highly anticipated results hold promise for revolutionising NSCLC treatment. -
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- Abstract
Abstract
ABSTRACT Rationale: Effective treatment for lung cancer requires accuracy in sub-classification of carcinoma subtypes. Objectives: To identify microRNAs in bronchial brushing specimens for discriminating small cell lung cancer (SCLC) from non-small cell lung cancer (NSCLC) and for further differentiating squamous cell carcinoma (SQ) from adenocarcinoma (AC). Methods: Microarrays were used to screen 723 microRNAs in laser-captured, microdissected cancer cells from 82 snap-frozen surgical lung tissues. Quantitative reverse-transcriptase PCR was performed on 153 macrodissected formalin-fixed, paraffin-embedded (FFPE) surgical lung tissues to evaluate 7 microRNA candidates discovered from microarrays. Two microRNA panels were constructed based on a training cohort (n = 85) and validated using an independent cohort (n = 68). The microRNA panels were applied as differentiators of SCLC from NSCLC and SQ from AC in 207 bronchial brushing specimens. Measurements and Main Results: Two microRNA panels yielded high diagnostic accuracy in discriminating SCLC from NSCLC (miR-29a and miR-375, AUC 0.991 and 0.982 for training and validation dataset, respectively) and in differentiating SQ from AC (miR-205 and miR-34a, AUC 0.977 and 0.982 for training and validation dataset, respectively) in FFPE surgical lung tissues. Moreover, the microRNA panels accurately differentiated SCLC from NSCLC (AUC 0.947) and SQ from AC (AUC 0.962) in bronchial brushing specimens. Conclusion: We found 2 microRNA panels that accurately discriminated between the 3 subtypes of lung carcinoma in bronchial brushing specimens. The microRNA panels could have considerable clinical value in differential diagnosis and play an important role in determining optimal treatment strategies based on the lung carcinoma subtype. -
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CALC.12 - IPF Caused by EGFR-TKIs in Asia (ID 3879)
11:25 - 11:35 | Author(s): Q. Hong
- Abstract
Abstract
Drug-associated interstitial lung disease (ILD) is not uncommon, but it may developed to fatal acute respiratory distress syndrome, so an accurate diagnosis based on clinical, radiological and histological manifestations is important. As an EGFR-TKI, Gefitinib or Erlotinib has been widely used in advanced NSCLC, although it may prolong the patient’s survival, the possibility of ILD associated with EGFR-TKI remains a big problem that we need to confront especially in Asian NSCLC patient. Diagnosis For the assignation of ILD, patient usually need to accord with the following requirements: (1) progressive dyspnea with or without cough or fever, (2) radiographic findings(HRCT recommended) show bilateral, diffuse, or patchy interstitial and/or alveolar opacifications, (3) lack of evidence of infection and progression of underlying lung cancer, (4) consistent pathologic findings if available. Establishing a diagnosis on EGFR-TKI associated ILD is often difficult, and is particularly challenging in a patient having been given chemotherapy and/or radiotherapy, chemotherapy and radiotherapy, either alone or in combination, have been associated with the development of ILD. In addition, infections, and other environmental exposures can also mimic ILD. The characteristic images of EGFR-TKI associated ILD were of patchy diffuse ground-glass shadows; several other characteristic HRCT patterns can also been observed. In acute forms of ILD, ground-glass attenuation is usually seen bilaterally in the lung fields. In chronic forms of the disease, “honeycombing” is seen that results from extensive pulmonary fibrosis and loss of acinar architecture of the lungs. Although ILD can occur during the first 3 months of treatment, the median time to onset was actually 24 to 42 days, and ILD developed in most patients within the first 4 weeks of treatment, with possibly rapid progression.On the other hand, ILD can develop in patients who are retreated with EGFR-TKI after a period of interruption. Therefore, all patients receiving EGFR-TKI who present with an acute onset of dyspnea, regardless of the presence of cough or low-grade fever, should be promptly evaluated, especially during the first month of treatment. Epidemiology There are more frequent reports of EGFR TKI-associated ILD in Japan than elsewhere in the world. The causes for this worldwide differences are unknown and require further scientific investigation. Several reasons have been suggested for this difference, including differences in follow-up period, the clinical characteristics of the study population, and the applied diagnostic criteria for ILD. Pre-existing ILD, including usual interstitial pneumonia, has been found in the reported EGFR-TKI induced ILD patients，the presence of IPF seems to be an important risk factor. Alternatively, there may be a specific increased genetic susceptibility to ILD among the Japanese population. However, this ethnic difference in reporting rates does not extend to other Asian countries, where the frequency of ILD is comparable with the rest of the world Mechanism of ILD The molecular mechanisms leading to ILD are also unclear. The distribution of EGF and EGFR in normal adult human lung has been demonstrated by immunohistochemistry, with expression observed in the basal cell layer of the bronchial epithelium . EGF signaling probably represents an important mechanism that helps coordinate the process of recovery from lung injury by stimulating epithelial repopulation and restoration of barrier integrity. Some investigator have suggested that EGFR-TKI therapy may augment any underlying pulmonary fibrosis via a decrease in EGFR phosphorylation with a coincident decrease in regenerative epithelial proliferation. Therefore, it is possible that EGFR inhibition will at least in part reduce the ability of pneumocytes to respond to lung injury. Compared with other EGFR inhibitors, the largest amount of information regarding the association with ILD is available for gefitinib, as this agent has been given to more patients than any other EGFR-TKIs. Treatment Treatment of EGFR TKI–induced ILD include supplemental oxygen, empirical antibiotics, and mechanical ventilation depending on the severity of the situation. Immediate discontinuation of the TKI drug is recommended . Acute pneumonitis commonly resolves on discontinuation of therapy, although in severe cases patients , systemic corticosteroids are usually prescribed, Prognosis with treatment is good if the diagnosis is made early; however, once fibrosis has occurred, the damage may be permanent with irreversible loss of lung function. -
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CALC.13 - Novel Lung Cancer Plasma Immunoinflammatory Complexes (ID 3880)
11:35 - 11:45 | Author(s): J. Hu
- Abstract
Abstract
The plasma protein complexes level was measured by electrophoresis analyses in 31 patients with advanced NSCLC treated with 125 or 150 mg/day icotinib hydrochloride until disease progression or unacceptable toxic effects or the patient refused further treatment. Eligibility criteria include performance status≤2, age≥18 years, and stage ⅢB-Ⅳ disease. Herein we found more than 87 % of the change in plasma IIRPCs appears at earlier time than histopathology occurs during the treatment with icotinib hydrochloride: (1) having a crest; (2) having a trough. The increasing or discreasing point always appears at earlier time in the treatment before histopathology occurs. There are no significant differences of the median PFS among the other clinical information groups, including: ages, gender, smoking history and EGFR mutation. Therefore, we showed that measurement of plasma protein complexes level during the treatment in patients with NSCLC may be a new surrogate marker for monitoring the therapeutic efficacy of icotinib and predicting the progression of the disease. -
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- Abstract
- Presentation
Abstract not provided
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MS22 - The Mediastinum 2013 (ID 39)
- Event: WCLC 2013
- Type: Mini Symposia
- Track: Pulmonology + Endoscopy/Pulmonary
- Presentations: 4
- Moderators:F.J. Herth, C. Bai
- Coordinates: 10/30/2013, 14:00 - 15:30, Parkside 110 A+B, Level 1
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MS22.1 - The Anatomy of the Mediastinum / CT Imaging (ID 562)
14:05 - 14:25 | Author(s): N. Kurimoto
- Abstract
- Presentation
Abstract
Overview of ultrasound imaging of the right and left bronchi using the radial probe The positional relationship between the peribronchial organs in EBUS images taken from the trachea corresponds to those in a reversed CT image (CT scans are cross-sectional images looking from the caudal direction). EBUS images taken distal to the bifurcation of the left and right main bronchi, however, are cross-sectional images of planes perpendicular to the long axis of the bronchus, and therefore have different positional relationship between the peribronchial organs to the CT images. To fully understand EBUS, it is essential to understand the positional relationship between the peribronchial organs during visualisation while the probe is being pulled out. 1. Right bronchi 1) Right lower lobe bronchi When the balloon is inflated in the right basal bronchus, the inferior pulmonary vein (V6) passes on the dorsal side of the bronchus, whereas anterior to the bronchus the pulmonary artery divides into A8, A9 and A10 positioned between 9 o’clock and 2 o’clock. As the probe is pulled back, A8, A9 and A10 meet at the 12 o’clock direction and the direction of the pulmonary artery changes gradually to the 3 o’clock direction. When the probe is pulled further back, it approaches the bifurcation of B6. Pulling the probe back further, the opening of the middle lobe bronchus, indicated by reflection of the ultrasound pulse, appears at 12 o’clock. The pulmonary artery has gradually moved round to the 2 o’clock position. 2) From the right intermediate bronchus to the right main bronchus As the probe is pulled from the distal intermediate bronchus to a point immediately below the origin of the upper lobe bronchus, the pulmonary artery crosses the bronchus from the right to the left. In the central section of the intermediate bronchus, the superior pulmonary vein can sometimes be seen anterior to the pulmonary artery. When the probe is pulled further back, the origin of the upper lobe bronchus is indicated by reflection of the ultrasound pulse at 3 o’clock. Pulling the probe back further, A1+3, originating from the pulmonary trunk, can be seen crossing horizontally anterior to the right main bronchus. Retracting the probe further, the origin of the left main bronchus at the carina is indicated by reflection of the ultrasound pulse at 9 o’clock. 2. Left bronchi 1) Left lower lobe bronchi When the balloon is inflated in the left basal bronchus, the inferior pulmonary vein (V6) passes on the dorsal side of the bronchus, whereas the A8, A9 and A10 branches of the pulmonary artery meet at 9 o’clock. As the probe is pulled back, it approaches the bifurcation of B6. Pulling the probe back further, the opening of the upper lobe bronchus, indicated by reflection of the ultrasound pulse, appears at 11 o’clock. The pulmonary artery is located below the origin of the upper lobe bronchus. 2) Left main bronchus The distal section of the left main bronchus is characterised by the left pulmonary artery at 10 o’clock, the descending aorta at 7 o’clock, and the left atrium from 1 o’clock to 3 o’clock. As we enter the central section of the left main bronchus, the left atrium disappears, and the oesophagus appears at 6 o’clock. The subcarinal (#7) lymph node is often visible medial to the oesophagus. Ultrasound imaging of mediastinal and hilar lymph nodes for EBUS-TBNA by the Convex Bronchoscope #7 LN: Subcarinal lymph node For approaching #7 LN, the convex bronchoscope is inserted into right main bronchus. While scanning at 9 o’clock direction, we can confirm the largest area of the #7 LN. While rotating right handed and scanning at 11 o’clock direction, we can watch the right main pulmonary artery. 11R LN: right intralobar lymph node (between right lower lobe bronchus and right middle lobe bronchus) For approaching #11R LN, the convex bronchoscope is inserted into right basal bronchus. While scanning at 12 o’clock direction, we can confirm the largest area of the #11R LN. While rotating right handed and scanning at 3 o’clock direction, we can watch the right pulmonary artery. 11R LN: right intralobar lymph node (between right intermediate trunk and right upper lobe bronchus) For approaching #11R LN, the convex bronchoscope is inserted into right intermediate trunk. On the bronchoscopic findings, right upper bronchus is locates at 12 o’clock direction from the intermediate trunk. While scanning at 12 o’clock direction, we can confirm the largest area of the #11R LN. While rotating left handed and scanning at 9 o’clock direction, we can watch the right main pulmonary artery. 11L LN: left intralobar lymph node For approaching #11R LN, the convex bronchoscope is inserted into left basal bronchus. On the bronchoscopic findings, left upper lobe bronchus is locates at 12 o’clock direction from left lower lobe bronchus. While scanning at 12 o’clock direction, we can confirm the largest area of the #11L LN. While rotating left handed and scanning at 10 o’clock direction, we can watch the right pulmonary artery. 4L LN For approaching #4L LN, the convex bronchoscope is inserted to the distal site of the trachea. On the bronchoscopic findings, the left side of the trachea is locates at 12 o’clock direction. While scanning at 12 o’clock direction, we can confirm the largest area of the #4L LN. While pushing the scope to distal site about 1-2cm, we can watch the left main pulmonary artery. While pushing the scope to proximal site about 1-2cm, we can watch aortic arch. 4R LN For approaching #4R LN, the convex bronchoscope is inserted to the distal site of the trachea. On the bronchoscopic findings, the membranous portion of the trachea is locates at 6 o’clock direction. While scanning at 2 o’clock direction, we can confirm the largest area of the #4R LN. While scanning 4R LN, we can watch superior vena cava (SVC) just below. While pushing the scope to proximal site about 1-2cm, we can watch aortic arch #4R LN.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MS22.2 - Further Staging Using Imaging - PET, MRI and PET/CT (ID 563)
14:25 - 14:45 | Author(s): E. Hsiao
- Abstract
- Presentation
Abstract
PET and PET/CT FDG PET scans have shown high sensitivity and specificity in detecting mediastinal nodal involvement. It works by detecting increased accumulation of F-18 fluorodeoxyglucose (FDG) in the neoplastic cells which have a deranged glucose metabolism. FDG undergoes similar uptake and metabolic pathway glucose molecules. The accumulation of positron emitting F-18 isotope can then be used to localise these hypermetabolic neoplastic tissue. Both 2003 and 2007 guidelines of the American College of Chest Physicians (ACCP) endorsed the use of PET imaging as a non-invasive staging tool for non-small cell lung cancer[1, 2]. FDG PET scan has become the standard of care in staging primary lung cancer. It is recognised as the most accurate non-invasive tool in the staging of lung cancer. It is also widely accepted that PET scanning improves detection of distant metastatic disease as well as unsuspected N2 or N3 disease particularly in the high-risk patients. Therefore, several series have shown that the use of PET imaging reduces unnecessary or futile surgical resection. Traditionally, a standard uptake value (SUVmax) of 2.5 or above is used as a threshold for malignancy, but this was initially based on the uptake of peripheral lung masses with diameter >2cm. Whether this can be applied to mediastinal nodes is questionable. The special resolution of a current generation PET scanner is approximately 7mm. Nonetheless, small or non-enlarged lymph nodes with highly aggressive tumour metastasis may be detected based on the higher intensity of uptake compared to the background. While FDG PET is clinically useful, it is an imperfect technique. The meta-analysis carried out by Silvestri et al [3]in the third edition of ACCP guideline demonstrated that the median sensitivity and specificity for detecting mediastinal metastases were 80% and 88% respectively. The findings demonstrate that PET is more accurate than CT scanning (median sensitivity 55% and median specificity 81%) [3]. However, it is important to know that neither technique is perfect. Interestingly, an increasing number of recent studies were performed using integrated PET/CT scanner. The meta-analysis by the ACCP showed a median sensitivity of 62% and median specificity of 90%[3]. The specificity is slightly higher although the sensitivity is lower. The reason for this observation remains unclear. Nonetheless, PET/CT hybrid cameras have superseded the role of stand alone PET scanners in nowadays. False negative results are more often seen with adenocarcinoma in situ, well-differentiated invasive adenocarcinoma, and typical carcinoid tumours. Small volume or micrometastasis can also be missed due to the finite spatial resolution of PET and perhaps by all imaging techniques. Studies have demonstrated that PET scanning is less sensitive for lymph nodes measuring <7-10mm diameter, and micrometastases have been detected in non enlarged lymph nodes without abnormal FDG uptake by invasive sampling[4]. Furthermore, in the presence of a central FDG avid lung cancer, N1 disease can be missed by FDG PET imaging in up to 25% of cases[5]. In the evolution of a peripheral T1A lesion particularly if the density of the nodule is ground glass or sub-solid. It is well known that these types of neoplasms have low incidence of mediastinal metastasis though the risk is not nil. It is important that the interpretation of a negative PET scan to be combined with clinical judgement as well as the pre-test likelihood of mediastinal metastasis. Furthermore the local availability and expertise in invasive biopsy procedures are also important factors. False positive findings are often due to infection or inflammation. Common causes include sarcoidosis, silicosis, reactive changes, fungal or mycobacterial infections. In summary, it is important to confirm N2 and N3 disease with tissue sampling to avoid delay or missing potentially curative surgery. In the presence of negative of PET and CT findings in the mediastinum, that the decision to operate or to have invasive tissue sampling requires careful consideration and clinical judgement. Combined with invasive mediastinal staging techniques Transbronchial biopsy has shown a median sensitivity of 78% and specificity of 100% in a systemic review. The sensitivity has been reported to be high in patients with positive CT or PET/CT findings. Occasional false positive results have been reported to be approximately 7%. The median negative predictive value in this systemic review is 77%. Endobronchial ultrasound with needle aspiration can achieve a median negative predicted value of 91%. This is further improved with combined EBUS and EUS which have a median negative predictive value is 96%[3]. For most patients undergoing PET/CT staging, the need of invasive mediastinal staging is not eliminated. It is important to confirm the presence of N2 or N3 disease in patients without evidence of metastatic disease to avoid withholding potentially curative surgery. FDG PET/CT can guide needle biopsy as to which nodal stations are considered high risk. Targeting lymph nodes with a higher pretest probability further decreases the inherent false negative rate of needle biopsy. The location of FDG avid nodal stations is important as to which technique will be most appropriate. For example, the identification of an FDG supraclavicular node (N3) can lead to ultrasound guided percutaneous biopsy. An FDG avid aortopulmonary lymph node may be sampled by using Chamberlain procedure, CT guided fine needle aspiration, or extended cervical mediastinoscopy. In cases with enlarged mediastinal lymph node with negative PET, confirmation by invasive techniques is also advised, as up to 21% of these can still have nodal involvement[4, 6]. There are two exceptions to the rule. First, it is known that in a patient with a peripheral T1 tumour (<3 cm), negative FDG uptake and no enlarged lymph node in the mediastinum carries a high negative predicted value with false negative rate being only 4%[3]. Therefore invasive staging is not recommended in these patients given the similar negative predicted value in a combined EBUS and EUS needle biopsy. Secondly, in lung cancer patients with infiltrative mediastinal mass on CT or PET/CT either from overt T4 disease or bulky nodal disease would not require invasive mediastinal staging. MRI and emerging Techniques MR imaging has mainly been used to evaluate non-small cell lung carcinoma when there is possible involvement of superior sulcus or brachial plexus. It is currently not a routine clinical tool in mediastinal nodal staging. New studies albeit with relatively smaller patient sample size have shown that MRI can detect nodal metastasis particularly using STIR and diffusion weighted imaging (DWI) [7, 8]. Several studies have shown comparable efficacy in relation to the PET/CT staging techniques[9]. Diffusion weighted imaging detect random thermal motion of water molecules, known as Brownian motion. Tissues with restricted diffusion will have a lower apparent diffusion coefficient (ADC) values. Hypercellular density, larger cellular nuclei and dense tumour cell membranes are known to cause restricted diffusion in malignant tissue. A study has confirmed the negative relationship between the SUV on FDG PET/CT scans and the lower ADC values on MRI[10]. Furthermore, MRI has the ability to differentiate tumour tissue from vasculature and mediastinal fat. It is therefore potentially useful to delineate direct tumour invasion of the mediastinum, chest wall, diaphragm or spinal column. More research is required in this field of MR mediastinal staging. The latest development in PET/MR imaging technique [11]using hybrid scanner will provide a fertile ground for future research in the use of non-invasive mediastinal staging. References 1. Silvestri, G.A., M.K. Gould, M.L. Margolis, et al., Noninvasive staging of non-small cell lung cancer: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest, 2007. 132(3 Suppl): p. 178S-201S. 2. Physicians, A.C.o.C. and H.a.S.P. Committee, Diagnosis and management of lung cancer: ACCP evidence-based guidelines. American College of Chest Physicians. Chest, 2003. 123(1 Suppl): p. D-G, 1S-337S. 3. Silvestri, G.A., A.V. Gonzalez, M.A. Jantz, 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): p. e211S-250S. 4. de Langen, A.J., P. Raijmakers, I. Riphagen, et al., The size of mediastinal lymph nodes and its relation with metastatic involvement: a meta-analysis. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery, 2006. 29(1): p. 26-29. 5. Pozo-Rodríguez, F., J.L. Martín de Nicolás, M.A. Sánchez-Nistal, et al., Accuracy of helical computed tomography and [18F] fluorodeoxyglucose positron emission tomography for identifying lymph node mediastinal metastases in potentially resectable non-small-cell lung cancer. J Clin Oncol, 2005. 23(33): p. 8348-8356. 6. De Leyn, P., D. Lardinois, P.E. Van Schil, et al., ESTS guidelines for preoperative lymph node staging for non-small cell lung cancer. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery, 2007. 32(1): p. 1-8. 7. Usuda, K., X.-T. Zhao, M. Sagawa, et al., Diffusion-weighted imaging is superior to positron emission tomography in the detection and nodal assessment of lung cancers. Ann Thorac Surg, 2011. 91(6): p. 1689-1695. 8. Ohno, Y., H. Koyama, M. Nogami, et al., STIR turbo SE MR imaging vs. coregistered FDG-PET/CT: quantitative and qualitative assessment of N-stage in non-small-cell lung cancer patients. J Magn Reson Imaging, 2007. 26(4): p. 1071-1080. 9. Pauls, S., S.A. Schmidt, M.S. Juchems, et al., Diffusion-weighted MR imaging in comparison to integrated [¹⁸F]-FDG PET/CT for N-staging in patients with lung cancer. European Journal of Radiology, 2012. 81(1): p. 178-182. 10. Heusch, P., C. Buchbender, J. Köhler, et al., Correlation of the Apparent Diffusion Coefficient (ADC) with the Standardized Uptake Value (SUV) in Hybrid 18F-FDG PET/MRI in Non-Small Cell Lung Cancer (NSCLC) Lesions: Initial Results. Rofo, 2013. 11. Kohan, A.A., J.A. Kolthammer, J.L. Vercher-Conejero, et al., N staging of lung cancer patients with PET/MRI using a three-segment model attenuation correction algorithm: Initial experience. Eur Radiol, 2013.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MS22.3 - Minimally Invasive and Endoscopic Options (ID 564)
14:45 - 15:05 | Author(s): D. Gompelmann
- Abstract
- Presentation
Abstract not provided
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MS22.4 - Surgical Techniques for Definitive Staging (ID 565)
15:05 - 15:25 | Author(s): U. Pastorino
- Abstract
- Presentation
Abstract not provided
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CALC - Chinese Alliance Against Lung Cancer Session (ID 79)
- Event: WCLC 2013
- Type: Other Sessions
- Track: Other Topics
- Presentations: 4
- Moderators:C. Bai, Y. Wu, D.C. Lam
- Coordinates: 10/27/2013, 07:30 - 12:00, Parkside Auditorium, Level 1
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CALC.01 - Welcome (ID 3865)
07:30 - 07:40 | Author(s): C. Bai
- Abstract
Abstract
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CALC.02 - Keynote: Epidemiology and Burden of Smoking Related Diseases in China (ID 3866)
07:40 - 08:30 | Author(s): C. Bai
- Abstract
Abstract
Epidemiology and Burden of Smoking Related Diseases in China Prevalence of Smoking in China Being the largest producer and consumer of tobacco across the globe, China produces one-third (2.66 million tons/year) of the global tobacco leaves [1] and consumes 30% of the world’s cigarettes [2]. According to the Global Adult Tobacco Survey (GATS) Collaborative Group, China had the highest number of tobacco users (300.8 million) and a low quit ratio compared to 16 countries [3]. The International Collaborative Study of Cardiovascular Disease in Asia showed that 147,358,000 Chinese male and 15,895,000 Chinese female aged 35–74 years had been current cigarette smokers [4]. Regardless of gender difference, such prevalence was higher in the rural population compared to the urban population (male 61.6% vs 54.5% P <0.001; female 7.8% vs. 3.4% P<0.001) [4]. A growing prevalence of smoking was also observed in women [5], adolescents and young adults [2,6-8]. Even among non-smokers, the threat of tobacco smoke remained because airborne nicotine had been detected in 91% of the 273 public locations sampled in rural and urban China [9]. Specifically, an estimated 50-72% of Chinese non-smokers had been exposed to secondhand tobacco smoke [10,11]. Considering active and passive smoking altogether, 72% of the Chinese population were tobacco exposed [12]. Such common exposure has aggravated tobacco-related morbidity and mortality which create a direct economic burden accounting for 42.31 billion yuan [13]. By increasing mortality from cancer, respiratory disease and cardiovascular disease [14-18], smoking currently costs over 1 million Chinese lives per year. If the trend continues, a predicted sum of 2 million Chinese may die of tobacco-related diseases in 2025 [19]. COPD and Smoking Chronic obstructive pulmonary disease (COPD) had an estimated prevalence of 8.2% (>43 million) in the Chinese population > 40 years old [20] and was ranked the fourth/third leading cause of death in urban/rural area respectively [21]. Prompted by the causative roles of active [22-24] and passive smoking [25], a yet increasing prevalence of COPD would be expected in the Chinese population. In the meantime, the expensive treatments and compromised productivity of COPD patients had already created an enormous economic burden equaling to 110% and 34% of the annual incomes in rural areas and urban areas respectively [26]. Even so, the situation might have been undermined due to premature mortality and impaired working capabilities within affected families. Anti-smoking measures could be the best solution since the absolute risks of COPD would fall by 56% in Chinese male and 63% in Chinese female 5 years after smoking cessation [27]. Lung Cancer and Smoking Smoking is the main risk factor for lung cancer regardless of smoking experience (ever, current and ex smoking), tobacco product variety (pipes, cigars and cigarettes) and histological subtypes [28].\\Lee et al. demonstrated the dose-response relationship between smoking and lung cancer pathogenesis [28]. Specifically, risk of lung cancer decreased with duration of smoking cessation but increased with an earlier age of smoking and elevations in (i) the amount and fraction of smoking; (ii) duration of smoking; and (iii) tar level. Analyzing data from10 cancer registries, the crude incidence rate of lung cancer in China was estimated to be 49.35 per 100,000 population (63.7 per 100,000 men and 35.0 per 100,000 women) in 2005 [29]. Compared to lifelong non-smokers, the mortality rate of lung cancer was found to be approximately 23 times and 13 times higher in current male smokers and current female smokers respectively [30]. As prevalence of smoking rose during the past 3 decades, lung cancer mortality also increased by 464.84% [31]. Since 2008, lung cancer has surpassed other malignant tumors to become the most common cause of death in Chinese cancer patients [32]. At present, the mortality rate of lung cancer is 600,000 per year [33]. If the current trend continues, it may reach 1 million by 2025 [33]. With an increased prevalence of lung cancer and more advanced technology, the total number of lung cancer inpatients increased from 174,066 to 364,484 while medical costs increased from 2.16 billion yuan to 6.33 billion yuan between 1999 to 2005 as illustrated in the China Statistical Yearbook. Nonetheless, such dedication did not effectively prove its worth since the 5-year survival rate of lung cancer remained relatively low (10% - 14%) [34]. To relieve the socioeconomic burden, measures should be taken to reduce the incidence of lung cancer and relevant medical costs. CAD and Smoking Smoking has been associated with increased risk of coronary artery disease (CAD). In China, the reported crude odd ratio varied between 1.37 - 5.19 in former and current smokers [35-38]. In a study about risk ratio for CAD mortality, former smokers and current smokers had a risk ratio of 0.68 and 1.81 respectively when compared to never smokers [37]. Nonetheless, such figures bore no significant difference if stratified by co-morbidity of diabetes. Perhaps not surprisingly, passive smoking was verified to independently increase the risk of cardiovascular heart disease (CHD) by 25% - 30% [39,40]. While the prevalence of coronary artery disease (CAD) have fallen in developed countries through control of preventable risk factors, China witnessed an opposite trend as CAD climbed from the fifth most common heart disease in 1948-1957 to the most common in 1980-1989 [41]. As reported, CAD caused 51.4% and 32.8% of mortality related to cardiovascular disease (CVD) in urban and rural areas respectively. Projected from 1990, 72.7 million Chinese male and 72.1 million Chinese female will have been diagnosed with CAD in 2020 [42]. Smoking, one of the modifiable risk factors of CAD, should be tightly controlled in China if the socioeconomic burden has to be alleviated. Conclusion COPD, lung cancer and CAD are common smoking related chronic diseases which occupy a large share of medical resources yet cost a massive number of lives in China. In order to improve the current situation, smoking cessation should be reinforced in China through introduction of effective measures supported by favorable policy. Reference 1. Wang H. Tobacco control in China: the dilemma between economic development and health improvement. Salud Publica Mex. 2006; 48(Suppl. 1): S140–7. -
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CALC.11 - MicroRNA Biomarkers in Lung Cancer (ID 3878)
11:15 - 11:25 | Author(s): C. Bai
- Abstract
Abstract
ABSTRACT Rationale: Effective treatment for lung cancer requires accuracy in sub-classification of carcinoma subtypes. Objectives: To identify microRNAs in bronchial brushing specimens for discriminating small cell lung cancer (SCLC) from non-small cell lung cancer (NSCLC) and for further differentiating squamous cell carcinoma (SQ) from adenocarcinoma (AC). Methods: Microarrays were used to screen 723 microRNAs in laser-captured, microdissected cancer cells from 82 snap-frozen surgical lung tissues. Quantitative reverse-transcriptase PCR was performed on 153 macrodissected formalin-fixed, paraffin-embedded (FFPE) surgical lung tissues to evaluate 7 microRNA candidates discovered from microarrays. Two microRNA panels were constructed based on a training cohort (n = 85) and validated using an independent cohort (n = 68). The microRNA panels were applied as differentiators of SCLC from NSCLC and SQ from AC in 207 bronchial brushing specimens. Measurements and Main Results: Two microRNA panels yielded high diagnostic accuracy in discriminating SCLC from NSCLC (miR-29a and miR-375, AUC 0.991 and 0.982 for training and validation dataset, respectively) and in differentiating SQ from AC (miR-205 and miR-34a, AUC 0.977 and 0.982 for training and validation dataset, respectively) in FFPE surgical lung tissues. Moreover, the microRNA panels accurately differentiated SCLC from NSCLC (AUC 0.947) and SQ from AC (AUC 0.962) in bronchial brushing specimens. Conclusion: We found 2 microRNA panels that accurately discriminated between the 3 subtypes of lung carcinoma in bronchial brushing specimens. The microRNA panels could have considerable clinical value in differential diagnosis and play an important role in determining optimal treatment strategies based on the lung carcinoma subtype. -
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CALC.14 - Summary and Close, Thanks to CALC, Speakers and Sponsors (ID 3881)
11:45 - 12:00 | Author(s): C. Bai
- Abstract
- Presentation
Abstract not provided
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