Virtual Library

Background:
Low-dose CT (LDCT) screening of smokers at high risk of developing lung cancer has been shown to reduce LC-specific and overall mortality. A retrospective analysis of the National Lung Screening Trial (NLST) data suggests that smoking cessation contributed to the mortality reduction. Pilot LDCT screening programs are being implemented in Ontario with smoking cessation integrated. The Canadian Partnership Against Cancer with Statistics Canada have developed a microsimulation model (OncoSim-LC, version 2.5) that projects the impact of cancer control measures on LC incidence, mortality and cost. Assuming that each annual visit for LDCT is a teachable moment to promote smoking cessation, we have modelled the potential cost and cost-effectiveness of integrating cessation into an organized screening program.

Method:
OncoSim-LC incorporates Canadian demographic characteristics, risk factors, cancer management approaches and outcomes and resource utilization to assess clinical, economic and healthcare system impacts. We compare a base case of organized screening with no cessation to various scenarios of screening with cessation. Modelling assumptions included: annual screening of 55-74 year olds with 30+ pack year smoking history, target participation rate reached over 10 years; one cessation intervention (nicotine replacement therapy + varenicline + 12 weeks of counselling) costs $490; up to 10 cessation attempts per eligible individual dependent on screening encounters; a permanent quit rate of 5% per cessation attempt. Cost-effectiveness was estimated with a lifetime horizon, health system perspective and 1.5% discount rate. Costs are in 2016 CAD.

Result:
Cessation within a screening program with 60% recruitment and 70% rescreening (adherence) would cost approximately $76 million (undiscounted) per year for 2017-2036 or 8% of the total cost of screening, treatment and cessation. Compared to screening with no cessation, approximately 110 fewer incident cases and 50 fewer lung cancer deaths would occur on average per year for 2017-2036 and cost $14,000/QALY (lifetime horizon). 90% recruitment and 80% rescreening would result in 260 fewer deaths and cost of $24,000/QALY. At a doubled permanent quit rate of 10%, screening with cessation would cost $6,000/QALY. A 50% increase in the cost of the cessation intervention would decrease cost-effectiveness to $22,000/QALY.

Conclusion:
Based on the OncoSim-LC model, a cessation program within an organized LDCT screening program would cost well under $50,000/QALY even over multiple quit attempts. Integrating robust smoking cession initiatives within a LDCT screening program could save lives and be relatively cost-effective.

Background:
Anecdotal reports of families carrying germline EGFR mutations force us to reconsider our understanding of inherited lung cancer risk in non-smokers. We launched this prospective trial (NCT01754025; ALCMI-002) to remotely enroll and characterize these rare families.

Method:
Eligible subjects were recruited at participating cancer centers or through an online referral system. Following consent (in person or by phone), subjects received genetic counseling and sequencing of saliva or blood for germline EGFR mutations. Cancer specimens and CT scans were additionally analyzed when available.

Result:
Between 12/2012-6/2017, 105 participants were enrolled from 30 US states. Germline EGFR mutations were found in 63% of patients (31 of 49) with EGFR T790M in their lung cancer at diagnosis, and in 62% (16 of 27) and 44% (4 of 9) of first- and second-degree relatives of germline carriers. Pedigrees were available for 32 unrelated kindreds (31 germline T790M, 1 germline R776H): 4 with no family history of lung cancer, 8 with a family history of lung cancer in non-smokers, 18 with multiple relatives with lung cancer. Characteristics of 31 lung cancer probands: median age of lung cancer diagnosis was 57 (range 28-82); 81% white, 19% black; 52% never-smokers; 65% stage IV at diagnosis; 65% were from states in or bordering the US Southeast. Tumor genotyping revealed somatic EGFR co-mutations in 29 (94%) of probands: 6 exon 19 del, 12 L858R, 6 G719X, 1 exon 19 del & G719R, 1 L861Q, 2 H773R, 1 V774M. Imaging analysis suggests a unique pattern of cancer evolution including an indolent multi-focal nodular phase which then progresses to lymph nodes and then remote metastatic disease. Of 8 probands with sensitizing EGFR co-mutations treated with osimertinib, no unexpected toxicities were seen, and 4 have had durable benefit exceeding 12 months. Of 9 relatives with germline EGFR mutations and CT imaging available, 2 have a lung cancer diagnosis and 6 others have lung nodules.

Conclusion:
This study confirms the high likelihood of a germline mutation in lung cancer patients with EGFR T790M detected at diagnosis, and suggests a risk of lung nodules and lung cancer in germline carriers. The regional enrichment in the US Southeast suggests a possible founder effect; haplotyping is planned. A registry is under development to continue follow-up of these rare individuals. Further investigation of germline risk alleles associated with lung cancer risk in non-smokers is needed. Funding: Bonnie J. Addario Lung Cancer Foundation, Conquer Cancer Foundation of ASCO.

Background:
In the National Lung Screening Trial (NLST), annual CT screening reduced lung cancer-specific mortality by 20% and all-cause mortality by 7% relative to chest x-ray (CXR) screening. However, in contrast to other screening approaches, recommendations for CT screening for lung cancer is limited to older heavy smokers, where the risk of death from all smoking-related complications is high, relative to the unscreened population. In the NLST, airflow limitation affects 35% of screening participants and is associated with a 2-4 fold increase risk of lung cancer. We have recently shown that for screening participants with COPD, the reduction in lung cancer-specific mortality with CT screening is only half that seen in those with no COPD (15% vs 28%). We hypothesise that this reduction is due in part to a “competing cause of death” effect.

Method:
Using 10,054 subjects from the ACRIN-NLST sub-study, the current study aimed to compare disease-specific mortality according to the severity of airflow limitation at baseline to better understand it’s relationship with dying of lung cancer and dying of other smoking-related diseases. We also examined this relationship according to baseline risk of lung cancer, using the Brock (Lung cancer risk) Model, and outcomes from screening.

Result:
After 6.4 years of follow-up, there were 699 deaths; 189 (27%) attributed to lung cancer, 166 (24%) to cardiovascular disease, 61 (9%) to respiratory disease and 150 (21%) to other cancers. After stratifying the 10,054 subjects according to severity of airflow limitation (baseline FEV1%predicted and GOLD grade), we found that the risk of dying of lung cancer and risk of dying of other diseases diverged favouring a stronger relationship with non-lung cancer causes. After stratifying the 10,054 subjects according to their risk of lung cancer (tertiles), we found that CT screening in those at highest risk (highest tertile) had only a 12% reduction in lung cancer-specific deaths compared to 23-24% in other lower risk tertiles. This was associated with higher deaths from cardiovascular disease, respiratory disease and other cancers.

Conclusion:
In a CT screening study, where smokers were followed for a mean of 6.4 years, we found worsening lung function and higher underlying risk for lung cancer was associated with a greater tendency to die of causes other than lung cancer. We suggest smokers at the greatest risk for lung cancer, and those with worse lung function, benefit less from CT screening due to a “competing cause of death” effect.

Abstract not provided

Background:
Disparities exist in cancer outcomes. NSCLC outcomes have improved in recent years but effects of socioeconomic factors have not been reported.

Method:
The National Cancer Database with NSCLC incident cases between 2004-2013 was analyzed. Overall survival (OS) was explored by several available factors with a focus on race and socioeconomic factors.

Result:
A total of 1,150,722 NSCLC patients were included with majority White (86.4%) followed by Black (10.6%) and a smaller proportion of Asians and Hispanics. Patients were evenly distributed among income quartiles and majority were insured (96.7%), lived in a metro area (81.7%) and treated at non-academic facilities (68.5%). Overall median OS was 13.1 months and significantly better for Asians (18.2 months) and Hispanics (16.6 months) as compared to Whites (13.2 months) and Blacks (11.5 months). (Figure 1, p<0.001) Outcomes were worse with higher comorbidity score, TNM stage and treatment at community or high-volume facility. Socioeconomic factors other than race associated with worse outcome included lower education and median income, uninsured status and Central geographic region. (Table 1) Figure 1 Figure 2





Conclusion:
In this largest analysis thus far, patient race and socioeconomic factors were found to significantly influence NSCLC survival. These must be addressed for equitable healthcare benefit and outcomes.

Background:
Several large genetic studies have consistently linked the cholinergic nicotinic receptor polymorphism (CHRNA3/5, rs 16969968) to lung cancer and smoking addiction. However, we have shown that this genetic variant was also independently associated with susceptibility to chronic obstructive pulmonary disease (COPD). To date this observation, independently linking CHRNA3/5 polymorphism to both COPD and lung cancer, has not been tested prospectively in a cohort study. Using 10,054 subjects from the ACRIN-NLST cohort, a sub-study of the NLST that recruited high risk smokers and followed them for an average of 6.4 years, we examined the association between the CHRNA3/5 variant in the development of lung cancer relative to its role in COPD and lifelong smoking exposure.

Method:
We compared the frequency of the high risk AA genotype in our cohort of 10,054 high risk smokers according to their smoking status, lung function and COPD status. We also compared the lung cancer incidence rate according to the CHRNA3/5 genotype. Lastly we used stepwise logistic regression and mediation analysis to examine the role of the AA genotype of the CHRNA3/5 variant in smoking exposure, COPD and lung cancer.

Result:
Relative to healthy smoking controls, the AA genotype was associated with the presence of COPD (OR=1.3, P<0.001) and the development of lung cancer overall (OR=1.5, P<0.01), lung cancer with pre-existing COPD (OR=1.5, P=0.04), lung cancer with no COPD (OR=1.5, P=0.04). Compared to the GG and AG genotypes, the AA genotype was associated with (a) lower FEV1%pred, lower FEV1/FVC and a 19% increase in risk of COPD; and (b) greater cigs/day, pack years exposure and a 47% increased risk of lung cancer. No differences were found for age, gender, smoking duration, years since quitting and current smoking status. In stepwise logistic regression, we found that age, BMI, AA genotype, smoking exposure and lung function were independently associated with getting lung cancer. In the mediation analyses we found that the AA genotype was independently associated with smoking (OR=1.42,P<0.05), COPD (OR=1.25,P<0.05) and getting lung cancer (OR=1.37, P<0.05).

Conclusion:
This is the first prospective study to confirm that while the CHRNA3/5 variant is associated with lung cancer, more importantly this variant is also independently associated with airflow limitation (COPD). It is also the first cohort study to show that while this genetic variant is also associated with smoking exposure (triple whammy effect), this is independent of its effects on predisposition to both COPD and lung cancer.

Background:
Treatment of NSCLC is rapidly advancing and academic centers are considered equipped with better expertise. NSCLC outcome trends in novel therapeutic era and impact of initial treatment at academic centers have not been reported.

Method:
The National Cancer Database (NCDB) with NSCLC incident cases between 2004-2013 was used. Overall survival (OS) was plotted by year of diagnosis and type of treatment facility, accounting for several available factors in NCDB.

Result:
A total of 1,150,722 NSCLC patients were included and separated by initial treatment facility type (academic: 31.5%, non-academic: 68.5%). Several characteristics were significantly different between the two cohorts (Table 1). Median OS for all patients was 13.1 months and improved significantly for those diagnosed in 2010-2013 (14.8 months) as compared to 2004-2009 (12.4 months) (p<0.001). Treatment at academic centers was associated with reduced risk of death [Multivariate HR=0.91 (95% CI 0.906-0.919), P<0.001]. Four-year OS for academic and non-academic cohorts was 25% and 19%, respectively (p<0.001), the difference more pronounced in stage 1-3. (Figure 1) Figure 1 Figure 2





Conclusion:
In this largest analysis thus far, NSCLC survival has improved over time and type of treatment facility significantly influences survival. Factors influencing treatment facility choice should be addressed for easier access to academic centers.

Background:
Lung cancer screening can reduce lung cancer mortality by 20%. It is currently recommended in the USA, but not in the UK and ensuring any potential psychological harm is minimised is important. Current evidence is limited to the psychological impact of CT lung cancer screening. This study assesses psychological responses in the Early Cancer Detection Test - Lung Cancer Scotland Study (ECLS Study), whose participants have a tumour antibody blood test (Early CDT®-Lung test) and CT scans only for those with positive blood tests.

Method:
ECLS study participants were randomised to an Early CDT®-Lung test group or a control group. A sample (n=1032) participated in a nested psychological outcomes study. Questionnaires measured psychological responses (positive and negative affect scale (PANAS), lung cancer worry scale (LCWS) and impact of events scale (IES)) at baseline and 1, 3, 6 and 12 months post-trial recruitment. Psychological responses over time were assessed using multilevel modelling and compared between those in the control group, the test-positive group and the test‑negative group.

Result:
In total, 350, 361 and 321 participants were in the control, test-negative and test-positive groups respectively. Follow-up questionnaire completion rates were ≥90% at all time-points. Baseline psychological measures did not differ significantly between groups. Significant differences were found between PANAS scores, but absolute differences between the groups were very small and unlikely to be clinically significant. The IES avoidance and intrusion scores were significantly higher in the positive than the negative group at all time-points and at 1, 3 and 6 months respectively. However, median scores for both subscales at all the time-points were in the subclinical range. Anxiety about future tests and treatment at 1 month was significantly higher in the test-positive group than the control (OR (95%CI) 3.55 (1.70, 7.41)), or the negative group (OR (95%CI) 5.74 (2.69, 12.2)). Worry about getting lung cancer in the future was significantly higher in the test-positive than the test-negative group at 1 month (OR (95%CI) 2.61 (1.35, 5.02)), 3 months (OR (95%CI) 2.52 (1.30, 4.87)) and 6 months ((OR (95%CI) 2.98 (1.53, 5.82)).

Conclusion:
Lung cancer screening using a blood test followed by CT scanning for test-positive individuals does not appear to impact on affect, intrusive thoughts or avoidant behaviour to a clinically important degree. However, anxiety about future tests and treatment and future worry about lung cancer needs to be addressed if lung cancer screening is implemented in the UK.

Abstract not provided

Background:
Our previous study has shown the feasibility and clinical application of circulating tumor DNA(ctDNA) detection in stage I-IIIA surgical non-small cell lung cancer (NSCLC) patients(NCT02645318). The aim of this prospective study is to investigate the perioerative changes of ct DNA in surgical NSCLC patients.

Method:
From 11/2016, suspected lung cancer patients who proposed radical tumor resection were enrolled prospectively. Six precise time points plasma samples were obtained before surgery(time A) and after tumor resection (time B to F, 5min-3days) before discharge. A series driver mutations were quantitatively evaluated by multiplex assay based on circulating single-molecule amplification and resequencing technology (cSMART). Positive plasma mutations were validated in tumor tissue by targeted sequencing. Normal tissue and white blood cell DNA were used as controls. Study protocol (NCT02965391) was approved by Medical Ethics Committee (2016PHB156-01).

Result:
The consort diagram was shown in Fig 1. Thirteen R0 resected patients met the inclusion criteria. Fifteen genetic alterations were identified including four EGFR, seven TP53, two PIK3CA, one KRAS mutation and one ALK rearrangement. Ten (76.9%) cases had a gradually decrease of mutation ratio as time went on, and the average mutation ratio was 3.32%, 2.68%, 1.38%, 0.07%, 0.04% and 0 at the time-points A to F, respectively. Eight patients’ and three patients’ mutation ratio in time point D and time point E were not decease to zero, respectively. Advanced stage patients were more likely to have a positive ctDNA in time D and E, although there was no significant difference. All the mutations’ ratio dropped to zero in time F. No patients’ had positive ctDNA one month after surgery.Figure 1



Conclusion:
This is the first prospective study to evaluate the dynamic changes of ctDNA in surgical lung cancer patients. ctDNA has a rapid clearance in R0 resected lung cancer patients, but is not completely regression until 72h after surgery.

Background:
cfDNA is a promising biomarker for early recurrence detection and disease monitoring in the NSCLC curative setting. However, less is known about cfDNA shedding characteristics and correlation with tumor burden in advanced NSCLC.

Method:
We reviewed cfDNA results of NSCLC patients tested at our institution between November 2015 and December 2016 with Guardant 360, a comprehensive cfDNA assay that detects genomic alterations in 70-73 cancer genes. 141 cases with evaluable imaging were selected for this analysis, enriching for EGFR and KRAS mutated cases to facilitate comparisons of major genomic subtypes (Table 1). Tumor burden was approximated using the sum of longest diameters (SLD), per RECIST v1.1.

Result:
There was a statistically significant correlation of moderate strength between cfDNA maximum variant allele frequency (VAF) detected and SLD (Spearman’s rho = 0.35, p < 0.001). This correlation was strongest in KRAS mutant cases (rho = 0.52, p = 0.001) and weakest in EGFR mutated tumors (rho = 0.21, p < 0.24). Multi-variate regression that included stage, histology, and mutation status confirmed the predictive value of cfDNA VAF for SLD (p = 0.03). TP53 mutants had higher cfDNA VAF (Wilcox p < 0.001), even after accounting for SLD. Increased cfDNA VAF was also seen with EGFR mutants and patients with visceral metastasis, though possibly confounded by concomitant EGFR amplification and increased tumor burden, respectively. CNS metastasis was not associated with differential cfDNA shedding. Figure 1



Conclusion:
In this primarily metastatic cohort, cfDNA VAF correlated with radiographic assessment of tumor burden by RECIST. This correlation was partially mediated by the presence of key driver mutations. TP53 and EGFR mutant tumors and the presence of visceral metastasis are associated with higher cfDNA VAF. These findings have potential implications for the use of cfDNA in advanced-stage NSCLC disease monitoring, where RECIST is more clinically applicable than formal volumetrics.

Background:
Identifying biomarkers to select patients who respond to immune checkpoint blockade in non-small cell lung cancer (NSCLC) remains a challenge. Cell-free circulating tumor DNA (ctDNA) has emerged as a non-invasive, quantitative method of monitoring genomic alterations in the peripheral blood. We evaluated the clinical utility of ctDNA mutant allele frequency (MAF) and tumor burden based on imaging as biomarkers for response to immune checkpoint blockade in NSCLC.

Method:
From a cohort of 136 patients with ctDNA samples, 20 patients were retrospectively identified with ctDNA testing before initiation of anti-PD-1/PD-L1 treatment or within 90 days of therapy initiation. ctDNA testing was performed by Guardant360 (Guardant Health, Redwood City, CA). MAF of the dominant clone was identified quantitatively for each patient. In addition, baseline tumor burden was estimated using RECIST version 1.1. MAF and tumor burden were correlated with progression free survival (PFS) and overall survival (OS). Logistic regression of response rate (RR) and clinical benefit rate (CBR) was also performed.

Result:
Higher median ctDNA MAF was correlated with significantly shorter PFS and OS (hazard ratio (HR) 3.4, p=0.03 and HR 10.4, p=0.03, respectively) (Figure 1). There was no significant association between tumor burden estimation and PFS and OS. However, tumor burden was significantly correlated with MAF (r=0.58, p=0.007). MAF and tumor burden estimation did not correlate with RR or CBR in this small sample. Figure 1



Conclusion:
ctDNA MAF appears to be a promising, non-invasive, prognostic biomarker for response to immune checkpoint blockade in NSCLC with higher MAF associated with shorter PFS and OS. ctDNA MAF may also serve as a surrogate for tumor burden. Prospective studies with serial ctDNA sampling are necessary to further validate these findings.

Background:
CheckMate 032 is a phase 1/2 clinical trial evaluating nivolumab ± ipilimumab in solid tumors, including small cell lung cancer (SCLC). Initial results have shown durable responses and encouraging survival, with benefit seen regardless of PD-L1 status. There is a need for improved biomarkers in SCLC. SCLC is nearly universally found in smokers and is characterized by high tumor mutation burden (TMB). The association of high TMB and clinical benefit from nivolumab ± ipilimumab in patients with SCLC was evaluated in an exploratory analysis of CheckMate 032.

Method:
CheckMate 032 evaluated nivolumab ± ipilimumab in non-randomized and randomized cohorts, which were pooled for this analysis. Whole exome sequencing (WES) was conducted on tumor and matched blood samples. TMB was defined as the total number of nonsynonymous somatic mutations. For the exploratory analyses, patients were equally divided into TMB tertiles (defined as low, medium, and high). Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan-Meier methods.

Result:
Among 401 patients in the intent-to-treat (ITT) population, 211 (53%) had an evaluable TMB result for these analyses (86% of the 246 patients with tissue available to attempt WES). Baseline characteristics and outcomes were similar between the ITT and TMB-evaluable populations. In TMB-evaluable patients treated with nivolumab (n=133), objective response rate (ORR), PFS, and OS were improved in the high TMB cohort vs the medium and low TMB cohorts (ORR: 21.3% vs 6.8% and 4.8%; 1-year PFS: 21.2% vs 3.1% and not calculable; 1-year OS: 35.2% vs 26.0% and 22.1%). Similar benefits were seen in TMB-evaluable patients treated with nivolumab + ipilimumab (n=78) in the high vs medium and low TMB cohorts (ORR: 46.2% vs 16.0% and 22.2%; 1-year PFS: 30.0% vs 8.0% and 6.2%; 1-year OS 62.4% vs 19.6% and 23.4%).

Conclusion:
In patients with SCLC, efficacy with nivolumab ± ipilimumab was enhanced in those with high TMB. Among patients with high TMB, ORR and 1-year OS rates were approximately double with nivolumab + ipilimumab compared with nivolumab monotherapy. TMB has a potential role as a biomarker in lung cancer. Optimization of TMB cutoff and prospective investigation are warranted.Acknowledgements: All authors contributed to and approved the abstract; writing and editorial assistance was provided by Beth Burke, PhD, CMPP, of Evidence Scientific Solutions, funded by Bristol-Myers Squibb.Trial Registration: clinicaltrials.gov, NCT01928394

Abstract not provided

Background:
Resistance to EGFR tyrosine kinase inhibitors (TKIs) limits treatment outcomes among patients with EGFR-mutant NSCLC. Resistance mechanisms have previously been conceptualized as binary “positive/negative” variables, but emerging evidence suggests resistant cancers are heterogeneous, and subclones may be appreciated through multiple biopsies.

Method:
We retrospectively analyzed 221 EGFR mutant pts at MGH who had >1 biopsy after progression on their initial EGFR inhibitor. Data on acquired resistance (AR) mechanisms observed at each biopsy, adverse events, and treatment were collected.

Result:
Among 221 pts with a total of 355 post-AR tissue biopsies, median age was 59 (range, 28-88), 69% were female, 64% had EGFR del19, 33% L858R and 3% other activating mutations. Median number of biopsies per patient was 1 (range, 1-4). Biopsies at first resistance to EGFR TKI showed 61% T790M, 5% MET amplification (amp), 3% SCLC transformation, 2% acquired PIK3CA and 1% acquired BRAF mutations. 83 pts had two biopsies during their post-resistance course; 43/83 (52%) had heterogeneity between biopsy 1 and 2. In particular, 20% “lost” T790M, while 11% “gained” T790M. Among 17 pts who lost T790M, 3 gained a separate resistance mechanism, including MET amp and BRAF V600E. In some cases, synchronous biopsies identified spatial heterogeneity. For example, an osimertinib-resistant patient had a T790M/C797S lung nodule, while a concurrent mediastinal lymph node was wild-type at both loci (both sites retained the activating EGFR mutation). Similarly, another osimertinib-resistant patient with MET amp in a pleural effusion cell block had a lung nodule biopsy which lacked MET amp; the patient was treated with combination EGFR and MET inhibitors with a partial response. Additional details regarding concurrent liquid biopsies, treatment histories and clinical outcomes will be presented.

Conclusion:
In this large cohort of EGFR mutant NSCLC patients, we frequently observed variations in resistance mechanisms in patients with > 1 post-AR biopsy. Our data highlights the heterogeneity of resistant cancers and the limitations of a single biopsy in fully capturing the spectrum of resistance mechanisms in each patient. Serial biopsies or non-invasive methods may be required to characterize resistance and identify potential therapeutic targets.

Background:
Cancers are composed of heterogeneous cell populations in terms of somatic mutations and dysregulated signaling pathways. We hypothesized that such heterogeneity, together with selection advantages conferred by distinct microenvironments, may contribute to tumor evolution and metastatic patterns.

Method:
We collected tumor specimens and non-cancer tissues from treatment-naïve autopsied patients to study the innate genetic evolution and spatial heterogeneity by RNA-sequencing. Our cohort consists of four NSCLC patients and one SCLC patient. Each patient had 5 – 9 primary and metastatic lesions, including metastases to lung, liver, colon (distant metastases), visceral or parietal pleura (pleural metastases), and intra- or extra-thoracic lymph nodes (lymph nodes metastases). Comprehensive data analyses were performed, including gene expression / pathway analyses and fusions / somatic variants detection.

Result:
Global unsupervised clustering analysis of expression data reveals that lesions from each patient clustered together, indicating that tumor cells themselves have greater effects on the gene expression signature than the microenvironment. Pathway analyses in individual patients revealed that the primary lesion is distinct from metastatic lesions in NSCLCs (Figure-left). For the SCLC patient, distant metastases and lymph node metastases clustered according to different parts of the primary tumor (Figure-right). Pathway analyses also revealed that cell-cycle, DNA replication, RNA polymerase, and spliceosome-related pathways are upregulated, while immune-related pathways are downregulated in all metastatic patterns compared with primary lesions. In particular, we observed that multiple immune-related pathways, related to NK cells and T-cells, were downregulated in pleural metastases. Detection of fusions / somatic variants identified the KIF5B-RET fusion as a founder mutation in a never-smoking adenocarcinoma patient. Notch signaling was upregulated, in this patient, in all metastatic lesions but not the primary site.Figure 1



Conclusion:
These data demonstrate the similarity and the heterogeneity between primary and metastatic lesions in lung cancer patients. In addition, we identified the correlation between tumor heterogeneity and metastatic patterns.

Background:
Oncogenic reactivation of transcription factors involved in fetal lung development is integral to lung adenocarcinoma (LUAD) biology, as observed with TITF1/NKX2-1 and the ETS transcription factors ETV4 and ETV5. ELF3 is an uncharacterized ETS family member implicated in fetal lung development encoded at 1q32.1. Interestingly, chromosome 1q is a region of frequent gain in LUAD that lacks a bona fide oncogene. We hypothesize that ELF3 is a novel oncogene and putative therapeutic target in LUAD.

Method:
Multiple independent datasets encompassing 1,685 clinical samples of LUAD, lung squamous cell carcinoma (LUSC), small cell lung cancer, and non-malignant lung tissues were analyzed to establish the frequency of ELF3 overexpression and underlying genetic mechanisms of selection. Protein-protein interaction (PPI) networks were constructed around ELF3, and integrated pathway analysis was performed to decipher the signaling network disruptions resulting from ELF3 overexpression. Isogenic cell lines were established to assess the ability of ELF3 to regulate oncogenic phenotypes. The effect of ELF3 loss on tumour growth was assessed in xenograft mouse models.

Result:
Strong ELF3 overexpression was frequently observed in LUAD (>2-fold: TCGA 40% p=1.5E-07; BCCA 73% p=1.6E-21), but was not observed in other lung cancer subtypes. Similarly, high ELF3 expression was significantly associated with poor overall survival of LUAD patients (all Stages p<0.0001, Stage I p<0.0001), but not LUSC patients (p>0.05). These clinical associations prompted further examination of ELF3 in the LUAD subtype of lung cancer. While mutations in ELF3 were rare, up to 80% of LUAD patients harboured focal amplification, DNA gain, and/or promoter hypomethylation at the ELF3 locus, which resulted in transcript overexpression. ELF3 overexpression induces remodeling of 23 direct PPI networks, resulting in loss of interaction with proteins such as MYC and GLI2, while forming new interactions with NKX2-1, HOXA5 and CDK8, among others. This reprogramming of PPI networks affects multiple oncogenic pathways including MAPK, TGF-beta and WNT. ELF3 knockdown in LUAD cell lines resulted in significantly reduced proliferation, viability, and anchorage-independent growth, demonstrating ELF3 has oncogenic properties. Loss of ELF3 abolished the ability of LUAD cells to establish tumours in xenograft mouse models, demonstrating the requirement of ELF3 expression for tumour growth.

Conclusion:
ELF3 is a novel LUAD oncogene encoded on chromosome 1q, activated in up to 73% of patients, and strongly associated with poor overall survival. As ELF3 inhibition abolished tumour growth, therapeutic targeting of ELF3 could benefit LUAD patient outcome.

Background:
The incidence of lung cancer has significantly increased over the last century and remains the most common cause of cancer deaths worldwide. Our better understanding of the tumor microenvironment and the systemic actions of tumors, combined with the recent advent of the liquid biopsy, may allow molecular diagnostics to be done with non-invasive method for detection and monitoring of patient tumors. Sputum has been the target for the discovery of non-invasive biomarkers for lung cancer because it contains airway epithelial cells, and molecular alterations identified in sputum are most likely to reflect tumor-associated changes. Since January of 2017, sputum samples have been prospectively collected at the time of diagnosis for future evaluation of actionable mutations in EGFR, KRAS, BRAF and NRAS in patients with non-small cell lung cancer in our center. Currently, from 20 sputum samples already collected, 5 are confirmed for driver mutations (one in KRAS and 4 in EGFR) in tissue biopsy, with 2 of the samples being positive for T790M in circulating tumor DNA (ctDNA) isolated from plasma. Our aim is to evaluate whether sputum may be representative in the detection of these mutations.

Method:
DNA was extracted from sputum using QIAamp DNA midi kit (Qiagen). Tumor somatic mutations were investigated by target-sequencing using a custom Ion Ampliseq™ Panel (ThermoFisher Scientific), containing hotspot regions of 14 genes frequently mutated in solid tumors (including EGFR). Multiplex amplification was performed with 10 ng of DNA using Multiplex PCR Master Mix (Qiagen) and high-throughput sequencing was performed using Ion Proton platform. Somatic mutations were considered if the variant allele was present in more than 0.5% of the reads, considering a minimum coverage depth of 20,000X. A medium coverage of 172,524X was obtained in the five samples.

Result:
We detected mutations in 3 out of 5 sputum samples of patients with previously known driver mutations (two exon 19 deletions and one exon 18 G719A in EGFR). The highest frequency was detected in the only patient with spontaneous sputum collection (23%).The other two mutations were detected in low frequencies (0.5 and 0.6%) in samples derived from sputum induction. We found T790M in one patient positive for T790M in ctDNA isolated from plasma.

Conclusion:
These preliminary findings indicate that driver mutations can be identified in sputum routinely obtained from sputum samples. Thus, the ability to examine sputum might provide a convenient source of sampling and may be adapted for future large-scale screening.

Abstract not provided

Abstract:
Surgery has historically been the primary treatment option for patients with Stage I non–small-cell lung cancer (NSCLC). Although Stage I NSCLC is technically curable, the presence of significant co morbidity increases the risk of postoperative complications and reduces the potential role of surgery even early stage NSCLC. Because nonsurgical treatment options such as conventional radiotherapy have historically achieved suboptimal outcomes, some have argued that the risks associated with surgery in patients with severe COPD were justified. The reason for poor tumor control with conventional radiation therapy has been shown to be due to insufficient total radiation doses which is usually 60 Gy or lower. Dose escalation with CRT have shown that a total dose of just above 80 Gy seems to be tolerable while doses exceeding 90 Gy, necessary for optimal tumor control, were associated with high risk of unacceptable lung toxicity. Since the 2000s, stereotactic body radiation therapy has rapidly spread as medical physics improved. Stereotactic body radiation therapy has been revealed to be equivalent to surgery in tumor ablation. With stereotactic body radiotherapy (SBRT) the radiation dose to normal tissue is minimized and the dose per fraction can be increased resulting in biologic doses up to twice as high as in CRT. This has resulted in improvement of local tumor control rates up to 88% to 100%, comparable to the rates after surgery. SBRT is a safe and effective treatment option for these patients, with outcomes that do not appear to be inferior to surgery. SBRT is not associated with the considerable initial risks of operative mortality and prolonged hospitalization. Patients who do undergo surgery may benefit from avoiding open lobectomy, instead using less invasive approaches such as video-assisted thoracoscopic surgery or open segmentectomy. All patients with Stage I NSCLC and severe COPD should be evaluated in a multidisciplinary setting and afforded an informed decision of the risks and benefits of both surgery and SBRT. In role of SBRT can also be extended even in patients with oligometastases and oligo-recurrence, the oligometastases and oligo-recurrence who sometimes cured with only local therapy. Radiotherapy (RT) can cause immunogenic tumor cell death resulting in cross-priming of tumor-specific T-cells, acting as an in situ tumor vaccine; however, SBRT alone has limit in inducing effective anti-tumor immunity resulting in systemic tumor rejection. Immunotherapy can complement SBRT to help overcome tumor-induced immune suppression, as demonstrated in many pre-clinical tumor models. There are many trials underway for combinations of different immunotherapies and SBRT.

Abstract:
Surgery as First Line Treatment Option for Small-Sized NSCLC Surgical resection has been the preferred standard of care for patients with well established expectations for survival after resection. A standard of care for patients who are deemed medically inoperable is definitive radiation therapy. Because of the proven effectiveness of radiation therapy in treating the medically inoperable patient with lung cancer, consideration is being given to treating medically operable lung cancer patients with definitive radiation therapy instead of surgery. However, recent clinical guidelines issued by ASTRO (Videtic et al) based on a review of the published data include among other recommendations, that ‘For stage I NSCLC patients with anticipated risk of operative mortality of <1.5%, SBRT is not recommended as an alternative to surgery outside of clinical trial settings. The recommended treatment for these patients remains lobectomy with systematic mediastinal lymph node evaluation’. The problem with such recommendations is as follows. The operative morbidity and mortality following pulmonary resection for the overall population of patients undergoing surgery have also been established. The morbidity and mortality in the overall population of patients following definitive radiation therapy is also well documented. What is not available is reliable data on the treatment-related risks faced by subgroups of patients treated with surgery or with definitive chemotherapy who differ in terms of competing risk factor for death, including age (Eguchi et al.) or their overall functional status ((or what is becoming known as the ‘fitness’ or conversely, the ‘frailty’ of a patient) Korc et al)). Emerging data shows that the frailty of a patient affects the likelihood of survival after surgery of diverse types and for diverse diseases. We have found that frail patients undergoing diverse surgeries for diverse malignancies require ICU admission after a given grade of complication at rates far above those required for fit patients (after Grade I complication 0% vs 20%, after Grade 2 complication 6% vs. 17%, and after Grade 3 complication 5% vs. 35% for fit vs. frail respectively) After ICU admission, frail patients remain at a persistent increased risk of death lasting at least to 600 days when compared to fit patients (50% survival vs. 90% survival for frail patients vs. fit patients after ICU care at 600 days) (unpublished data courtesy of Armin Sharokhni, MD). Similar data is not available for patients with NSCLC treated with definitive radiation therapy. Because of this lack of information, objective comparisons of the feasibility and effectiveness of surgical resection with definitive radiation therapy are likely prone to error due to selection biases.A plausible hypothesis is that the population of patients referred for definitive radiation therapy for NSCLC are frailer, and the decreased long-term survival after radiation therapy is due to frailty rather than cancer-related. In this talk, we will review the data available on: 1. Current perioperative morbidity and mortality following lung resections including MIS and sub-lobar procedures 2. Current likelihood of long-term survival following curative lung cancer surgery 3. The competing risks for short- and long-term survival after surgery including age and frailty 4. The methods of risk stratification, including frailty, for a patient being considered for lung cancer surgery 5. The methods of risk stratification that have been used in retrospective and prospective comparisons of surgery and definitive radiation therapy Based on this review, proposals for prospective trials comparing SBRT and surgery for objectively defined medically operable early stage NSCLC will be made. References: Eguchi et al. Impact of Increasing Age on Cause-Specific Mortality and Morbidity in Patients With Stage I Non-Small-Cell Lung Cancer: A Competing Risks Analysis. J Clin Oncol. 2017;35:281-290 Korc-Grodzicki et al. Surgical considerations in older adults with cancer. J Clin Oncol 2014;32:2647-53.. Videtic et al. Stereotactic body radiation therapy for early-stage non-small cell lung cancer: Executive Summary of an ASTRO Evidence-Based Guideline. Practical Radiation Oncology (in press)

Abstract:
The approach that has most commonly been reported as an alternative to surgery or SBRT for non-small lung cancer (NSCLC) is thermal ablation. There are also different ablative modalities, of which radiofrequency ablation (RFA) has been the most widely reported. RFA was reported for human lung tumors in 2000 [1]. RFA has been shown to be feasible and safe in several studies[2,3]. However, many studies have involved heterogeneous patient populations that included patients with metastatic tumors and NSCLC. Additionally, in those series focusing on NSCLC, patients with different stages. Have been included. Another consideration is that in several centers, these procedures have been performed by interventional radiologists, who are not traditionally part of the multidisciplinary oncology team, and rarely have follow-up clinics, so accurate reporting of recurrence and survival rates has not been optimal. Lastly, other modalities such as microwave or cryoablation, are gaining in popularity [4],[5] Despite some perceived improvements in technology, there is no clinical data that supports one ablative modality over another with respect to cancer outcomes[6] . Currently thermal ablation is reserved for medically inoperable patients with NSCLC. In those series that have reported outcomes specifically for stage I NSCLC outcomes have been good, and comparable with studies of SBRT, when looking at survival rates. One study included 56 patients with stage I NSCLC[7]. Median survival was 29 months. A prospective multi-center phase II trial involving 54 patients was recently reported[8]. Overall survival was 87.3% at 1-year, and 69.8% at two-years. Two-year survival was superior in patients with tumors <2cm (83%). There were only two grade 4, and one grade 5 event within 90 days (not attributable to the RFA). Our group has also treated 21 patients with stage Ia NSCLC (submitted for publication). Three-year survival in our series was 52%. One issue when comparing results of trials using different modalities is how comparable are patient groups. The medically inoperable group in this prospective phase II trial were compared to a medically group in an RTOG phase II trial of SBRT[9]. Although both groups were labelled medically inoperable, lung function was significantly better in patients treated with SBRT. This argues for the need for prospective studies comparing these modalities for medically inoperable patients. The main issue with thermal ablation has been higher rates of local recurrence in most studies. Tumor size is important, and results are better for tumors <2cm[7,8]. This certainly would be an argument for SBRT over RFA. However how recurrence is measured and defined may impact on reporting of local control, and there are differences in how these have been identified in different studies. In the absence of a prospective trial using similar end-point recording, overall survival is the cleanest endpoint with which to make comparisons. In summary, thermal ablation remains a viable option for small stage I NSCLC patients who are deemed medically inoperable. Future innovations include developments in energy source and, also in bronchoscopic delivery to peripheral tumors[10]. References 1. Dupuy DE, Zagoria RJ, Akerley W, et al: Percutaneous radiofrequency ablation of malignancies in the lung. AJR Am J Roentgenol 174:57-9, 2000 2. Ambrogi MC, Fanucchi O, Cioni R, et al: Long-term results of radiofrequency ablation treatment of stage I non-small cell lung cancer: a prospective intention-to-treat study. J Thorac Oncol 6:2044-51, 2011 3. Lencioni R, Crocetti L, Cioni R, et al: Response to radiofrequency ablation of pulmonary tumours: a prospective, intention-to-treat, multicentre clinical trial (the RAPTURE study). Lancet Oncol 9:621-8, 2008 4. Zhong L, Sun S, Shi J, et al: Clinical analysis on 113 patients with lung cancer treated by percutaneous CT-guided microwave ablation. J Thorac Dis 9:590-597, 2017 5. Ahrar K, Littrup PJ: Is cryotherapy the optimal technology for ablation of lung tumors? J Vasc Interv Radiol 23:303-5, 2012 6. Vogl TJ, Nour-Eldin NA, Albrecht M, et al: Thermal Ablation of Lung Tumors: Focus on Microwave Ablation. Rofo, 2017 7. Simon CJ, Dupuy DE, DiPetrillo TA, et al: Pulmonary radiofrequency ablation: long-term safety and efficacy in 153 patients. Radiology 243:268-75, 2007 8. Dupuy DE, Fernando HC, Hillman S, et al: Radiofrequency ablation of stage IA non-small cell lung cancer in medically inoperable patients: Results from the American College of Surgeons Oncology Group Z4033 (Alliance) trial. Cancer 121:3491-8, 2015 9. Crabtree T, Puri V, Timmerman R, et al: Treatment of stage I lung cancer in high-risk and inoperable patients: comparison of prospective clinical trials using stereotactic body radiotherapy (RTOG 0236), sublobar resection (ACOSOG Z4032), and radiofrequency ablation (ACOSOG Z4033). J Thorac Cardiovasc Surg 145:692-9, 2013 10. Koizumi T, Tsushima K, Tanabe T, et al: Bronchoscopy-Guided Cooled Radiofrequency Ablation as a Novel Intervention Therapy for Peripheral Lung Cancer. Respiration 90:47-55, 2015

Abstract:
For certain extra-pulmonary malignancies, such as colorectal cancer or sarcomas, the existence of curable oligometastatic disease state has been well established. Oligometastasis is a state of stage IV disease associated with limited spread of disease at the time of diagnosis. This condition may reflect a more indolent phenotype than that associated with more widespread disease at presentation. Recently, it becomes more clear that the patients with Stage IV NSCLC are heterogenous and hence, some patients have high disease burden whereas others have isolated metastatic lesions. In the 8th TNM staging system, M-stage was reclassified into M1a, M1b, M1c, and the patients with M1b may represents the oligometastatic status of NSCLC. It has been demonstrated that the predominant pattern of failure in patients with oligometastasis treated with the first-line systemic chemotherapy was mainly a local failure, the fact which leads an idea that the local treatment may improve cure rates in such patients. The incidence of oligometastasis in NSCLC has been reported 7-26% of NSCLC [1, 2], with the major sites of metastases being bone, brain, adrenal glands and liver. In general, the successful treatment of patients with oligometastasis requires the ability to eradicate the primary site, the ability to image all sites of metastatic disease, the ability to ablate all metastatic sites, and having effective systemic therapy to eradicate undetected micrometastatic disease. Recently, routine use of improved diagnostic imaging tools such as PET-CT or Brain MRI, can better detect latent metastases in patients who would otherwise have been thought to have a localized disease, and hence, the diagnosis of “true” oligometastatic disease may be increasing [3]. Development of local treatment modalities such as minimally invasive surgery (MIS) or stereotactic radiotherapy (SABR) enabled effective local abrasion of the metastatic sites without major morbidities. Above all, rapid development of effective molecular target agents and immune check point agents in the treatment of NSCLC are encouraging to reconsider surgery for the treatment of oligometastatic NSCLC patients. Most evidence of treatment effect of local treatment for oligometastasis derives from the survival data from retrospective patients groups. For brain metastases, 5-year survival rates have been reported 6.6-35% and adrenal gland metastases showed similar results (5-year survival rates 12-40%). In a well-designed propensity score matching study suggested an improvement in survival favoring local abrasive therapy, but definite conclusions on the efficacy of local therapy for the treatment of extra-cranial oligometastatic NSCLC could not be reached [4]. A meta-analysis which included 49 studies, suggested overall median overall survival of 19 months after local ablative treatment (5.9-52 months)[5]. Most recent study by Gomez and colleagues demonstrated a progression free survival benefit favoring local consolidative therapy [6]. Hopefully, ongoing prospective trials may provide more strong evidence of the effect of local ablative therapy for oligometastasis in near future. Despite many reports that support local treatment for oligometastasis, the lack of control data in almost all reports is a problematic issue. Since local treatment for the oligometastasis is only performed in selected patients with relatively indolent disease, there is often no actual denominator for the entire group of patients who developed metastasis [7]. Thus, determining the survival advantage of ablative local treatment of oligometastasis compared to palliative systemic therapy is difficult because the majority of existing data are with a substantial degree of selection bias. In the other aspect, however, we have learned that the patient selection is critical for the application of local treatment on the oligometastasis. In general, local treatment is indicated in metastatic NSCLC patients with favorable prognostic factors including absence of mediastinal lymph node metastasis, small number of metastases, complete control of primary lesion, meta-chronous metastasis, and good performance status of the patients. Although there are relatively large numbers of papers on the brain or adrenal metastases, the reports of extra-cranial or extra-adrenal metastases are rare. In a meta-analysis, the 5 year overall survival rates of extra-cranial / extra-adrenal metastasis was 50% and the prognosis was mainly influenced by lymph node metastasis status[ 8]. First used in the literature in 2012 [9], the concept of oligoprogressive disease has been rapidly adopted. It can be best described in patients with tumors harboring actionable mutations who are treated with molecular targeted therapies. Initially, the response rate is great but the duration of response is relatively short, with resistance to therapy generally emerging within a year of start of treatment as a result of various genetic mechanisms. Not uncommonly, disease progression during molecular targeted therapy occurs at a limited number of anatomic sites. Recently, several studies reported improved progression free survival and overall survival in either intra-cranial or extra-cranial oligopregressive diseases by applying local abrasive therapy on those acquired resistant oligoprogressive diseases and by resuming target agents [10]. Furthermore, the combination of immune check point agents and SABR on primary tumor and/or metastatic sites may be promising for treating oligometastatic NSCLC, due to a possible abscopal effect. In conclusion, although current evidence of local treatment of oligometastases is limited in NSCLC, with aid of recent diagnostic tools by which more stringent patient selection is possible, local ablative treatment of metastatic lesions can lead improved survival of patients with oligometastasis in conjunction with molecular target agents or immune check point agents. 1. Albain KS, Crowley JJ, LeBlanc M, et al. Survival determinants in extensive-stage non-small-cell lung cancer: the Southwest Oncology Group experience. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 1991;9:1618-1626. 2. Parikh RB, Cronin AM, Kozono DE, et al. Definitive primary therapy in patients presenting with oligometastatic non-small cell lung cancer. International journal of radiation oncology, biology, physics 2014;89:880-887. 3. Tonnies S, Tonnies M, Kollmeier J, et al. Impact of preoperative 18F-FDG PET/CT on survival of resected mono-metastatic non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands) 2016;93:28-34. 4. Sheu T, Heymach JV, Swisher SG, et al. Propensity score-matched analysis of comprehensive local therapy for oligometastatic non-small cell lung cancer that did not progress after front-line chemotherapy. International journal of radiation oncology, biology, physics 2014;90:850-857. 5. Ashworth A, Rodrigues G, Boldt G, et al. Is there an oligometastatic state in non-small cell lung cancer? A systematic review of the literature. Lung cancer (Amsterdam, Netherlands) 2013;82:197-203. 6. Gomez DR, Blumenschein GR, Jr., Lee JJ, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. The Lancet Oncology 2016;17:1672-1682. 7. Fiorentino F, Treasure T. Pulmonary metastasectomy: a call for better data collection, presentation and analysis. Future oncology (London, England) 2015;11:19-23. 8. Salah S, Tanvetyanon T, Abbasi S. Metastatectomy for extra-cranial extra-adrenal non-small cell lung cancer solitary metastases: systematic review and analysis of reported cases. Lung cancer (Amsterdam, Netherlands) 2012;75:9-14. 9. Weickhardt AJ, Scheier B, Burke JM, et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2012;7:1807-1814. 10. Iyengar P, Kavanagh BD, Wardak Z, et al. Phase II trial of stereotactic body radiation therapy combined with erlotinib for patients with limited but progressive metastatic non-small-cell lung cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2014;32:3824-3830.

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Abstract:
Introduction Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting toxicity. Its prevalence and impact on quality-of-life (QOL) has variable documentation in the literature, due to differing assessment modalities utilized. Objectives To discuss the natural history and characteristics of chemotherapy-induced peripheral neuropathy (CIPN) in patients receiving taxane- and platinum-based chemotherapy. Methods for the study Prospective longitudinal study including patients commencing on taxane or platinum-based therapy, with assessment time-points at baseline, end of each chemotherapy cycle, and 6, 9 and 12-months. Assessments of neuropathy included: sensory assessment using 10gr monofilament and cotton wool, clinician neuropathy grading systems: WHO scale(1-item) and NCI-CTCAE(2-items), and FACT&GOG-Ntx scale. Results In total, 348 patients were recruited to undergo up to 10 assessments over 12 months from three centres in Hong Kong (n=215), Singapore (n=95) and UK (n=38). Participants received taxanes (n=157,46%), platinum (n=111,32%) or a combination of both (n=78,22%). CIPN demonstrated cumulative increase through the chemotherapy cycles and reached a peak at 6 months. Each assessment method showed different CIPN incidence The sample included 343 patients providing 2,399 observations. There was wide variation in CIPN prevalence rates (14.2-53.4%) using different assessments. Patient self-reported scales tended to double or triple the CIPN estimates compared to clinician-based or objective measures. Peak prevalence was around cycle six and the 6-month assessment (Figure 1). Prevalence was highest in taxane-based chemotherapy, followed by taxane-platinum combination. Platinum-based chemotherapy showed the lowest CIPN rate. Motor symptoms were more predominant than sensory ones. Time since chemotherapy was the only predictive factor of CIPN (ORs=9.6-66 depending on the scale used). Cumulative dose had no impact in the development of CIPN. There were relatively moderately to low correlations between the scales, suggesting validity issues. Quality of Life was significantly affected (p=0.48 to <0.001 for different domains at 6-months, 9-months,12-months assessment). Conclusions CIPN is common with taxane/platinum chemotherapy although less prevalent in this largely Asian population compared to past studies involving predominantly Caucasians. Current assessment methods are suboptimal and often limited only to sensory problems, while motor disturbances receive less attention. The variability in CIPN prevalence seen in past work may be the result of the type of assessment used. CIPN prevalence may be lower than that reported in the literature. It seems that from the moment CIPN appears it will run its course over time, irrespective of the chemotherapy cumulative dose, raising issues around the current practice of dose reduction/discontinuation. Assessment in practice needs to also consider motor neuropathic problems. Current scales may not be all appropriate to measure CIPN in a valid way, and a combination of scales is needed in practice. Key References: Cavaletti G., Frigeni B., Lanzani F., Mattavelli L., Susani E., Alberti P., CortinovisD., Bidoli P. (2010). Chemotherapy-Induced Peripheral Neurotoxicity assessment: A critical revision of the currently available tools. European Journal of Cancer, 46(3):479-494. Haryani H, Fetzer SJ, Wu CL, Hsu YY. Chemotherapy-Induced Peripheral Neuropathy Assessment Tools: A Systematic Review. Oncol Nurs Forum. 2017; 44(3):E111-E123. Le-Rademacher J2, Kanwar R, Seisler D, Pachman DR, Qin R, Abyzov A, Ruddy KJ, Banck MS, Lavoie Smith EM, Dorsey SG, Aaronson NK, Sloan J, Loprinzi CL, Beutler AS. Patient-reported (EORTC QLQ-CIPN20) versus physician-reported (CTCAE) quantification of oxaliplatin- and paclitaxel/carboplatin-induced peripheral neuropathy in NCCTG/Alliance clinical trials. Support Care Cancer. 2017 Jun 20. doi: 10.1007/s00520-017-3780-y. [Epub ahead of print] McCrary JM, Goldstein D, Boyle F, Cox K, Grimison P, Kiernan MC, Krishnan AV, Lewis CR, Webber K, Baron-Hay S, Horvath L, Park SB; IN FOCUS Delphi working party. Optimal clinical assessment strategies for chemotherapy-induced peripheral neuropathy (CIPN): a systematic review and Delphi survey. Support Care Cancer. 2017 Jun 7. doi: 10.1007/s00520-017-3772-y. [Epub ahead of print] Mols F, Beijers T, Vreugdenhil G, van de Poll-Franse L. Chemotherapy-induced peripheral neuropathy and its association with quality of life: a systematic review. Support Care Cancer. 2014; 22(8):2261-9 Seretny M, Currie GL, Sena ES, Ramnarine S, Grant R, MacLeod MR, Colvin LA, Fallon M. Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis. Pain. 2014; 155(12):2461-70. Miaskowski C, Mastick J, Paul SM, Topp K, Smoot B, Abrams G, Chen LM, Kober KM, Conley YP, Chesney M, Bolla K, Mausisa G, Mazor M, Wong M, Schumacher M, Levine JD. Chemotherapy-Induced Neuropathy in Cancer Survivors. J Pain Symptom Manage. 2017 Jan 4. pii: S0885-3924(16)31243-X. doi: 10.1016/j.jpainsymman.2016.12.342. [Epub ahead of print] Alberti P, Rossi E, Cornblath DR, Merkies IS, Postma TJ, Frigeni B, Bruna J, Velasco R, Argyriou AA, Kalofonos HP, Psimaras D, Ricard D, Pace A, Galiè E, Briani C, Dalla Torre C, Faber CG, Lalisang RI, Boogerd W, Brandsma D, Koeppen S, Hense J, Storey D, Kerrigan S, Schenone A, Fabbri S, Valsecchi MG, Cavaletti G; CI-PeriNomS Group. Physician-assessed and patient-reported outcome measures in chemotherapy-induced sensory peripheral neurotoxicity: two sides of the same coin. Ann Oncol. 2014; 25(1):257-64. Acknowledgements Cheng H, School of Nursing, The Hong Kong Polytechnic University, Hong Kong SAR; Au JSK, Leung KT, Wong KH, Li YC, Department of Oncology, Queen Elisabeth Hospital, Hong Kong SAR; Lopez V, Chan A, Ng TRD, Sundar R. National University of Singapore, Singapore; Yorke J, The University of Manchester, UK

Abstract:
Patients and their family and friends consistently report that communication with health care providers has a major impact on their experience of lung cancer. In particular, being informed of treatment choices and being involved in care decisions are highly valued elements of health care by patients. Effective communication has become an increasingly important element of person centred care as treatment advances mean that patients with lung cancer are faced with more complex decisions and treatment choices. In this context, the process of advance care planning has grown in popularity as an important strategy to achieve optimal end of life care. Advance care planning is a process where a person discusses their values and healthcare preferences with their family, friends and healthcare team.[1] Advance care planning is a process that can be undertaken at any time and documented to inform health care decisions if the person can no longer communicate them. Various approaches to advance care planning have been described and a range of health care professionals can be involved in the process. Key elements of advance care planning include discussions of personal values and preferences for healthcare at end of life, establishing clear recommendation regarding future treatment, including discussions about palliative care, documenting patient values and preferences in an accessible site in the medical record, and encouraging the patient to discuss wishes with family/proxy.[2] The process also involves discussions about substitute decision makers who will act on the person’s behalf should the patient not be able to do so.[1] Studies report advance care planning improves ongoing and end-of-life care and personal and family satisfaction, and that families of people who have an advance care plan have less anxiety, depression, and stress.[3] However, studies across a number of countries suggest limited uptake by community members and by health care professionals, as well as poor knowledge and skills of health team members in advance care planning.[4] This is due to a range of factors, including health care professionals’ lack of confidence and skills in conducting sensitive and challenging conversations about end of life issues. Health care professionals are encouraged to have advance care planning conversations early, however there is no clear consensus about what early means in this context and how readiness for such conversations is interpreted from patient to patient. Advance care planning can also oversimplify the decision making process, as such decisions are inherently personal, will change of time, and are influenced by a range of sociocultural and health literacy factors. Negotiating the different perspectives of health professionals, family members, and patients is also very complex. In addition, legal issues give rise to confusion about the process in practice and current pressures to contain costs in health care means that some patients could feel pressured to make choices that do not reflect their true preferences. To address these concerns, advance care planning documentation is often extremely complex, creating even more barriers to the process. A further critical limitation of advance care plans is that even when they are documented, they are not accessible in practice, and where they are available, health care professionals and family members do not always follow the documented preferences. Significant advances are being made across many countries to address the limitations of advance care planning and optimise its use in practice. These advances are in areas including health care professional education and skills building, development of tools to guide practice, greater clarity about the inclusion of advance care planning in care pathways, and leveraging off developments in electronic medical records. Important work in terms of community awareness and understanding of advance care planning is also underway. References 1. What is advance care planning? Available at www.advancecareplanning.org.au, accessed 5[th] July 2017 2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Palliative Care V.1.2016. © 2016 National Comprehensive Cancer Network, Inc. 3. Detering, KM, Hancock, AD, Reade, MC, Silvester, W, 2010, ‘The impact of advance care planning on end of life care in elderly patients: randomised controlled trial’, British Medical Journal, 340: c1345.doi:10.1136 4. Lovell, A, Yates, P. 2014, Advance care planning in palliative care: A systematic literature review of the contextual factors influencing its uptake 2008-2012. 28(8), 1026-35.

Abstract:
Surgical treatment for malignant pleural mesothelioma (MPM) has an interesting history and currently remains the foundation of the best treatment for select cases of MPM. At its outset a radical pleural pneumonectomy was fraught with very high surgical mortality which overshadowed any possible benefit. As surgical technique, anesthesia and post-operative care improved the mortality plummeted to low single digits thus allowing the benefit of surgery to emerge. Currently the median survival for patients with MPM is 21, 19, 14 and 10 months for stage I, II, III and IV disease per IASLC data (1) Certain well selected subgroups of patients treated surgically in a multimodal fashion have a median survival up to 4 years or more (2). The optimal surgical procedure and multimodal protocol is currently in flux but the principles that are important include a complete macroscopic resection either by extended pleurectomy and decortication that generally includes resection of the diaphragm and pericardium or by an extrapleural pneumonectomy that includes the entire pleural envelope, lung and en-bloc pericardium and diaphragm. A complete node dissection is vital as nodal involvement is a negative prognostic factor in most series. Reconstruction of the diaphragm and pericardium is an important feature of the operation and when done well will limit the post-operative morbidity significantly. Intra-operative adjuncts such as photodynamic therapy, heated intrapleural chemotherapy or heated povodone-iodine have been shown in select series to likely improve local control and perhaps survival. Systemic chemotherapy and radiation therapy also are important to the outcome but the exact type and sequence is controversial. (3-5). The correct surgical technique and sequence is critical to a good outcome. Similarly, choosing the best patient for surgery is complex and of vital importance. Generally patients should have reasonable cardiopulmonary reserve and limited co-morbidities. Age is not a sole determinant and probably less important than the functional status of the patient but patients over age 80 should be approached with caution. An extensive cardiopulmonary workup and staging evaluation is mandatory. Assessment of pulmonary function including split function with a quantitative ventilation and perfusion scan, cardiac reserve with an echocardiogram (look at pulmonary artery pressures) and stress test and general assessment of functional status are basic points of information that are needed to move forward with surgery. Evaluation of tumor burden with a magnetic resonance chest scan, PET scan and mediastinal node evaluation with either endobronchial ultrasound or cervical mediastinoscopy are important to avoid operating on patients with disease outside the chest or disease involving N2 nodes. Induction therapy on a protocol is reasonable particularly if patients have mediastinal nodal disease or non-epithelial histology. Also assessment of either tumor thickness or tumor volume helps prognosticate and determine likelihood of nodal involvement. Other factors such as severe pain or a high platelet count portend a poor outcome. Right sided resections particularly pneumonectomy have a higher risk and if at all possible a pleurectomy/decortication procedure is preferred . However if the lung is contracted or so involved by tumor that the only way for complete resection is to remove the lung then it should be done particularly if the functional contribution is 20% or less. A generous posterolateral thoracotomy through the bed of the resected 6[th] rib is carried out. The extrapleural plane is entered and fully mobilized so that it is clear the tumor is resectable. Posteriorly, the aorta and esophagus must be free, apically the tumor should come off the subclavian artery, anteriorly the tumor should be able to be freed from the pericardium. The pericardium is often resected en-bloc with the tumor. It should be opened early to be sure there is no invasion of the heart. Inferiorly the diaphragm is resected bluntly at its origin from the chest wall and care is taken to be sure the pleural recesses are respected such that all of the pleura is taken with the specimen. The peritoneum is left intact from the overlying diaphragm. Care is taken to avoid injury to the inferior vena cava near its entrance into the right atrium. At this point the pleural envelope should be opened and the lung assessed. If the tumor can be completely resected by taking the visceral pleura then this is preferred and the lung is spared. If the lung is so involved that gross tumor will be left behind if significant lung is not removed then a pneumonectomy is carried out. A full mediastinal node dissection is performed and hemostasis is obtained. If an intra-operative adjunct is to be used it is given at this point. Following that, the stump is covered with local tissue, likely a strip of pericardium and in some cases omentum. The pericardium and diaphragm are reconstructed, each with a goretex patch, which has been described in referenced publications. For the left side the operation is very similar other than the inferior vena cava is not an issue and if a pneumonectomy is required is generally well tolerated (6). Newer molecular techniques are proving very useful in aiding the surgeon in making decisions about how aggressive a strategy to use (7). References 1. Rusch VW, Chansky K, Kindler HL et al. The IASLC mesothelioma staging project: proposals for the M descriptors and for revisions of the TNM stage groupings. J. Thorac Oncol. 2016;11:2112-9. 2. Sugarbaker DJ, Gill RR, Yeap BY et al. Hyperthermic intraoperative pleural cisplatin chemotherapy extends interval to recurrence and survival among low-risk patients with malignant pleural mesothelioma undergoing surgical macroscopic complete resection. J Thorac Cardiovasc Surg. 2013;145:955-63. 3. Friedberg JS, Simone CB 2[nd], Culligan MJ, et al. Extended pleurectomy-decortication-based treatment for advanced stage epithelial mesothelioma yielding a of nearly 3 years. Ann Thorac Surg. 2017;103:912-919 4. Lang-Lazdunski L, Bille A, Papa S, et al. Pleurectomy/decortication, hyperthermic pleural lavage with povidone-iodine, prophylactic radiotherapy and systemic chemotherapy in patients with malignant pleural mesothelioma: a 10-year experience. J. Thorac Cardiovasc. Surg. 2015;149:558-65. 5. Sugarbaker DJ, Richards WG, Bueno R. Extrapleural pneumonectomy in the treatment of epithlioid malignant pleural mesothelioma: novel prognostic implications of combined N1 and N2 nodal involvement based on experience in 529 patients. Ann Surg. 2014;260:577-80. 6. Sugarbaker DJ, Norberto JJ, Swanson SJ. Extrapleural pneumonectomy in the setting of multimodal therapy for diffuse malignant pleural mesothelioma. Semin Thorac Cardiovasc Surg. 1997 Oct;9(4):373-382 7. De Rienzo A, Cook RW, Wilkinson J et al. Validation of a gene expression test for mesothelioma prognosis in formalin-fixed paraffin-embedded tissues. J. Mol. Diagn. 2017,19:65-71.

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Abstract:
A ground-glass nodule (GGN) is a morphologic description of pulmonary nodule category on thin-section chest computed tomography (CT). Pure GGNs are defined as focal nodular areas of increased pulmonary attenuation through which pulmonary parenchymal structures, such as pulmonary vessels or bronchial structures, can be observed. Part solid nodules present with ground-glass and solid components, in which the underlying pulmonary architecture cannot be visualized, whereas solid nodules are without ground-glass components. These nodules differ in pathological condition and natural history by type, and management corresponding to these differences is required. Transient GGNs, which disappear after 3 months in repeated CT, are likely due to inflammation or infection. If many small GGNs are present, these are more likely to represent atypical adenomatous hyperplasia (AAH), and follow-up with annual CT scans is advised. The majority of persistent solitary pure GGNs are pathologically atypical adenomatous hyperplasia, adenocarcinoma in situ (AIS), and minimally invasive adenocarcinoma (MIA); these nodules do not grow, or progress very slowly. Pure GGNs less than 15 mm in diameter are followed up after 3 months, 1 year, and 2 years with CT. In the meantime, when the GGN increases in size, or if solid components appear in the nodule, a definite diagnosis is made, although such cases are extremely rare. Even when a solid component appears inside the GGN, there are options for further follow-up as long as the diameter of the solid component remains less than 5 mm. A solitary pure GGN that is unchanged for 5 years could remain unchanged even after 10 years. Of solitary pure GGNs 5 mm or less in diameter, approximately 10% will grow, with 1% developing into invasive adenocarcinomas or MIAs. Therefore, it is recommended that solitary pure GGNs smaller than 5 mm be rescanned after 3 to 5 years, in order to look for development of a solid component. In cases of part solid nodules, which present with both ground-glass and solid components, the underlying pulmonary structures cannot be observed. These nodules are more suspicious than pure ground-glass nodules and thus require more aggressive management if they persist. Persistent part solid nodules usually represent lepidic predominant adenocarcinomas or MIAs. In particular, if the margin of a part solid nodule is well-defined on thin-section CT, it is often dianogsed as lepidic predominant adenocarcinoma or MIA. Some inflammatory lesions show part solid nodules on CT; if the nodules do not disappear or decrease in size on CT after 3 months, they are highly likely to be adenocarcinomas. Usually, a lung adenocarcinoma showing part solid nodules on CT does not grow rapidly in 3 months. Therefore, a 3-month CT follow-up is effective for diagnosing a partly solid nodule (which is difficult to diagnose). Small solid nodules are most commonly observed, although few are malignant. These nodules are easily detected on CT, but it is difficult to diagnose their malignancy. Nodules over 10 mm in diameter are suspicious for malignancy, and an attempt should be made to obtain a definitive diagnosis. Solid nodules with a maximum diameter of 5 to 10 mm in smokers should be followed up until after 3 months, 6 months, 1 year, and 2 years on CT. In non-smokers, however, intervals of follow-up could be longer. Solitary nodules less than 5 mm in diameter are very rarely malignant and only require annual follow-up if patients have risk factors such as smoking. The reasons why intervals of follow-up differ between smokers and non-smokers are because smokers have a higher risk of lung cancer, and the tumor doubling time is shorter in the case of lung cancer in smokers. If the size of a nodule increases during follow-up, a definitive diagnosis is needed. If the size of a solid nodule is unchanged for 2 years, the possibility of lung cancer is extremely low, and follow-up observation may be completed; however, in smokers, emphysema is often complicated, and the diagnosis is more difficult as the shape and margin of the nodule also vary. In the case of small cell carcinoma, hilar and mediastinal lymph node metastasis may occur 3 months after nodule detection, and the early diagnosis of small cell lung cancer is extremely difficult. In the present lecture, the outcomes of follow-up of these various small pulmonary nodules will be illustrated. Figure 1CT image at detection Figure 210 years later

Abstract:
Diagnostic procedures for lung cancer can broadly be defined as those that lead to the initial diagnosis, evaluation of extent of disease, and obtaining tissue for further characterization of molecular and genetic properties of the cancer. In each of these areas there have been tremendous technologic advances which ultimately lead to added complexity in terms of best utilization of tissue. Tissue can be obtained by the radiologist through either the use of fine needles (either single-needle or co-axial) or through the use of cutting needles which obtain cores of tissues) and through a variety of guidance techniques including fluoroscopy, CT guidance (including CT fluoroscopy), sonography, and MR. Most commonly, now for lung procedures is CT guidance. With the increasing use of CT imaging lung nodules are detected at smaller and smaller sizes and the diagnostic approach becomes increasingly challenging. In addition, since there is better chance for cure when treatment is performed earlier the desire to obtain early diagnosis is strong. The question that arises primarily relates to what level of confidence is needed before a definitive surgical procedure is performed. Factors to be balanced are the diagnostic accuracy of competing non-invasive tests such as growth analysis or PET-CT, compared to needle biopsy. All this must also be balanced with the type of surgical procedure that is being considered and the tremendous improvements that often allow patients to be discharged within 1-2 days post surgery. Evaluating extent of disease includes biopsy of either lymph nodes or other structures such as ribs, adrenal glands, liver etc. Within the chest, evaluation of lymph nodes pre-operatively has been greatly enhanced through the use of bronchoscopy with ultrasound. However, there are many nodal stations that remain difficult to reach using this approach that can be reached with CT guided needle biopsy, including all compartments of the mediastinum and hilum. Lesions outside the lung can also be evaluated including the soft tissues and the ribs. These lesions are often detected on PET-CT and are amenable to needle biopsy. Most rib lesions can easily be accessed with simple aspiration type needles. The need for further characterization of cancers through molecular or genetic testing is rapidly gaining in importance. As new therapeutic techniques become available the need for more complete characterization of tumors becomes increasingly important. Here the question relates to how much tissue is needed to perform the desired test. This is a continuously evolving area and depends on which particular tests are being requested, availability of the institution to perform the particular test, and the potential to obtain the appropriate amount of material given the particular characteristics of the lesion. Critical to these considerations is developing a close working relationship with the pathology department so as to make sure all of these considerations are taken into account prior to performing a procedure. Collaboration with the pathology department is critical on many levels and may need to vary depending on available resources. Best would be having rapid on-site evaluation (ROSE), although this is not always possible. For each situation, a plan as to how to best maximize yield needs to be developed. In this talk, I will outline the many considerations for how best to optimize the diagnostic yield of material obtained by interventional radiologist depending on the characteristics of the lesion and present various strategies to integrate these approaches into various scenarios where tissue is required.

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