Virtual Library

Background:
Rovalpituzumab tesirine (i.e. SC16LD6.5) is a Delta-like protein 3 (DLL3) targeted antibody-drug conjugate (ADC) comprised of a humanized monoclonal antibody, dipeptide linker, and pyrrolobenzodiazepine (PBD) dimer toxin with a drug-to-antibody ratio of 2. DLL3 is highly expressed in human neuroendocrine tumors and their tumor-initiating cells, including approximately two-thirds of small cell lung cancer (SCLC). DLL3 is not expressed at detectable levels in normal tissues. Rovalpituzumab tesirine induced tumor regression and prolonged time to progression significantly outperforming cisplatin/etoposide in DLL3-expressing SCLC patient-derived xenograft tumor models. Based on this promising activity, a first-in-human phase I trial in patients (pts) with recurrent SCLC was initiated and preliminary results are reported below.

Methods:
SCLC pts with progressive disease after 1 or 2 previous lines of therapy received escalating doses of rovalpituzumab tesirine as a single agent once every 3 weeks (Q3W) in 1-3 pt cohorts until dose limiting toxicities (DLTs) were observed. The doses were 0.05, 0.1, 0.2, 0.4 and 0.8 mg/kg Q3W. Midway through accrual, pharmacokinetic data revealed a longer than expected ADC half-life of ~11 days, prompting evaluation of a Q6W schedule. A DLL3 antibody was developed and utilized to assess antigen expression in archived tumor specimens. Biomarker positive (BM+) tumors were defined by IHC membrane-associated H-Scores ≥ 120.

Results:
52 pts were treated: 34 Q3W and 18 Q6W; 24F/28M; median age, 61 years (44-82). Acute and chronic DLTs of thrombocytopenia and capillary leak syndrome (CLS) were observed at 0.8 and 0.4 mg/kg Q3W, respectively. Maximum tolerated doses (MTD) of 0.2 mg/kg Q3Wx3 cycles and 0.3 mg/kg Q6Wx2 cycles were further evaluated in expansion cohorts. The most common treatment emergent adverse events of any grade among all pts were fatigue (40%), rash (39%), nausea (29%), dyspnea (23%), decreased appetite (21%) and vomiting (21%). Grade 3+ CLS and thrombocytopenia were seen in 7 (14%) and 3 (6%) pts, respectively, with no reported Grade 5 toxicity. Of 38 archived tumor specimens received from enrolled pts, 23 (61%) were DLL3 BM+. Among the 16 confirmed DLL3 BM+ pts treated at the MTDs, 7 pts (44%) had partial response (PR) and 8 pts (50%) achieved stable disease (SD) for a combined clinical benefit rate (CBR) of 94%. In all evaluable pts treated at the MTD without regard for DLL3 biomarker status (n=32), the ORR was 22% (n=7 PR) and SD 53% (n=17), for a CBR of 75%. Notably, all pts with PRs that were treated at the MTD, and those having the most durable clinical benefit (up to 569 days OS), were BM+. Similar response rates were observed among pts sensitive and refractory to first-line therapy, and in the third-line setting where no standard-of-care currently exists.

Conclusion:
Rovalpituzumab tesirine, a first-in-class DLL3-targeted ADC, has manageable toxicity and demonstrated significant anti-tumor activity (44% ORR and 95% CBR) as a single agent in second- and third-line pts with recurrent DLL3 BM+ SCLC. A pivotal study is being planned.

Background:
Selected patients with good responses to platinum based chemotherapy and good performance status were candidates for continuum platinum based chemotherapy versus chemo-radiotherapy in Extensive-stage small cell lung cancer (ES-SCLC). To evaluate the efficacy and toxicity of continuum platinum based chemotherapy versus chemo-radiotherapy in ES-SCLC in Asian Indian patient population.

Methods:
Between July 2008 and December 2009, 358 patients with ES-SCLC treated with induction Cisplatin (60-80mg/m2 d1) + Etoposide (80-120 mg/m2 d1-3) × 3 cycles for every 3 weeks. Patients with CR at both local as well as distant sites or PR at the local site, but CR at distant sites were randomized 1:1 to two treatment groups (n=287). A total of 287 patients with response were randomized to accelerated hyperfraction thoracic RT (45Gy/1.5 Gy twice daily) plus PE × 4 (144) versus PE × 4 alone without radiation (n=143). The PE doses were similar as in induction. All patients received prophylactic cranial irradiation (25Gy/10 fraction/5/week). The primary endpoint was the comparison of progression free survival (PFS) between the two arms and the secondary endpoints included overall survival (OS). All statistical analyses were performed by using SPSS version 20.0.

Results:
Baseline characteristics were well balanced. Mean age was 58 years (range 32-69), 78% had ECOG 0-1; 22% ECOG 2. In the CRT arm 66.67% and in CT only arm 57.34% patients were smoker. Median PFS 15 months (CRT arm) versus 10 months (CT only) (HR, 0.78; 95% CI, 0.56-1.18; p=0.06) and 5-year OS 10.3% (CRT arm) versus 6.2% (CT only) (HR, 0.83; 95% CI, 0.49 to 1.29; p=0.47) respectively. The survival difference at 1 year was not statistically significant (39% vs 31%; HR=0.89, CI 0.69-1.13; p=0.091). The survival difference at 3 years was just significant (18% vs 11%; HR=0.83, CI 0.72-1.08; p=0.047). Local control trended better in CRT arm, but no difference in distant metastasis control in both arms.

Conclusion:
CRT arm showed better PFS and OS than CT only arm within Asian Indian patient population. Thus, the CRT may be used as a continuum treatment in Asian Indian patients of ES-SCLC after induction chemotherapy.

Background:
Although TRT in patients with ES-SCLC did not lead to a statistically significant difference in overall survival (p=0.066), it did improve 2-year survival rates (p=0.004) in the CREST trial (Slotman et al., Lancet 385:36-42:2015). The failure to meet the primary study endpoint has evoked some controversy in the lung cancer community as to which patients should be offered TRT routinely. To define which patients benefit most from radiotherapy, analysis for overall survival (OS), progression free survival (PFS) and recurrence pattern was performed in patients with and without RITD, which was one of the stratification factors in the randomized study.

Methods:
Patients with confirmed ES-SCLC who responded to 4-6 cycles of platinum-etoposide were randomized to TRT (30 Gy/10fx) or control. All received prophylactic cranial irradiation (PCI). The primary study endpoint was OS. Secondary endpoints were PFS, intrathoracic control. relapse pattern and toxicity.

Results:
Out of 495 patients in the intent-to-treat analysis, 434 had RITD (215 allocated to TRT and 219 to the control arm) and 61 had not (32 allocated to TRT and 29 to the control arm). No significant differences in patient characteristics were observed between the groups. In patients with RITD, OS was significantly longer in the TRT-arm (HR 0.81,95% CI 0.66-1.00;p=0.044). Survival rates in the TRT and control arm were 33% (95%CI 27-40) vs 26% (95%CI 21-33) at 1 year, and 12% (95%CI 8-19) vs. 3% (95%CI 1-8) at 2 years, respectively. PFS was also significantly longer in the TRT-arm (HR=0.70, 95%CI 0.57-0.85; p<0.001). Intrathoracic progression was reported in 43.7% of the TRT arm vs. 81.3% in the control arm (p<0.001). There was no significant difference in the risk of brain metastases (10.2% vs. 5.5%). Exclusive progression outside thorax and brain occurred in 37.2% in the TRT arm, compared to 5.9% in the control arm (P<0.001). In patients without RITD, there was no significant difference in OS (HR 1.02, 95%CI 0.59-1.77, p=0.937) and PFS (HR=1,00, 95%CI 0.59-1.70, NS) between the TRT and control arms.

Conclusion:
This additional analysis of the CREST data shows that ES-SCLC patients with RITD after chemotherapy have a statistically significant improvement in OS, PFS and risk of intrathoracic progression if they undergo TRT. No such benefit for TRT is seen in patients without RITD. These findings support the routine use of TRT in patients who respond to chemotherapy but still have residual intrathoracic disease.

Background:
Patients with extensive-stage disease (ED) small cell lung cancer (SCLC) have limited treatment options and poor survival following failure of platinum-based chemotherapy. Pembrolizumab, a humanized IgG4 monoclonal antibody against PD-1 designed to block the interaction between PD-1 and its ligands PD-L1 and PD-L2, has demonstrated robust antitumor activity and a manageable toxicity profile in several advanced cancers, including NSCLC. We assessed the safety and efficacy of pembrolizumab in patients with PD-L1–positive SCLC in the ongoing, multicohort, phase 1b KEYNOTE-028 study (ClinicalTrials.gov, NCT02054806).

Methods:
Key eligibility criteria for the SCLC cohort include failure of or inability to receive standard therapy, ≥1 measurable lesion per RECIST v1.1, ECOG performance status 0 or 1, PD-L1 expression in ≥1% of cells in tumor nests or PD-L1–positive bands in stroma as assessed by IHC using the 22C3 antibody at a central laboratory, no autoimmune disease, no interstitial lung disease, and no prior anti–PD-1 or anti–PD-L1 therapy. Pembrolizumab is given at 10 mg/kg every 2 weeks for 24 months or disease progression, intolerable toxicity, or investigator decision. Patients with progressive disease who are clinically stable may continue treatment until confirmation of progression 4 weeks later. Response will be assessed per RECIST v1.1 by investigator review every 8 weeks for the first 6 months, then every 12 weeks thereafter. Adverse events (AEs), including potentially immune-related adverse events, will be collected throughout the study and for 30 days (90 days for serious AEs) thereafter. Primary end points are safety and tolerability and the overall response rate. The relationship between pembrolizumab antitumor activity and potential biomarkers, including the level of PD-L1 expression, is an exploratory end point.

Results:
Of the 147 patients with SCLC who had evaluable tumor samples and were screened for PD-L1 expression, 42 (29%) had PD-L1–positive tumors. Overall, 24 patients with SCLC were enrolled and received ≥1 pembrolizumab dose. Among the 20 patients treated as of March 13, 2015, median age was 59.5 years, 55% were men, and 75% had an ECOG performance status of 1. All patients had received prior chemotherapy with a platinum + etoposide.

Conclusion:
Analyses of safety and tolerability and response are ongoing, as are analyses on the relationship between the level of PD-L1 expression and pembrolizumab response. These data will be available for presentation.

Abstract not provided

Background:
With the advent of modern chemotherapy, patients previously thought to have unresectable small cell lung cancer (SCLC) may have tumors amenable to surgery. This study was undertaken to test the hypothesis of whether surgery, in the setting of modern adjuvant therapies, offers a survival advantage among patients with node-positive SCLC.

Methods:
Overall survival (OS) of patients with pT1-2 pN1-2 M0 SCLC who underwent non-operative management (chemotherapy ± radiation) vs surgery (with adjuvant chemotherapy ± radiation) in the National Cancer Data Base (NCDB) from 2003-2011 was assessed using propensity-score-matched analysis. Groups were matched for common prognostic co-variates (year of diagnosis, age, sex, race, insurance status, facility type, distance from facility, Charlson/Deyo co-morbidity score, pathologic T and N status, and tumor location). NCDB data is prospectively collected by certified tumor registrars and include over 70% of cancer cases diagnosed annually in the U.S.

Results:
Of 1,071 patients who met inclusion criteria, 359 (33.5%) patients underwent surgery with adjuvant chemotherapy ± radiation and 712 (66.5%) underwent non-operative management. After propensity-score matching, 11 covariates were balanced between the surgery (n=231) and non-operative (n=231) groups. Surgery was associated with a significantly higher OS than non-operative management (5-year OS 28.1% vs 18.3, log-rank p<0.01) (Figure 1). To minimize treatment selection bias due to comorbidities, we limited the propensity-matched analysis to patients with no comorbidities; surgery remained significantly associated with a higher OS than non-operative management (5-year OS 32.1% vs 21.8%, log-rank p<0.01) (Figure 2). Figure 1 Figure 2





Conclusion:
In a propensity-matched analysis of a national population-based cancer database, surgery followed by adjuvant chemotherapy ± radiation for SCLC pT1-3 pN1-2 patients had improved outcomes when compared to non-operative medical treatment. These results support an increased role of surgery in multimodality therapy for more advanced limited-stage small cell lung cancer.

Background:
NCCN, ACCP and Japanese guidelines suggest surgery for patients with c-stage I small-cell lung cancer (SCLC), while ESMO guidelines recommend surgery for patients with c-stage II (T1,2 N0,1). In addition, the clinical impact of surgery with other variables on patients with early-stage SCLC has yet to be determined. Therefore, clarification of the clinical profile of surgically resected SCLC is required. Suppression of MED12, a subunit of the transcriptional MEDIATOR complex in conjunction with cell surface expression of TGF-βRII was reported to be correlated with the resistance mechanism of EGFR-TKIs, crizotinib, and chemotherapy. Few investigators examined the expression profile of MED12 as well as receptor tyrosine kinases in SCLC. A next-generation sequencing (NGS) system is a novel technology for sequencing genomes at high-throughput and with great accuracy using deep sequencing. It has been instrumental for translational study integrating the detection of genetic alteration analysis into the better understanding of tumor biology, as well as treatment of various types of cancers. Recently, SOX-2 amplification, histone modification, and genetic alterations in the PI3K/AKT/mTOR pathway were reported to be potential targets of SCLC using NGS through whole exon analysis. However, further investigation is needed for the personalized treatment of SCLC. We updated the molecular data using NGS, which had been presented at ESMO 2014 (abstract ID: 5724).

Methods:
We reviewed the clinical courses of 156 patients with SCLC who had undergone surgery at 17 institutes from January 2003 through January 2013. One hundred twenty-five formalin-fixed paraffin-embedded tissue samples were subjected to immunohistochemistry using seven antibodies (MED12 and TGF-βRII, ALK, c-Met, EGFR, c-kit, and VEGFRII) and to NGS systems using MiSeq and TruSight Tumor Sequencing Panel (Illumina) loading 26 cancer-specific genes. (UMIN registration No. 000010116 /10117).

Results:
Median relapse-free survival and overall survival (OS) were 15.6 (95%CI=6.8-24.5) and 33.3 (20.9-45.8) months, respectively. Multivariate analysis revealed that OS was longer in patients without a history or presence of other types of cancer (HR: 0.545, 95%CI=0.335-0.887, p=0.014), with preoperative diagnosis (HR: 0.510, 95%CI=0.299-0.871, p=0.014), with c-stage II and under (HR: 0.288, 95%CI=0.154-0.541, p<0.001) and with prophylactic cranial irradiation (HR: 0.300, 95%CI=0.092-0.976, p=0.045). Of the 125 patients whose samples were available, MED12 and TGF-βRII were highly expressed in nucleus and cytoplasm, respectively in 92% and 55% of the samples. None of the tumors expressed ALK. There was no relationship between the expression of c-Met, EGFR, and VEGFRII and either of RFS or OS. Multivariate analysis demonstrated that high expression of c-kit in tumor is an independent factor for longer OS (HR=0.543, 95%CI: 0.310-0.953, p=0.033). Seventy-nine samples have been subjected to NGS. Three actionable gene mutations, EGFR (E746_A750del), KRAS (G12D), and AKT1 (E17K) were found.

Conclusion:
These results supported the ESMO guidelines for the management of early-stage SCLC, and indicated that presence or history of other types of cancer might be a major decisive factor for surgery. The results of immunohistochemistry using antibodies of selective molecules and NGS assist us in gaining a better understanding of the biology and treatment strategy of SCLC.

Abstract not provided

Background:
MPM median overall survival (OS) did not exceed 13 months with pemetrexed-platinum doublet, with virtually no surviving patients at 5 years. Vascular endothelial growth factor is a potent mitogen for MPM cells.

Methods:
In this French multicenter randomized phase 3 trial, eligible patients had unresectable, histologically proved MPM, age < 76, no prior chemo, PS 0-2, no thrombosis, nor bleeding. Randomized patients (1:1) received pem 500 mg/m2, CDDP 75 mg/m2 at D1, with (arm B) or without bevacizumab (arm A), 15 mg/kg Q21D, for 6 cycles. Arm B non-progressive patients received bevacizumab maintenance therapy until progression or toxicity. Primary endpoint was OS. 445 patients were to be randomized, and 385 events observed, to show a significant OS improvement, with 80% statistical power, 5% a-risk.

Results:
From Feb. 2008 to Jan. 2014, 448 patients were included in 73 centers. Males: 75.4%, median age: 65.7 years (range 34.7-75.9), PS 0-1: 96.7%. The IDMC recommended a second interim analysis after 85% of events. On 01-Jan-2015, the duration since last news was < 30 days in 105 out of 106 still living patients. Overall survival was significantly longer in the experimental arm (median: 18.8 months, 95%CI[15.9-22.6] vs. 16.1 months, 95%CI[14.0-17.9] for the reference arm, (adj.HR = 0.76, 95%CI[0.61; 0.94], p = 0.012). With only 46/448 non-progressive patients at the date of analysis, median PFS was 9.6 months, 95%CI[8.5-10.6] in bevacizumab arm vs. 7.5 months, 95%CI[6.8-8.1] (adj.HR = 0.62, 95%CI[0.50-0.75], p < 0.0001). G3-4 hematological toxicities did not significantly differ in the two arms (49.5% vs. 47.3%). Significantly more G3 proteinuria (0.0 vs. 3.1%), G3 hypertension (0.0 vs. 23%), G3-4 arterial thrombotic events (0.0 vs. 2.7%) were observed in bevacizumab arm. QOL and exploratory biomarkers studies will be also presented at time of the meeting.

Conclusion:
Bevacizumab addition to pemetrexed/cis-platin provides a significantly longer survival in pts with MPM, with acceptable toxicity, making this triplet a new treatment paradigm.

Background:
Anetumab ravtansine (BAY 94-9343) is a novel fully humanized anti-mesothelin IgG1 antibody conjugated to a ravtansine, a maytansine derivative DM4 antitubulin cytotoxic agent. We report results from a phase I study evaluating the safety, PK and tumor response in patients (pts) with advanced solid tumors treated with anetumab, with a particular focus on patients with mesothelioma.

Methods:
Anetumab was given IV every 21 days (q3w) in 77 pts: 45 pts in 10 dose escalation cohorts from 0.15 to 7.5 mg/kg (21 mesothelioma, 9 pancreatic, 5 breast, 4 ovarian, 6 other), and 32 pts in 2 expansion cohorts (12 mesothelioma and 20 ovarian); 38 pts were treated at MTD in escalation and expansion cohorts (16 mesothelioma, 21 ovarian, 1 breast). Clinical and laboratory safety assessments were made on D1, D8 and D15 in C1-C3 and on D1 in subsequent cycles. Tumor assessments were made q6wks up to C8 and q12wks thereafter. Mesothelin expression in archival tumor samples was assessed retrospecively by IHC (SP74, Ventana).

Results:
Thirty-two males and 45 females were treated [mean age 62 yrs (range, 18-84 yrs), body weight 77 kg (44-113 kg), ECOG ≤1, median prior cytotoxic regimens: overall 4 (1-9), mesothelioma 1 (1-4)]. Non-tolerated anetumab dose was 7.5 mg/kg (DLTs: 1 pt with G2 keratitis and G3 neuropathy, 1 pt with G4 keratitis and G2 neuropathy). Anetumab MTD was 6.5 mg/kg (DLT: G3 AST increase). Only one DLT occurred at doses below MTD (G3 hyponatremia, 5.5 mg/kg). No drug-related deaths and few drug-related SAEs (7 total and 5 at MTD) were reported. Seventeen of 38 (45%) pts total or 7 of 16 (44%) mesothelioma pts at MTD had drug-related AE requiring dose reduction (G1-4 keratitis, G2-3 neuropathy, G3 fatigue, anorexia, asthenia, diarrhea, N&V, AST increase). LFT increases were the most common drug-related laboratory abnormality at MTD: AST in 7 pts (2 G3), ALT in 6 pts (no G3), alkaline phosphatase in 4 pts (one G3) and bilirubin increase in 1 pt (no G3). There were no drug-related G3 hematological abnormalities at any dose. Fourteen of 38 (37%) pts total or 4 of 16 (25%) mesothelioma pts at MTD had G1-4 keratitis (worst G3-4 in 3 pts, blurred vision in 10, dose reduction in 8, dose delay in 11, all fully reversible). Anetumab at the MTD showed a PR in 6 pts (19%) and SD in 18 pts (47%) overall. Five of 16 (31%) mesothelioma pts at the MTD had durable PR (>600 days in 4 pts) and 7 (44%) had SD. Five PRs occurred in 11 mesothelioma pts who received anetumab as second line treatment (45% response rate).

Conclusion:
Anetumab at the MTD (6.5 mg/kg) showed encouraging efficacy with durable PR in pts with advanced mesothelioma. At the MTD, all drug-related AEs were reversible and non-life-threatening but required dose reduction in about half of pts, most commonly due to G1-4 keratitis and G2-3 peripheral neuropathy. Given this benefit-risk ratio, the recommended phase II dose of anetumab in second line treatment of advanced mesothelioma is 6.5 mg/kg IV q3w.

Background:
Targeting the programmed death receptor 1 (PD-1) pathway is a valid therapeutic target in a variety of solid tumors and hematologic malignancies. Pembrolizumab (MK-3475) is a potent, highly selective humanized monoclonal antibody against PD-1 and is approved in the United States for the treatment of advanced melanoma that progressed following ipilimumab and, if BRAF[V600] mutant, a BRAF inhibitor. We have previously reported preliminary antitumor response and safety data for pembrolizumab in patients with MPM enrolled in the KEYNOTE-028 study. Here we present updated safety and efficacy data, including survival, for these patients.

Methods:
KEYNOTE-028 (ClinicalTrials.gov, NCT02054806) is a nonrandomized, multicohort phase 1b trial of pembrolizumab in patients with PD-L1–positive advanced solid tumors. Other key eligibility criteria included measurable disease, failure of standard therapy, ECOG PS 0-1, adequate organ function, and no autoimmune disease or interstitial lung disease. PD-L1 positivity was defined as expression in ≥1% of tumor cells by IHC at a central laboratory. Patients received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Response was assessed per RECIST v1.1 by investigators every 8 weeks for the first 6 months and every 12 weeks thereafter. Primary end point was the ORR. Secondary end points included safety and tolerability and PFS.

Results:
Of the 84 patients with MPM screened for PD-L1 expression, 38 (45%) patients had PD-L1–positive tumors. Of these 38 patients, 25 met the eligibility criteria and were treated with pembrolizumab. As of March 20, 2015, ORR is 28% (n = 7); 12 (48%) patients had stable disease, resulting in a disease control rate of 76%. In the 15 patients with only 1 prior line of therapy, ORR and DCR are 20% and 73%, respectively. Responses are durable, and 10 (40%) patients remain on treatment (duration, 24+ to 36+ weeks). With a median follow-up duration of 8.6 months, median PFS is 5.5 months (95% CI, 3.4-NR), and the 6-month PFS rate is 49.4%. No new safety signals were observed. 15 (60%) patients experienced a drug-related adverse event (DRAE), including 3 (12%) who experienced grade 3-4 DRAEs. Only 2 patients required dose interruption because of immune-related adverse events (transaminitis and uveitis [n = 1 each]). There was no treatment-related mortality, and no patients discontinued because of DRAEs.

Conclusion:
Single-agent pembrolizumab has significant clinical activity in patients with PD-L1–positive MPM. The durability of responses and the 49.4% 6-month PFS rate in this pretreated patient population warrants further investigation. Updated safety and survival data, as well as the correlation of antitumor activity with the level of PD-L1 expression, will be available at the time of presentation.

Abstract not provided

Background:
Limited treatment options exist for patients with thymic malignancies (TM), and chemotherapy efficacy is often restricted by cumulative toxicity such as neuropathy (taxanes) and cardiomyopathy (anthracyclines). Single agent amrubicin, a third generation anthracycline and topoisomerase II inhibitor with minimal cardiac toxicity, was investigated in TM pts in this trial.

Methods:
This was an open-label single drug trial at 2 institutions. Eligible pts had TM (thymoma (T) or thymic carcinoma (TC)) with progression or relapse after at least 1 prior chemotherapy regimen, and adequate organ function including left ventricular ejection fraction (LVEF) of >50%. The initial treatment plan consisted of amrubicin at 40 mg/m[2] IV days 1-3 repeated in 3-week cycles.

Results:
From 7/11 to 4/14, a total of 33 patients (14T/19TC) were enrolled. There were 14 women and 19 men; age range of 30-81 years; 9 Asian, 1 African-American, 1 Hispanic and 22 non-Hispanic White pts. A high rate of febrile neutropenia (FN) led to an amended starting dose of 35 mg/m[2] days 1-3 repeated in 3-week cycles. In total, 7 pts experienced FN with 1 related death. Other grade 3/4 related events included: thrombocytopenia (n=2), neutropenia without fever (n=3), hyponatremia (n=2), hypokalemia (n=2), anemia (n=7), lethargy/fatigue (n=7), perirectal abscess (n=2), palmar-plantar erythrodysesthesia (n=3), syncope (n=2), venous embolism (n=2), and 1 pt each with sepsis, oral abscess, mucositis, chest pain, and epigastric pain. Other toxicities were generally mild and well tolerated. No significant changes in LVEF were noted on serial echocardiograms. There were 6 partial responses (4T/2TC), 21 with stable disease, and 4 with progressive disease (PD) or death at or before first assessment for a response rate (RR) of 18% and a disease control rate (DCR) of 88% (29%/11% RR in T vs TC and 100%/78% DCR in T vs TC). All but 5 patients received at least 4 cycles, and 15 tolerated >10 cycles, with 36 cycles as the highest number to date. Five patients remain on therapy.

Conclusion:
Amrubicin, at 35 mg/m[2 ]IV days 1-3 on a 3-week cycle, shows promise as a single agent in pre-treated patients with thymoma and thymic carcinoma with an 18% RR and no unexpected toxicity. Response rate and disease control rate was higher in the thymoma patients compared to the thymic carcinoma patients. Further exploration of amrubicin as a single drug or in combination is warranted in thymic malignancies.

Background:
We conducted a prospective phase II study of cisplatin plus Cremorphor EL-free paclitaxel (Genexol-PM) in patients with unresectable thymic epithelial tumors (TETs) in order to determine the efficacy and tolerability of the combination.

Methods:
Patients were treated with cisplatin (70 mg/m[2]) and Genexol-PM (230 mg/m[2]) every three weeks for a maximum of six cycles. The primary end point of this study was objective response rate (ORR), and secondary end points included toxicity, progression-free survival (PFS), overall survival (OS), correlation between early [18]F-FDG PET/CT response and PFS, and correlation between baseline FDG uptake and histology.

Results:
Forty-two patients with unresectable thymoma (n=14) or thymic carcinoma (n=28) were enrolled. The median age was 59 years (range, 25-77) and 30 (71%) patients were male, and 39 (93%) had an ECOG PS of 1. The median number of treatment cycles was six (range 1-6). For 40 assessable patients, the ORR was 62.5% (95% confidence interval [CI] 47.6-77.4) with rates of 46% (95% CI 23.3-76.9) for advanced thymoma (n=13) and 70% (95% CI 52.0-82.1) for thymic carcinoma (n=27). With a median follow-up of 15.5 months, the median PFS was 9.8 months (11.4 months for thymoma vs. 8.1 months for thymic carcinoma, with median follow-ups of 16.1 vs. 15.5 months, respectively). The two-year OS was 77.9% for thymoma and 65.9% for thymic carcinoma. There were no treatment-related deaths. The most common grade 3 and 4 treatment-related adverse event was neutropenia in 11 patients (26%). Sixteen (38%) patients experienced grade 2 hypersensitivity reactions. There was no correlation between early PET response and PFS, but tumor histology (thymoma vs. thymic carcinoma) was correlated with SUV~max~ before chemotherapy.

Conclusion:
These data suggest that the combination of cisplatin and Genexol-PM is highly effective and tolerable for the treatment of unresectable TETs, especially in patients with thymic carcinoma.

Background:
Preoperative CT imaging assists in the management of thymic malignancies (TMs), discerning resectability and the need for neoadjuvant chemotherapy. Here, we examine preoperative CT imaging characteristics in relation to the newly proposed IASLC/ITMIG TNM pathologic staging system for TMs.

Methods:
Inclusion criteria for this retrospective study were as follows: 1) diagnosis of thymoma, thymic carcinoma, or thymic carcinoid, 2) definitive primary surgery performed at Stanford University, and 3) pretreatment CT imaging available for review. From 01/1997-03/2015, we identified 119 TM patients who had surgery, and 47 TM patients met all inclusion criteria. The most common reason patients were excluded was for either a missing pretreatment CT (outside imaging not routinely uploaded until 2008) or having surgery for biopsy or recurrent disease. The radiologist (D.T.) was blinded to clinical data, and examined baseline CT imaging per the International Thymic Malignancy Interest Group (ITMIG) standard report terms: contour, calcification, internal density, size of longest diameter, infiltration of mediastinal fat, abutment of mediastinal vessels, vascular endoluminal invasion, abutment/invasion of mediastinal structures, elevated hemidiaphragm, pleural nodules, pleural effusion, mediastinal lymph node enlargement. A univariate analysis and a Lasso regularized general transformation prediction model were performed with all variables to examine the association with pathologic IASLC/ITMIG TNM stage (p<0.05 significant; p<0.10 trend).

Results:
Of 47 TM patients, 9 received neoadjuvant chemotherapy. IASLC/ITMIG pathologic stage included 35 I, 1 II, 7 IIIA, 2 IIIB, 1 each of IVA and IVB. By T stage, there were 36 T1 (encapsulated or unencapsulated+extension into mediastinal fat or mediastinal pleura), 1 T2 (pericardium), 8 T3 (lung, brachiocephalic vein, SVC, chest wall, phrenic nerve, or hilar pulmonary vessels) and 2 T4 (aorta, arch, main pulmonary artery, myocardium, trachea, or esophagus). Only one patient each had N2 and M1a disease (separate pleural or pericardial nodule). Histologies included 5 A/micronodular thymoma, 13 AB, 5 B1, 14 B2, 5 B3, and 5 C/carcinoid. There was a significant positive association with aggressive histology and higher stage (OR=10.0;p=0.02). The following CT characteristics had a statistically significant positive association with higher stage (stage 1 vs. others, T1 vs. others) in a univariate analysis: lobulated contour, infiltration of mediastinal fat, invasion of mediastinal structures, vascular endoluminal invasion, elevated hemidiaphragm. There was a trend for higher stage with larger size and the presence of calcification. In a prediction model, vascular endoluminal invasion and elevated hemidiaphragm were the most important for predicting higher stage followed by invasion of mediastinal structures>abutment of mediastinal vessels>calcification>lobulated contour> mediastinal lymph node enlargement. When excluding clearly invasive CT characteristics, only abutment of mediastinal vessels was significantly associated with higher stage.

Conclusion:
Preoperative CT characteristics, especially those indicating clear invasion, are most useful in delineating more advanced stage disease by ITMIG/IASLC criteria in TMs. Other primary tumor characteristics including contour, calcification, and abutment of mediastinal vessels are moderately helpful. This study is limited by the small sample size, the predominance of stage I disease, the inclusion of patients who received neoadjuvant chemotherapy, and the inherent bias of a definitive surgically treated population.

Abstract not provided

Background:
People living with lung cancer (LC), LC survivors and carers are impacted by LC in different ways. The Global Lung Cancer Coalition (GLCC) recognises lung cancer patients’ and carers’ isolation and the challenges they face (GLCC, 2015). However for those affected by LC, limited data exists on the priority of their challenges, their ability to cope with these challenges and if enough relevant information and support is available. Identifiable variances between patient and carer experience and how challenges differ based on gender, age and nationality are also unknown. In 2013, The GLCC and Boehringer Ingelheim collaborated to create a global survey to identify these priorities and variances.

Methods:
A unique web-based survey was designed to isolate the single greatest challenge faced by individuals affected by LC. 200 specific and globally relevant challenges were identified by LC experts from the GLCC, grouped into categories and illustrated, with a small text descriptor. At survey entry, respondents identified their greatest challenge relevant to either daily life or medical care. Via an associated illustration, respondents chose subsequent sub-categories of challenges until one specific challenge was identified as the most significant. Respondents answered 3 questions in relation to that challenge regarding 1) availability of information 2) ability to cope 3) level of support required. Screening was conducted for age, gender, treatment and nationality. Respondents were asked to identify if they were living with LC, a LC survivor or a carer. The survey was available in 11 languages and promoted through the GLCC, LC clinicians, charities and associated support groups.

Results:
2871 individuals visited the survey site. 725 (25%) completed the survey. 64% of LC patients chose a daily life challenge as their most significant, compared to a medical care challenge (36%); 55% of carers also chose a daily life challenge, compared to a medical care challenge (45%). Of all participants who chose daily life, 19.8% identified emotional and/or social needs as the most significant sub-topic, 14.8% identified survivorship/ caring for myself; 13.8% body image and 7.6% stigma. Of all participants who chose medical care, 20.5% identified diagnosis as the most significant sub-topic; 18.9% identified treatment planning & options; 14.9% receiving treatment and 10.2% end of life issues. 56.2% of individuals who chose one of the top 16 challenges (n=589, 81% of all participants) requested more information about the challenge identified.

Conclusion:
Psychosocial issues related to daily life and a lack of relevant information posed some of the greatest challenges to LC patients. LC patients were more likely to identify daily life issues such as dealing with emotional needs, self-care, body image or changing relationships as their greatest challenge rather than medical care issues such as diagnosis, treatment planning or screening. Lung cancer patients have the right to have the enormous burden of lung cancer acknowledged by professional carers, policy makers and the general public (GLCC, 2015). Daily life challenges should be identified and alleviated as part of routine LC care to ensure LC patients and carers receive the necessary spectrum of support and information.

Background:
Over the past decades, researchers have evaluated numerous treatment options for lung cancer with varying degrees of success. The stepwise nature of innovation in this process has made it difficult to assess progress across different therapeutic areas. Stakeholders therefore frequently disagree about the extent of past achievements, the current greatest unmet needs, and priorities for future efforts. In an effort to bridge this gap, Lilly Oncology’s Patient Access to Cancer care Excellence (PACE) initiative developed the Continuous Innovation Indicators[TM ](CII): a robust tool to generate consistent measures of progress in cancer treatments with flexibility to accommodate different cancer subtypes and treatment modalities.

Methods:
Trained analysts review references from the primary literature and record statistical measures of relevant outcomes in a standardized format called “Pieces of Evidence.” A Value Matrix classifies each Piece of Evidence by its therapeutic goal, creating a map of available treatments across different stages of disease. A transparent algorithm then tallies these records and generates Evidence Scores (E-Scores), a novel measure of progress over time. Analyses can be weighted by therapeutic goals or restricted to specific disease subtypes or classes of treatment. The Indicators currently contain data on non-small cell lung cancer (NSCLC) and 11 other solid tumors.

Results:
The first data release of the CII demonstrates steady progress in the development of chemotherapeutic agents against NSCLC, particularly since 1990 (Panel A). Analysis of the data by histological subtype reveals relatively greater progress against non-squamous compared to squamous NSCLC (Panel B). Data from the CII further indicate the relative contributions to progress against NSCLC from different classes of treatment (Panel C). Aligning progress curves with drug approval dates allows us to better understand how the value of new treatments evolves over time (Panel C). Importantly, the CII highlight a critical unmet need in NSCLC (Panel D): there are no curative therapies for regional or metastatic disease supported by current evidence.Figure 1



Conclusion:
Through the use of treatments in multiple classes and combinations, steady progress has been made against NSCLC. Still, pressing unmet needs remain. By offering a standardized and comprehensive approach, the Continuous Innovation Indicators[TM] can help researchers, policymakers, and advocates objectively understand past progress and current needs of NSCLC in a broader context. A link to the public interface is available on the PACE Continuous Innovation website at: https://pacenetworkusa.com/continuousinnovation.php.

Background:
LC may be associated with negative societal perceptions compared to other cancers. This study measured the explicit, conscious attitudes (EAs), implicit, unconscious attitudes (IAs) and implicit stereotypes of LC relative to breast cancer (BC), explored the demographic factors associated with the explicit and implicit biases in LC, and whether these biases affect the LC drug treatment rates.

Methods:
EAs were derived from participants (Ps) [cancer patients (n = 493), caregivers (n = 1332), healthcare providers (HCPs, n = 623), and the general public (n = 1356)] ratings about how patients with LC and BC “do feel” (descriptive attitudes) or “ought to feel” (normative attitudes) about their disease. IAs and implicit stereotypes were measured with the Implicit Association Test (IAT). Analysis of covariance (ANCOVA) was used to assess the demographic factors associated with bias toward LC. Linear regressions were performed to analyze the association between the biases against LC and LC treatment rates across different states in the United States.

Results:
Females (p < 0.001), higher income (p = 0.015), and people reporting themselves with more knowledge about cancer disease (p < 0.001), caregivers (p = 0.008), and whites (p < 0.001) expressed stronger negative descriptive attitudes toward LC. Males (p = 0.007), and higher income (p = 0.010) expressed less-positive normative attitudes toward LC. Females (p < 0.001), higher education (p = 0.003), non-cancer patient participants (p = 0.019), and whites (p = 0.031) had stronger negative IAs about LC. State-level analysis showed that the lower drug treatment rates for LC patients are significantly associated with older patients population (p = 0.011) and higher percentage of government as payer (p = 0.023). State-level analysis shows no significant association between IAT scores and LC treatment rates.

Conclusion:
Explicit and implicit bias against LC compared to BC was associated with gender, education, income levels and cancer knowledge, but not treatment rates.

Abstract not provided

Background:
Survival of incurable cancer patients is improving gradually. Several hundred new therapies are under development. However, internationally, regulatory complexity slows progress by increasing drug development costs (hence, fewer drugs can be assessed with available resources) and by producing numerous speed bumps that delay approval of useful drugs and that increase resources required to document that other agents are ineffective.

Methods:
We assessed cancer therapies undergoing phase III trials between 2001 and 2015. To be included, trials had to document statistically significant improvement in overall survival. We excluded adjuvant trials and trials in uncommon malignancies. To determine the number of life-years potentially lost per year required for drug approval, we multiplied the improvement in median survival in years by the estimated number of patients (North American and worldwide) dying annually from the relevant malignancy.

Results:
In the Table, we present the life-years lost per year required for approval for 21 therapies in 10 malignancies. When the combined impact of all tumor sites and drugs are considered together, there were 29 life-years lost in North America per hour of delay in therapy approval (1 for every 2 minutes of delay) and 260 life-years lost worldwide per hour of delay (1 for every 14 seconds of delay). These numbers do not take into account impact of drugs non-evaluable due to cross-over or missing survival data, drugs that were prematurely abandoned, drugs still undergoing investigation, or approaches for non-malignant lethal diseases. Figure 1



Conclusion:
Clearly, the survival gains associated with the foregoing drugs are only modest. Despite this, there would be a large negative impact associated with approval delays even if factors such as co-morbidities, performance status, ability to pay, etc, limit the number of patients treated to a fraction of the total dying from a specific malignancy. There are numerous opportunities to improve efficiency of cancer drug approval without sacrificing safety or data integrity. This requires urgent attention.

Background:
Participation in oncology clinical trials has historically been low compared to the number of individuals diagnosed with cancer each year. It has been reported that between 3% and 5% of adults with cancer participate in clinical trials. However, research into this statistic usually focuses on the reasons why patients choose not to participate, rather than whether or not clinical trials are designed adequately to capture a proper patient sample truly representative of the population being studied. This study explored a sample of lung cancer patients who received treatment with proton therapy and compared the group to the eligibility requirements of two lung cancer trials. We hypothesized that most patients treated with proton therapy would not be eligible to participate in the currently accruing cooperative group studies.

Methods:
The Proton Collaborative Group’s (PCG) prospective registry was mined for information on all lung cancer patients who received proton therapy between the years of 2010 and 2015. These patients were then evaluated to determine if they would have been eligible to participate in either of the two active cooperative group clinical trials for proton therapy currently enrolling patients with inoperable stage II-IIIB non-small cell lung cancer (NSCLC): PCG LUN005 (phase I/II trial of hypofractionated proton therapy) and RTOG 1308 (phase III trial randomizing to protons versus photons).

Results:
A total of 244 consecutive patients with lung cancer were available in the registry for evaluation. Patients were ineligible for LUN005 and RTOG 1308 due to exclusionary stage (n=77), histology (n=37), performance status (n=66), prior surgery for lung cancer (n=53), and/or prior radiation therapy (RT) for lung cancer (n=53). Of the remaining 55 patients, 27 were enrolled in the PCG registry prior to LUN005 or RTOG 1308 opening for accrual. This left 28 patients. Those patients were ineligible for the following reasons: prior chemotherapy (n=3), prior RT within the treatment field (n=3), prior cancer (n=6), weight loss (n=2), outdated procedures (n=2), oxygen dependence (n=1), disease progression prior to RT start (n=2), or not felt to be an upfront candidate for concurrent chemotherapy and RT (n=2). This left 7 patients who were ultimately eligible for enrollment, one of which refused trial participation and one of which the reason for not participating was unknown. Reasons for lack of enrollment of the 5 remaining patients on LUN005 were due to administrative issues (ex: protocol enrollment on hold pending interim review), whereas RTOG 1308 was unavailable for those patients at their treating center.

Conclusion:
The vast majority of patients treated with proton therapy for lung cancer on PCG’s prospective registry were not eligible for participation cooperative group trials. Given the high ineligibility rate among patients found in this study, pragmatic trials with more inclusive eligibility criteria are needed to better mirror the general population of patients with newly diagnosed, locally advanced NSCLC. More inclusive trials may allow for increased rates of trial participation and further advances and improvements in survival.

Background:
Twitter is a social media platform that may improve clinical trial awareness and enrollment. Little is known about current communication on Twitter regarding clinical trials.

Methods:
We searched the keyword “lung cancer” in Twitter messages from January 5 - 21, 2015. Duplicate and non-English tweets were excluded. Randomly selected tweets were independently evaluated for content and user type by two coders (kappa=0.71). An exploratory analysis was conducted on tweets regarding lung cancer clinical trials. Differences in user type by content were evaluated by Pearson’s chi square test.

Results:
We found 26,059 tweets with the keyword “lung cancer” from 10,039 unique users with 72,239,356 followers, including 15,346 unique tweets. We randomly selected 1,516 (10%) as the study cohort. Table 1 summarizes tweet categories and Table 2 shows tweet content by user type. Most of the dialogues focused on support and prevention. 221 (15%) of tweets were about clinical trials. 92 (42%) were from individuals, such as patients, health advocates, health providers and non-health users (p-value < 0.001). Of clinical trial tweets, 183 (83%) concerned therapeutic trials, 28 (13%) non-therapeutic, and 10 (4.5%) basic research. 144 (65%) of the therapeutic clinical trial tweets concerned immunotherapy. Most of the 183 therapeutic clinical trial tweets, 158 (86%), had embedded-links directing users to news articles. Only 1 tweet linked to a recruitment website with patient enrollment information.

Table 1. Lung cancer tweets by content type

Tweet categories	Frequency, N (%)
Support	358 (24)
Prevention	357 (24)
Miscellaneous (non-health related)	256 (17)
Clinical Trials	221 (15)
Treatment	86 (6)
Diagnosis	78 (5)
General Information	69 (4)
Screening	53 (3)
Symptoms	38 (2)

Table 2. Lung cancer tweets by user type

Tweet categories	Individual	Organization	News Media
Support	258	28	42
Prevention	210	50	74
Miscellaneous	221	6	11
Clinical Trials	92	48	71
Treatment	48	13	17
Diagnosis	35	15	26
General Information	23	33	8
Screening	19	23	9
Symptoms	26	1	7

Conclusion:
A significant proportion (15%) of lung cancer tweets concern clinical trials and are from individuals. Most of these tweets focus on immunotherapy. Our data suggest that Twitter represents a contemporary medium that could connect patients and other interested individuals with information about clinical trials, including links on screening and enrollment. The ubiquity of current social media use and our findings suggest that tailored messages about clinical trials on Twitter could have utility, improve awareness, trial referral and perhaps enrollment.

Abstract not provided

Abstract:
Proton therapy, in particular, and ion therapy, just beginning, are becoming an increasing focus of attention in clinical radiation oncology. Proton therapy is a type of radiation treatment that uses protons rather than x-rays to treat cancer. Protons, however, can target the tumor with lower radiation doses to surrounding normal tissues. Proton therapy is particularly useful for treating cancer in children because it lessens the chance of harming healthy, developing tissue. In addition, proton therapy may be used to treat Lung cancer. Compared with standard radiation treatment, proton therapy has several benefits. It reduces the risk of radiation damage to healthy tissues; may allow a higher radiation dose to be directed at some types of tumors, which may keep the tumor from growing or spreading; and may result in fewer and less severe side effects (such as low blood counts, fatigue, and nausea) during and after treatment. However, there are some drawbacks such as higher cost and lack of convincing evidence from randomized trials proving their efficacy, justifying the higher costs involved in these therapies. Carbon ion therapy is another type of radiotherapies that can deliver high-dose radiation to a tumor while minimizing the dose delivered to the organs at risk; this profile differs from that of photon radiotherapy. Moreover, carbon ions are classified as high-linear energy transfer radiation and are expected to be effective for even photon-resistant tumors. There are several centers in Asia and Europe using carbon beam to treat lung cancer patients. In this session, we will provide an overview of the current status of clinical trials in proton therapy, including recent developments in ion therapy for lung cancer. We will also attempt to highlight some of the challenges that surround clinical trials in particle therapy.

Abstract not provided

Abstract:
Despite advances in treatment, lung cancer remains the leading cause of cancer mortality in most countries. About one third of patients with non-small cell lung cancer (NSCLC) presents with locally advanced non-metastatic disease (stages IIIA and B). Although 5-year overall survival (OS) ranges from 60 to 73% for completely resected pathologic stage I disease, OS decreases to less than 25% for pathological stage III disease. Patients with potentially resectable stage IIIA-N2 can be treated with induction chemotherapy followed by radical surgery. Prospective studies report 5-year OS rates from 20% to 30%, with about 30% of the patients reporting local recurrence (LR). When surgery is performed first, for patients presenting with node-positive disease at the time of resection, meta-analysis data demonstrate that adjuvant platinum-based chemotherapy has been shown to decrease distant metastases and locoregional recurrence (LRR), resulting in an approximately 5% OS advantage, and is now considered standard of care for patients with resected node-positive NSCLC. However, these patients have a 20% to 40% risk of LRR, and LRR correlates independently with worse OS. Thus, postoperative radiotherapy (PORT) holds great appeal as a means to reduce LRR and improve OS. Several phase III trials investigated the role of PORT after surgical resection in NSCLC. In 1998, the PORT Meta-analysis Trialists Group undertook an individual participant data (IPD) meta-analysis (of both published and unpublished trial data) of PORT versus surgery alone in NSCLC [1]. The original meta-analysis, based on 9 randomised controlled trials and 2128 patients, concluded that PORT was detrimental with a 7% absolute reduction in 2-year OS and a 4% reduction in recurrence-free survival. Subgroup analyses suggested that PORT was increasingly detrimental with decreasing stage (p = 0.0003) and lower nodal status (p = 0.016). The updated results for OS, and for local, distant and overall recurrence-free survival are unchanged, continuing to show a detrimental effect of PORT(2) : For the whole patient group, PORT decreased the OS at two years by 6% (52% vs. 58%). This deleterious effect was detected in patients with pN0–1 disease. No effect was detected in patients with pN2 disease. The PORT meta-analysis raised a lot of criticism for the following reasons: significant heterogeneity between trials, inclusion of trials with old radiotherapy techniques (notably, most of these trials, conducted principally in the 1960s to 1970s, included outmoded RT techniques and doses). The deleterious effect of PORT has been attributed to an excess of intercurrent deaths, with a high incidence of cardiac and respiratory complications due to poor radiotherapy techniques. In support of this hypothesis, several more recent trials with contemporary radiation techniques did not report an increase of death from intercurrent disease. Kepka et al. did not detect a difference in QoL scores, cardiopulmonary morbidity or non-cancer related deaths between patients receiving PORT and those treated with surgery alone (3). Two Surveillance, Epidemiology, and End Results (SEER) analyses and a secondary analysis of data from the Adjuvant Navelbine International Trialist Association (ANITA) trial suggest that PORT may be safely delivered in a modern cohort of patients with a potential OS benefit for stage IIIA (N2) disease (4, 5). In addition, being now established that the use of adjuvant chemotherapy in stage III disease prolongs OS, it is then hypothesised that with the reduction of distant metastases with chemotherapy, the survival benefit by improved local control after three-dimensional conformal (3D-CRT) PORT will occur. Then, recently, the National Cancer Data Base (NCDB), joint program of the Commission on Cancer of the American College of Surgeons and the American Cancer Society, has been queried to study the impact of modern PORT in the setting of standard-of-care adjuvant chemotherapy for pathologic stage IIIA (N2) NSCLC (6). Data of 1850 patients who received PORT between 1998 and 2010 were obtained. Use of PORT, compared with no PORT, was associated with a significant increase in median OS (45.2 v 40.7 months, respectively), 3-year OS (59.3% v 55.2% , respectively), and 5-year OS (39.3% v 34.8%, respectively; P=.014. This analysis of the NCDB for patients with pathologic N2 disease, receiving adjuvant chemotherapy, shows that PORT seems to confer an additional improvement in OS. In conclusion, modern radiotherapy techniques should be evaluated in stage III patients, as already stated in the initial individual-patient-data meta-analysis. This new evaluation is justified for several reasons: (a) the N2 population has changed because of a better selection with pre-treatment PET-CT scan and brain imaging; (b) adjuvant chemotherapy has become a standard of care in these patients; (c) technical advances of radiotherapy may enhance the ability of PORT to improve local relapse-free survival and possibly overall survival. Thus, based on the previous studies, the underlying hypotheses remain to be proven, with sufficiently powered new randomised trials. A prospective randomized phase III trial, LungART (Lung Adjuvant Radiotherapy Trial), designed with the primary aim of investigating the benefits of conformal radiotherapy in completely resected pN2 NSCLC, together with adjuvant chemotherapy, is currently ongoing in Europe, and should help answering definitely this question, investigators are strongly encouraged to enroll patients on this randomized trial. 1 : PORT Meta-analysis Trialists Group. Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. PORT Meta-analysis Trialists Group. Lancet 1998; 352:257-63. 2 : PORT Meta-analysis Trialists Group: Postoperative radiotherapy for non-small cell lung cancer. Cochrane Database Syst Rev 2:CD002142, 2005 3 : Kepka L, Bujko K, Orlowski TM, et al. Cardiopulmonary morbidity and quality of life in non-small cell lung cancer patients treated with or without postoperative radiotherapy. Radiother Oncol 2011;98:238–43. 4 : Lally BE, Zelterman D, Colasanto JM, et al. Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the surveillance, epidemiology, and end results database. J Clin Oncol 2006; 24:2998-3006. 5 : Douillard JY, Rosell R, De Lena M, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer. Adjuvant Navelbine International Trialist Association ANITA: a randomised controlled trial. Lancet Oncol 2006;7: 719-27. 6 : Robinson CG, Patel AP, Bradley JD et al. Postoperative radiotherapy for pathologic N2 Non small Cell lung cancer treated with adjuvant chemotherapy : A review of the National Cancer Data Base. J Clin Oncol 2015 ; 33 :870-77

Abstract:
Evolving Role of Radiation for Oligometastases The key objectives of this presentation are to review the fundamental biology underlying metastatic disease, understand the definition and clinical evidence for oligo- (or limited) metastatic disease, analyze key clinical trials showing the potential role of stereotactic body radiation therapy (SBRT) for oligometastases and address challenges regarding this “high-tech” strategy. In the early 1900s, Halsted suggested that breast cancer spread via the local regional lymphatic vessels in a stepwise manner. Thus, once there are metastases, local therapy had no clear role. Later in the 20[th] century, an opposing theory (the “Fisher” theory) suggested that cancer is a systemic disease that, if it will ever metastasize, will already have done so early in the disease course. Local therapies are therefore less important than systemic therapies. A counterpoint to these approaches was proposed by Hellman and Weichselbaum, postulating that cancer is a spectrum from localized to wide-spread disease at the time of diagnosis, with many intermediate states (Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol. 1995 Jan;13(1):8-10). “Oligometastases” are essentially early metastases which are limited in number and location and based on a state of limited metastatic capacity. The hypothesis based on this approach is that there may be a subset of patients with oligometastatic disease for whom aggressive local treatment (such as surgery or SBRT) could change their outcome. Clinical evidence for oligometastasis includes the surgical experience for lung or liver metastases showing long-term survivals of approximately 20%. Studies are now emerging suggesting similar results utilizing SBRT. In an individual patient data meta-analysis of outcomes after surgery or SBRT, Ashworth et al. reported a 5-year survival rate of approximately 30% in patients with oligometastatic non-small cell lung cancer (Ashworth AB, et al. An individual patient data metaanalysis of outcomes and prognostic factors after treatment of oligometastatic non-small-cell lung cancer. Clin Lung Cancer. 2014 Sep;15(5):346-55). They developed a risk classification schema showing a better prognosis for metachronous vs. synchronous oligometastases (of which node-negative was favorable to node-positive). Other studies have shown that, among patients treated with SBRT for 1-5 oligometastases, those with ≤3 metastases had better outcomes compared to those with 4-5 metastases. The size of the metastases also appears to be important, as well as the biological equivalent dose (BED) of the SBRT. Studies have begun to explore the role of SBRT for oligometastases involving the lung, liver, adrenal, and other sites. It is likely that host-related factors (for example, immune mediated anti-cancer activity) and tumor related factors (such as genomics and proteomics) also affect the spectrum of disease aggressiveness. Challenges to this new “high-tech” approach will also be addressed, including issues related to patient selection, the level of evidence, and the cost effectiveness of this approach. Other approaches for improving the outcome for patients with metastatic disease will also be discussed, including the role of early palliative interventions. In summary, emerging (albeit non-randomized) data suggests that SBRT appears to be a promising strategy in selected patients with oligometastases. The patients most likely to benefit from SBRT have metachronous (vs. synchronous) metastases, N0 (vs. N+) disease, 1-3 metastases (vs. more), small metastases, and the ability to receive a higher radiation dose (BED >100Gy). Randomized trials are needed to establish whether SBRT improves progression free and/or over survival in this setting.

Abstract not provided

Abstract:
Substantial progress has been made toward understanding the tumor biology of non-small cell lung cancer (NSCLC) during the last few years, and major discoveries in the molecular pathogenesis of lung cancer have led to successful applications of targeted therapeutic strategies. One representative of these successes is the subset of lung cancer patients with epidermal growth factor receptor (EGFR) mutations who have shown improved clinical response to tyrosine kinase inhibitors (TKIs).1 The prevalence of EGFR mutation is higher in the East Asian population than in Western populations. Asian NSCLC patients were reported to show a higher response rate and a longer survival to EGFR tyrosine kinase inhibitors (EGFR TKIs) as well as traditional chemotherapy. Therefore, genetic testing prior to treatment is becoming increasingly important and considered essential to select appropriate treatment strategies for NSCLC patients, especially in Asia. The exact mechanisms underlying these differences are not clear. However, approximately 45% of patients with NSCLC in the US are women whereas only 25% to 30% of patients with lung cancer are women in Eastern Asia. In addition, In the US, approximately 10% of patients with lung cancer are neversmokers (<100 lifetime cigarettes). In Asia, more than 30% of patients with lung cancer are neversmokers.2 Some international studies and global surveys have been conducted during the past few years to establish the current status of EGFR mutation testing and to establish the standard testing protocols.3-5EGFR mutation test is not yet available in many South East Asian medical institutions. In the medical facilities which do perform EGFR mutation test, the overall testing rate of newly diagnosed NSCLC is 31.8%, varying from 18.3% - 64.8%, the highest EGFR mutation testing rate was observed in Japan and the lowest in South East Asian Countries. Sex, smoking status and histological subtype are the main determining factors for EGFR mutation tests.5 However, the College of American Pathologists (CAP), International Association for the Study of Lung Cancer (IASLC), and Association for Molecular Pathology (AMP) guidelines recommended that patients with lung adenocarcinoma should not be excluded from testing on the basis of clinical characteristics that include ethnicity, smoking history, and sex. Factors associated with EGFR mutation status were country, sex, ethnicity, smoking status, smoking pack-years, disease stage and histology type. 4 In most countries, EGFR mutation rate and clinical pathologic factors are in line with previous reports in Asia, and the variations of EGFR mutation prevalence between countries are due to the selection of the tested populations. The majority of Asian institutions use PCR-based DNA direct sequencing methods to detect EGFR mutation. Other predictive biomarkers for EGFR TKI therapy are also available, including EGFR gene copy number, single-nucleotide polymorphisms of the EGFR gene, EGFR protein expression. 3 Next Generation Sequencing (NGS) and multiplex assays have made feasible the widespread adoption of molecular diagnostics for clinical use. According to our survey, the NGS is not available in clinics in most Asian medical institutions, and can be used for diagnosis of rare diseases and/or research. In China, sequencing based methods are the most commonly used, followed by the amplification mutation refractory system (ARMS).6 In Korea, the PNA clamp method is the most commonly used testing method, followed by direct sequencing methods.7 PCR-INVADER is the most commonly used test in Japan, followed by PNA-LNA PCR clamp.5 The materials for EGFR mutation analysis are usually from diagnostic samples, thus in most countries, small biopsy and cytology specimens are the most commonly used, followed by surgically resected tissues. Cytological specimens including smear slides and/or cell blocks have been shown to be suitable for EGFR mutation test.3, 5At present, the potential barriers to EGFR mutation testing in Asia include the cost, the number of laboratories capable of performing the test, communications between the clinicians and pathologists, and the predefined criteria for the type of patients who should be tested.3 The cost for EGFR mutation tests vary from U.S.$170 to 500. In most countries the costs are funded by the patients, but in a few countries are funded by pharmaceutical companies, while the insurance does not cover the cost of molecular testing in most Asian countries. Currently, National Comprehensive Cancer Network (NCCN)'s guidelines recommend EGFR-TKI as the first line treatment for patients with NSCLC harboring EGFR sensitizing mutations. Randomized first-line trials have demonstrated consistent improvement in tumor response rate and progression-free survival, but failed to prove overall survival benefit. These finding make TKI the second-line or third-line treatment options for NSCLC. Current data on treatment outcomes of second- and/or third-line EGFR therapy are still inconsistent.8 Patients treated with EGFR-TKI inevitably experience ac¬quired resistance by various molecular mechanisms. Many clinical trials are ongoing to explore the novel agents and strategies for better response and overcoming TKI resistance. In our questionnaire-based survey, four of seven Asia countries have ongoing clinical trials. The clinical trials include the first line and second line and maintance therapy using first generation and new generation EGFR TKIs. In 2013, more than 1000 studies with Chinese trials were registered on ClinicalTrials.gov and some trials used a local pharmaceutical company TKI, icotinib. Phase II studies of crizotinib in East Asian patients with ROS1-positive NSCLC are onging in China, Japan, South Korea and Taiwan. Anaplastic lymphoma kinase (ALK) rearrangement accounts for about 2–13% of unselected Asian patients with NSCLC, and occurs predominantly in younger individuals with adenocarcinoma who never smoked or light smokers (< 40 pack years). There is no strong evidence to suggest an ethnic difference of translocations among patients with NSCLC. The CAP/IASLC/AMP guideline recommended ALK FISH assay using FDA-approved specific companion test (Vysis ALK Break-Apart FISH Probe Kit, Abbott Molecular, Des Plaines, IL) for selecting patients for ALK tyrosine kinase inhibitor therapy. ALK immunohistochemistry (IHC) may be considered as a screening methodology to select specimens for ALK FISH testing. The ALK rearrangements have been shown to be 4.3% in men and 7.5% in women in Asian NSCLC by meta-analysis. Most Asia countries use FISH to detect ALK rearrangement, in Japan, reverse transcription–PCR (RT–PCR) is commonly used. In China, the Chinese Food and Drug Administration (CFDA) had approved VENTANA ALK IHC assay to aid the identification of patients for crizotinib treatment. The price of FISH detection range from US$415-800, and IHC range from US$14-220, most of which is funded by the patients.9 Recently, two additional oncogenes, RET and ROS1, were added to the list of driver oncogenes that are targetable with existing TKIs, and several clinical trials investigating the efficacy of such TKIs in Asia have been conducted. FISH and IHC are suitable for the diagnosis of ROS1 fusion, but some studies showed IHC is not suitable for the diagnosis of RET fusion.10 Over the past decades, we have witnessed rapid advances in molecular and cellular biology of lung cancer biology, and new data are upcoming which should facilitate personalized biomarker-based therapy in lung cancer, including characterization of driver mutations, genomic abnormalities and epigenetic changes. Individual centers should develop a multidisciplinary approach to integrate a molecular testing algorithm. Next generation sequencing should be able to resolve much of the complexity of molecular testing, especially in situations where there is only a small amount of tissue available. REFERENCES 1. Janku F, Stewart DJ, Kurzrock R. Targeted therapy in non-small-cell lung cancer--is it becoming a reality? Nat Rev Clin Oncol 2010;7:401-414. 2. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-957. 3. Salto-Tellez M, Tsao MS, Shih JY, et al. Clinical and testing protocols for the analysis of epidermal growth factor receptor mutations in East Asian patients with non-small cell lung cancer: a combined clinical-molecular pathological approach. J Thorac Oncol 2011;6:1663-1669. 4. Shi Y, Au JS, Thongprasert S, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol 2014;9:154-162. 5. Yatabe Y, Kerr KM, Utomo A, et al. EGFR mutation testing practices within the Asia Pacific region: results of a multicenter diagnostic survey. J Thorac Oncol 2015;10:438-445. 6. Wang S, Wang Z. EGFR mutations in patients with non-small cell lung cancer from mainland China and their relationships with clinicopathological features: a meta-analysis. Int J Clin Exp Med 2014;7:1967-1978. 7. Shim HS, Chung JH, Kim L, et al. Guideline Recommendations for EGFR Mutation Testing in Lung Cancer: Proposal of the Korean Cardiopulmonary Pathology Study Group. Korean J Pathol 2013;47:100-106. 8. Sculier JP, Berghmans T, Meert AP. Advances in target therapy in lung cancer. Eur Respir Rev 2015;24:23-29. 9. Fan L, Feng Y, Wan H, et al. Clinicopathological and demographical characteristics of non-small cell lung cancer patients with ALK rearrangements: a systematic review and meta-analysis. PLoS One 2014;9:e100866. 10. Kohno T, Nakaoku T, Tsuta K, et al. Beyond ALK-RET, ROS1 and other oncogene fusions in lung cancer. Transl Lung Cancer Res 2015;4:156-164.

Abstract:
Introduction Identification of molecular targets is now essential for the diagnosis, classification, selection and treatment monitoring of an increasing number of cancers. The analysis of these biomarkers must therefore be accessible to all patients, regardless of the healthcare facility where they are treated. Despite a decrease, lung cancer remains the leading cause of cancer-related deaths worldwide, often detected at an advanced stage with association with a poor prognosis. Recently, genetic alterations involved in adenocarcinomas have been discovered; some of these tumors harbor a driver mutation involving EGFR, KRAS, HER2, BRAF or PI3KCA gene or a rearrangement (ALK, ROS1, RET genes). Nearly 40% of NSCLC harbor one of those genetic abnormalities and several targeted therapies have been approved in USA and in Europe, such as erlotinib and gefitinib and crizotinib for NSCLC with EGFR mutation or ALK translocation, respectively. As many other targeted therapies are ongoing in lung cancer, molecular testing becomes a huge challenge worldwide, raising both financial and organizational issues.The French INCa molecular testing network: In 2006, the French National Cancer Institute (INCa) and the French Health Ministry have created a national network of 28 regional genetics platforms throughout the French territory, in order to offer molecular tests to all patients regardless of the institution where they are treated, i.e. university hospitals, cancer centers, hospital centers or private institutions, to enable that each innovative test could be rapidly implemented after new targeted therapies become available, and to guarantee the quality of the tests. The 28 regional platforms include a pathology laboratory in charge with the samples monitoring, and several laboratories with complementary expertise in molecular testing of hematological malignancies and solid tumors; as the tests are free of charge for the patients and the institutions, initial funds were given to all INCa genetics platforms to buy equipment (€4.7 million) and to hire non-medical personnel. The majority of these were technicians (58.32 FTE) and engineers (20.5 FTE); in addition, genetics platforms are financed on a basis of quarterly and annual activity reports to adjust budget and allocation. This initial funding was fol­lowed by the allocation of €4 million in annual funding for the centres and staff from the French Ministry of Health. The data sent in those reports are the number of tests performed each year, the number of patients undergoing tests, the percentage of patients found to have a molecular abnormality, the percentage of non-contributive results and the origin of requests. The INCa also set up a quality-assurance program with mandatory external quality evaluations, and publishes guidelines available on the Inca website. The markers studied are predictive markers that determine access to targeted therapy, markers guiding the diagnostic process, markers that contribute to establishing a diagnosis, prognostic markers guiding patient treatment strategy, and markers allowing the monitoring of residual diseases. Molecular genetics platforms do not have to perform all molecular tests: they must ensure that patients in their region have access to these tests via a referral platform. Tests concerning a large number of patients are carried out by all or almost all platforms (BCR-ABL quantification, KRAS and EGFR mutations, JAK2 mutations, MSI tests). For tests concerning a small number of patients, some platforms perform regional or national referral activity (ABL mutation screening in CML, cKIT and PDGFRA mutations in GIST, NMYC amplification in neuroblastomas, chromosomal abnormalities in sarcomas). Whereas the initial program included only EGFR and KRAS mutations’ detection in lung cancers and KRAS and BRAF mutations in colorectal cancers, a new program for detection of emerging biomarkers was set up in 2011; for lung non-squamous cell carcinoma patients at advanced stages those biomarkers were EGFR, K-RAS, HER2, BRAF and PI3KCA mutations and ALK translocations, and BRAF and KIT mutations in metastatic melanomas. In 2008, 1,269 EGFR activating mutation tests were performed, versus 2,667 in 2009, and 21,995 and 8,696 regarding EGFR mutation and ALK rearrangement, respectively in 2012. In 2013, 23,336 lung cancer samples were tested for EGFR mutations (10% were mutated), 18,861 for ALK rearrangement (3.5% rearranged), 22,9858 for KRAS mutations (27% mutated), 20,100 for BRAF mutation (2% mutated), 17,843 for HER2 mutation (0.7% mutated) and 17,375 for PI3KCA mutations (2.4% mutated).The German Network Genomic Medicine (NGM) Lung Cancer: The NGM is a health care provider network offering centralized high-quality next generation sequencing -based multiplex genotyping for lung cancer patients. Since NGS based genotyping is not reimbursed in Germany, the AOK Rheinland/Hamburg, one of the largest German public health insurances has contracted with the NGM for reimbursement of NGS-based multiplex genotyping of lung cancer in April 2014. In 2014, 4,500 lung cancer patients were gentotyped, representing nearly 10% of stage IV NSCLC patients in Germany.The Cancer Research UK (CRUK) Stratified medicine programme 1 and 2: There is no to date any national policy in UK for molecular testing for lung cancer patients, and a great variation exists regarding providers, funding and access; most of the time, the decision of referring for molecular testing depends on the clinician in reference to NICE clinical guidance. Nearly 7,300 UK patients were tested for EGFR mutations in 2010-2011 and depending on the units, ALK testing is performed either by IHC and /or FISH. In 2011, the Cancer Research UK (CRUK) Stratified Medicine Programme 1 and 2 has set-up a collaborative network of 26 hospitals and 8 CRUK Experimental Cancer Medicine Centres to provide genetic testing in lung, bowel, breast cancers and melanoma. The next plan for the NHS of England is to increase testing activity, to equitable access, to improve the quality assurance procedures and the cost values.References: 1. Collection Reports and summaries, collective volume edited by INCa, Boulogne-Billancourt, sept 2010 http://www.e-cancer.fr/Expertises-et-publications/Catalogue-des-publications/Molecular-genetic-testing-for-equal-access-to-targeted-therapies-in-France-in-2011 http://www.e-cancer.fr/Expertises-et-publications/Catalogue-des-publications/The-French-national-network-of-28-hospital-molecular-genetics-platforms-summary-of-the-activity-in-2009 http://www.e-cancer.fr/Expertises-et-publications/Catalogue-des-publications/Molecular-genetic-tests-for-access-to-targeted-therapies-in-France-in-2012 2. Nowak, F. et al. Tumour molecular profiling for deciding therapy—the French initiative. Nat. Rev. Clin. Oncol. 9, 479–486 (2012) 3. Nowak, F. et al. Europe Does It Better: Molecular Testing across a National Health Care System—The French Example; 2013 ASCO EDUCATIONAL BOOK | asco.org/edbook 4. Kostenko, A. et al. The network genomic medicine cost reimbursement model for implementation of comprehensive lung cancer genotyping in clinical routine. J Clin Oncol 33, 2015. ASCO Abstract e12556 5. CR UK Stratified Medicine Programme 1 and 2. http://www.cancerresearchuk.org/funding-for-researchers/how-we-deliver-research/our-research-partnerships/stratified-medicine-programme

Abstract:
This presentation comprises data from Central and South America, as well as Mexico since all of us, as Latin American countries share similar characteristics. The countries included in this group are considered “developing countries” and are characterized by their racial, geographic, cultural, political and economic heterogeneity. In order to obtain data about the current situation in the region, I have sent a survey to the institutions that perform molecular tests in these countries for which I could get contact information. The survey has been sent to 34 laboratories in 12 countries. I tried to be as inclusive as possible, although in some cases it was rather difficult to get adequate contact information. My apologies to those who did not received the survey and would have liked to participate. Nineteen laboratories answered the survey ¹. Although not updated, I also added information from 5 other laboratories presented at LALCA 2014². Despite these results do not represent every country nor all molecular laboratories in the region, many common factors can be identified which allow for a relatively accurate analysis. The results show: Molecular tests are run by a small group of laboratories concentrated in the main cities of these countries. Most frequently, molecular testing is financed by pharmaceutical companies or private health care programs; however, in some cases the government, through the public healthcare system, supports the cost of the tests, and occasionally the patient pays for it. The pharmaceutical companies centralize molecular testing in a few laboratories in each country. Although frequency is generally low, some specimens are analyzed abroad, mainly in the USA. Some regional laboratories perform the tests for those countries that do not have adequate technology for molecular testing. The general opinion was that sending specimens to molecular center did not pose major complications, except in big countries where the geographic distance tends to delay the transport. Pharmaceutical companies provide the logistic structure to aid in the transfer of specimens, thus, accelerating the process. Specimen rejection rate can be divided into two groups: insufficient tissue or inadequate specimen quality by poor tissue preservation. The average rejection rate was 5 to 22%, more frequently around 15%. As for quantity, some institutions improved the amount of tissue obtained and specimen handling over time. When consulted on the possibility to perform molecular tests for treatment and/or research, the answer were: 2 laboratories only make test for research, 10 only run them for treatment purposes and 9 perform tests both for treatment and research. In most of the countries research is more frequently economically supported by the government than by other sources. When oncologists participate in clinical trials the tests are usually run abroad, mainly in the USA. Table 1 shows the available test platforms in the laboratories that participated in the survey and their access to quality control (QC) programs. For sequencing, all the laboratories began with Sanger sequencing, but many of them have changed to PCR-allele specific real-time platform. Some countries are introducing NGS. Most countries do not have local regulations for quality control of molecular tests. A half of the laboratories included in the survey have a kind of international QC, represented by participation in CAP or European QC programs or sending material to reference laboratories for interobserver concordance of results. Table1

Country	Argentina	Brazil	Chile	Colombia	Costa Rica	Ecuador	Mexico	Peru	Uruguay
Laboratories	6	2/2*	2/1*	2/1*	1	1*	2	1	2
EGFR	6	3	3	3	1	1	2	1	2
ALK	6	4	3	3	1	1	2		1
Other tests	5	3	2	3		1	2	1	2
Sanger Seq.	5	2	1	2					2
PCR allele specific-real time	4	2	2	2	1	1	2	1	1
NGS	3	1							1
FISH	4	3	3	2	1	1	2		1
IHQ	5	2	1	2		1	1		1
External QC	3	1	1	1	1	1			1

* LALCA surveys information not updated Information on the total tests performed in the region is still incomplete and the number varies from country to country. In spite of this, the main reference laboratories are included in the survey and the data obtained reveals an insufficient number of tests related to the frequency of advanced lung cancer cases in the region. I did not include in this survey the test results but published Latin American data³¯⁴¯⁵ shown regional/country variability in the frequency of EGFR mutation and sometimes in ALK fusion test, probably related to genetic variability in the Latin American population. What are the challenges of molecular testing in Latin America? One of them is the quality and quantity of tissue available for molecular tests. In the region we still struggle against badly-fixed or inadequately processed specimens. In this field, probably, there is much education and interdisciplinary work to do yet. Reimbursement is another challenge. In most of the countries, pharmaceutical companies have financed so far the cost of molecular tests, but if this were not the case in the future when the need for many other tests arises, health care systems will have to bear testing and treatment costs. A careful evaluation will be required in each country to organize the most balanced use of the available resources. A particularly important challenge for the region is molecular testing quality certification. The access to international quality control programs is very expensive for the majority of the regional laboratories but quality control must be ensured. A group of us is trying to organize a stratified system that allows for a more affordable program to all laboratories. It is still a project in development. 1-Survey participants: Argentina: Esteban Mocetti: Hospital Italiano. Buenos Aires. Marina Gutierrez: Laboratorio Stamboulian. Buenos Aires. Erica Rojas Bilbao:Hospital Roffo. Buenos Aires. Guillermo Bramuglia: Argenomics. Fundacion Investigar. Buenos Aires. Valeria Denninghoff: Instituto CEMIC. Buenos Aires. Jorge Palazzi: IICT Labs. Rosario. Brasil: Fernando Soarez. Isabela Werneck da Cunha: AC Camargo Cancer Center. Sao Pablo. Fabio Tabora:Argos Lab / Messejana Hospital. Fortaleza. Chile: Cristina Fernández Ferradás:. Instituto Nacional del Tórax. Santiago de Chile. Antonio Piottante Becker: Clínica Las Condes. Santiago de Chile. Colombia: Andres Felipe Cardona. July Rodriguez: Foundation for Clinical and Applied Cancer Research Bogotá. Ruby E. Ríos Quintana-Roberto Jaramillo: Unidad de Diagnostico Hemto-Oncologico. Cali.Costa Rica: Luis Corrales Rodriguez: Centro de Investigación y Manejo del Cancer.(CIMCA y CCSS). San José. Mexico: Graciela Cruz Rico: Instituto Nacional de Cancerología. Distrito Federal. Erica Sagrario Peña Mirabal: Instituto de Enfermedades Respiratorias. Distrito Federal. Perú: Juan Carlos Gomez de La Torre Petrell: Laboratorios ROE. Lima. Uruguay: Alejandra Torres: Laboratorio Genia. Montevideo.Gonzalo Manrique, María Noel Zubillaga. Asociación Española. Montevideo. 2. LALCA 2014 surveys, not updated: Cintya Sternberg. INCA. Rio de Janeiro.Brasil, Vinicius Duval Da Silva Pontificia Universidade Catolica do Rio Grande do Sul. Brasil. Yumay Pires. Clinica Alemana. Santiago de Chile. Ana Margarita Baldión Elorza. Hospital Universitario Fundación Santafé de Bogota. Colombia. Nicolas Vivar Diaz. Hospital Carlos Andrade Marin. Quito Ecuador 3: Arrieta O, Cardona A, Martin C et al. Updated Frequency of EGFR and KRAS mutations in NSCLC in Latin America. The Latin-America Consortium for the Investigation of Lung Cancer (CLICaP) JTO 2015;10: 838-843 4: Bacchi C. et al. EGFR and KRAS mutations in Brazilian lung cancer patients. CLINICS 2012;67 (5):419-424 5: De Melo A et al. Mutational Profile and new IASLC/ATS/ERS classification provide additional prognostic information about lung ADC. A study of 125 patients from Brazil. Oncology 2015; Apr 1.(Epub ahead of print)

Abstract:
Background: The Global Lung Cancer Coalition (GLCC) is a unique partnership dedicated to improving disease outcomes for all lung cancer patients worldwide. The GLCC has a clear objective to place lung cancer on the global agenda. There are known to be significant variations both between and within countries in terms of: lung cancer incidence, mortality and survival; access to the latest treatments and to high quality specialist healthcare professionals; and investment in research and clinical trials. Evidence of variations can be a powerful tool for advocates – both clinicians and patient advocacy groups – to use to engage with policymakers about the ways in which legislative or regulatory policies can be shaped to optimise treatment and care for people living with lung cancer. However, there was no single statistical resource for the global lung cancer community to use in comparing countries, benchmarking progress, and campaigning. In 2014, therefore, the GLCC created the Global Lung Cancer E-Atlas, making accessible in one place the latest published information about lung cancer's global impact and outcomes, in an interactive format. Creating the E-Atlas: Potential data sources were mapped to identify the most current and comparable available. Incidence and mortality data were drawn from GLOBOCAN 2012[i], which provides contemporary estimates of the incidence, mortality and prevalence from major types of cancer, at national level, for 184 countries. The estimates are based on the most recent data available at the International Agency for Research on Cancer (IARC) though more recent figures may be available directly from local sources. Survival data were drawn from a variety of sources, where available. These included: CONCORD-2[ii], which includes data provided by 279 cancer registries in 67 countries; the EUROCARE-5 study[iii], which provides the most up-to-date survival analysis for patients diagnosed with cancer across 29 European countries; and the International Cancer Benchmarking Partnership (ICBP)[iv], which includes data from population-based cancer registries in 6 countries – Australia, Canada, Denmark, Norway, Sweden and the United Kingdom. The E-Atlas also details whether each country operates a cancer plan or has implemented the World Health Organization Framework Convention on Tobacco Control with data drawn from responses to the World Health Organization Noncommunicable Diseases Country profiles[v], covering 184 countries. GLCC members were invited to validate data for their country and identify any more recent national data. If more recent data were found then these were added. Using the E-Atlas: The E-Atlas allows anyone to compare statistics for lung cancer across the world. It is publically accessible on the GLCC’s website: http://www.lungcancercoalition.org/atlas/ (Figure 1): Figure 1 Figure 1: GLCC Global Lung Cancer E-Atlas home page By clicking on individual countries, or using the search function, users can 'zoom in' on different areas to see the figures for that nation. The E-Atlas also has a comparison tool, enabling the user to select up to four countries and directly compare the figures for them (Figure 2). Figure 2 Figure 2: the comparator tool GLCC campaigners have been using the E-Atlas to support engagement with national policy-makers and influencers. To support this, the project team produced a campaigning toolkit, giving headline figures, tips for engagement and template materials (press releases, briefing documents and a presentation for adaptation). Conclusions: Feedback from GLCC members confirms that the E-Atlas is a helpful resource in their campaigning and advocacy. The GLCC is continuing to develop the E-Atlas, and it will be updated with breakdowns by age and gender. The GLCC is also keen for the E-Atlas to be shared and to receive feedback (via http://www.lungcancercoalition.org/atlas/contact.php) on additional national data for inclusion or suggestions for further development. References: [i] GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 11, Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray, F. Lyon, 2013, France: International Agency for Research on Cancer. Available at: http://globocan.iarc.fr/Default.aspx [ii] Global surveillance of cancer survival 1995–2009: analysis of individual data for 25 676 887 patients from 279 population-based registries in 67 countries (CONCORD-2), C Allemani, H Weir, H Carreira, R Harewood, D Spika, X Wang, et al. The Lancet, Volume 385, No. 9972, p977–1010, 14 March 2015. [iii] EUROCARE-5-a population-based study of cancer survival in Europe 1999-2007 by country and age. Available at: https://w3.iss.it/site/EU5Results/ [iv] Cancer survival in Australia, Canada, Denmark, Norway, Sweden and the UK, 1995-2007 (the International Cancer Benchmarking Partnership): an analysis of population-based cancer registry data, MP Coleman, D Forman, H Bryan, J Butler, B Rachet, C Maringe, et al. The Lancet Volume 377, No. 9760, p127–138, 8 January 2011. [v] Noncommunicable Diseases Country Profiles 2011, World Health Organization (WHO), 2011. Available at: http://whqlibdoc.who.int/publications/2011/9789241502283_eng.pdf

Abstract not provided

Abstract:
Background Despite recent advances, lung cancer remains a disease characterised by negativity, late diagnosis and poor outcomes. The need for advocacy in lung cancer is obvious. Recent years have seen an increase in the number of organisations and individuals advocating for improvements in this disease. All organisations engaging in lung cancer advocacy are different and respond to the particular cultures and needs of their regions or countries. However, there are a number of common campaign themes: Integrated Tobacco Control programs. Increased funding for lung cancer research Increase in the number of patients enrolled in Clinical Trials Earlier diagnosis Equitable access to best practice treatment and care The Need for High Quality Data Underpinning advocacy in all of the above, is the need for advocates to access high quality, timely data on survival, quality of life and patient experience. Such data, not only provides a benchmark for the quality and outcomes of lung cancer services, but also provides advocates with a tool to campaign for improvement and showcase good practice. A good example is the work of the International Cancer Benchmarking Partnership [1], which has shown huge variation in one year and five year survival in lung cancer across the study countries, prompting health policy makers to investigate differences. The publication of the recent CONCORD- 2 data [2] has had a similar effect, with advocates highlighting 5 years survival inequalities. In November 2014, the Global Lung Cancer Coalition launched it’s online e-atlas [3 ], bringing together international lung cancer data sets and information, where available, in every WHO country. An important national initiative is the UK’s National Lung Cancer Audit [4], which is examined in further detail The UK’s National Lung Cancer Audit (NLCA) – Example of a tool for advocates The NLCA has taken around 20 years from conception to its establishment as a gold standard national clinical audit. The first discussions around the need to audit services and patient outcomes took place among a small group of UK lung cancer clinicians, in 1994. Since then, the NLCA has developed into a national audit which captures information on almost every case of lung cancer and mesothelioma that reaches hospital in the UK. It captures data on a range of demographics, clinical features and key process measures in treatment and care, spanning the patient journey. The NLCA is used by a wide variety of stakeholders within the lung cancer community to understand how care is being delivered across the country and to drive improvements to services. It includes data which are as close to real-time as possible. As contained in the Roy Castle Lung Cancer Foundation’s 2014 report on the NLCA [5], this audit has been vital to lung cancer advocates in driving improvements in lung cancer service provision. Findings of this Report highlight the NLCA’s vital contribution to: Improving clinical practice – average rates of active treatment, surgery, histological diagnosis and access to lung cancer nurse specialists have all improved during the lifetime of the audit Creating further advocacy tools - this audit data has been extensively used by UK advocacy groups, as in the web based ‘Smart Map’ [6], displaying the data in a patient friendly, easily accessible format. Supporting clinical research –The 2014 RCLCF Report [5] notes that there were at least 13 clinical research projects ongoing across the UK which were making use of NLCA data. Also, 175 key clinical journal articles published between 2006 and 2013 referenced the NLCA. Informing cancer policy and guidelines – the NLCA has been cited in much policy documentation.. The 2014 RCLCF Report [5] notes that the National Institute for Health and Care Excellence (NICE) references the NLCA at least 36 times in documents ranging from guidance, implementation guides, and audit tools to briefings. Also. the National Cancer Intelligence Network (NCIN) references the NLCA 32 times in the documents currently available on its website and uses most of the NLCA’s ‘headline indicators’ in its on-line lung cancer service profiles Raising awareness of lung cancer issues - the annual NLCA report helps to raise awareness of lung cancer issues among national and local decision-makers and the general public. It has been used almost exclusively to positively evaluate the major clinical impact of the 2011 and 2012 national public awareness campaigns (the Be Clear on Cancer campaign for lung cancer [7]), relating to persistent cough as an early warning symptom of lung cancer. Roy Castle Lung Cancer Foundation has used data from the NLCA to raise awareness of lung cancer, and variations in lung cancer care and outcomes across England and Scotland, through the publication of two reports[i] on variations in lung cancer care across the country [8,9]. Learnings for all lung cancer advocates There is a need for high quality, timely, lung cancer data on incidence, mortality, survival. Also, a need for high quality, timely data to assess health services – on diagnositics, treatment availability and support/care provision. If the above is not available – advocates need to ask why not and campaign for data collection Quality data provides lung cancer advocates with a key tool to highlight good practice, variation and inadequacies. Thus, advocating for change and improvement. References 1. Coleman MP et al, ‘Cancer survival in Australia, Canada, Denmark, Norway, Sweden, and the UK 1995-2007 (the international Cancer Benchmarking Partnership): an analysis of population-based cancer registry data’, The Lancet, Vol. 377, January 2011 2. Allemani C, Weir HK, Carreira H, et al., and the CONCORD Working Group. Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2). Lancet 2015; 385: 977–1010 3. GLCC website – Global Lung Cancer e-Atlas. http://www.lungcancercoalition.org 4. Health and Social Care Information Centre, National Lung Cancer Audit annual reports, via: http://www.hscic.gov.uk/lung 5. Roy Castle Lung Cancer Foundation, Leading the information revolution in lung cancer intelligence: why the National Lung Cancer Audit is the key to transforming lung cancer outcomes, January 2014. 6. Roy Castle Lung Cancer Foundation’s Smart Map. http://roycastle.org/news-and-campaigning/campaigns/interactive-map 7. Be Clear on Cancer – Lung Cancer campaign, via http://www.campaigns.dh.gov.uk/category/beclearoncancer/ 8. Roy Castle Lung Cancer Foundation, Explaining variations in lung cancer in England, July 2011 9.Roy Castle Lung Cancer Foundation, Explaining variations in lung cancer in Scotland, 2011

Abstract:
Lung cancer was a rarity a century ago. A dramatic increase in the use of tobacco, in the form of cigarettes, and the science-based reformulation of tobacco that renders the modern cigarette so addictive, the world would not be in the grip of the current lung cancer epidemic. Several other critical factors contributed. These include ready access for sale and purchase, few limitations on time and place of tobacco use and highly skilled promotion and marketing. This combination of corporate success and health tragedy was supported by carefully orchestrated public disinformation and the achievement and maintenance of political influence. It follows from these observations that reversing the course of this epidemic requires that each of these be addressed. Now that legislation for the introduction of mandatory plain packaging of tobacco products has been passed in Ireland and the United Kingdom, Australia is not unique in any single tobacco control action. However, it has been innovative and the extent and breadth of activity is world-leading. A non-exhautive list of innovations includes Pack warnings and regulation Simple text messages(1972) Rotating text messages Graphic health warnings(2004) Mandatory plain packaging(2012) Product and sale restrictions Public information on tar content Restrictions on sales to minors Prohibition of "kiddy-packs" with <20 cigarettes Smoke-free indoors policy - non smoking in Workplaces (Federal Government initially in 1985) Domestic aircraft(1987) Public transport vehicles (bus/train/tram) Large shopping centres Motor vehicles carrying cars Indoor restaurants/bars Hospitals and health centres Smoke-free outdoors policy Al fresco dining Sports stadiums Children’s play areas Beaches and parks Railway stations and bus/tram stops Counter-advertising First TV campaign in late 1970's. Several innovative TV and radio campaigns since including "Every cigarette is doing you damage". Aims were to broaden knowledge of harms and bring risk into the present Tobacco Advertising and Promotion Restriction Voluntary banning of tobacco advertsing by the Medical Journal of Australia Banning TV and radio and later print advertising Elimination of sports and arts sponsorships Price and taxation Introduction of hypothecated tax to replace tobacco sponsorship income Removal of tobacco from consumer price (inflation) index calculation Aggressive tax increases (current Marlbro 20's > $US25) From time to time, opportunistic targetting a single state or local government entity, aimed at a specific innovation, has established a policy precedent. This has been achieved with a relatively small group of tobacco control advocates and effective health NGOs. Effective use of media has been critical in the process. The tobacco industry, in tactics used to oppose effective interventions, is quite predictable. Separate from simplistic themes of civil liberties, crystallised in the absurdist “nanny-state” concept. Common themes used to oppose evidence-based actions, include the threat of large legal penalties, spectre of illicit tobacco sales and the harm potentially caused to Australia more generally as a place to do business. Effective lobbying campaigns can be transplanted. For example, promoting the right of workers to work long hours in safe workplaces can aid arguments in favour of smoke-free dining and other public places. All of the policy victories achieved are within the scope of aims of the Framework Convention on Tobacco Control. This remains the international template and its objects are proven able to be implemented. These policy innovations have been achieved despite tobacco industry interference via the political process and well-documented donations to major political parties. Although major parties have eschewed tobacco company donations by law or choice in recent years, influence is still peddled. To counter interference, the case for tobacco control was made politically impelling. That is, the community was perceived by political decision takers to have a desire to be rid of the harms of smoking that exceeds any concerns about restrictions that need to be imposed to achieve this. A lesson from Australia is that health professionals interested in tobacco control must educate communities at the same time as they seek to alter public policy.

Abstract not provided

Abstract:
Lung cancer remains the leading cause of cancer-related mortality in men and women. Since about 85% of all lung cancer care in the United States is provided in the community setting (1), it is imperative to optimize the delivery of accessible, high-quality lung cancer care in this environment. Implementation of a multidisciplinary clinic is not enough to strengthen physician care across large hospital systems. Many systems have an established weekly tumor board to review patient cases. These multidisciplinary conferences are a venue for involved specialties including thoracic surgery, medical oncology, pulmonary medicine, radiology, radiation oncology, and pathology to provide an opinion regarding the management of each presented case. This forum for open dialogue results in reinforced recommendations and streamlines patient care (2). It can be challenging for physicians in a community setting who are managing multiple tumor types to remain abreast of evolving information regarding each subgroup. Expanding multidisciplinary care beyond the case conference provides a more robust collaboration for physicians managing these patients. For physicians, journal club, continuing medical education programs, and standardized guidelines provide direction regarding the latest advances in diagnosis and management. Specifically in lung cancer, launching a screening program builds partnerships with radiologists pursuing early detection and expands relationships with other practitioners monitoring abnormal chest imaging. For patients, access to smoking cessation directives, chemotherapy teaching, palliative medicine, and survivorship programs enhances the care delivered in community lung cancer programs. A nurse navigator is an invaluable resource providing the patient and family support and education to improve the cancer experience. The navigator also serves as a liaison to ensure interdisciplinary coordination of cancer management. Clinical trials, genetic counselors, interpreters and geriatric oncologists should supplement well-integrated lung cancer networks. Even when all of these components are implemented into a community lung cancer program with the goal to provide the best care, if the core physician care is not strengthened as a part of this process, in a large hospital system, the program will fall short. Thus it is just not what should be executed but how. In large hospital systems, clinicians can become engaged through regional councils, designed to establish the aims of a cohesive lung cancer program and to create a model that will service these recommendations (3). Allowing system-wide participation in customizing the organizational structure of a lung cancer program will result in team development. If team is defined as “a group of people with complementary skills who are committed to a common purpose, performance goals, and approach, for which they hold themselves mutually accountable” (4), then it seems that strengthened care is inevitable. In a large health system, physician teams need to have shared goals and values, need to understand and recognize the competencies of other team members, and need to learn from other disciplines and respect their different views and perspectives. Individual team members may need to reassess exclusive claims to specialist knowledge and authority in order to form effective multidisciplinary teams which can provide the best care. By establishing a one-tiered system, physicians of various expertise find a comfortable niche that is not rewarded by self-promotion. Some physicians may maintain a more traditional generalized oncology clinic. Other physicians may adopt a more academic practice with subspecialty care, clinical trial participation, and literature publications. Collegiate collaborations between these two models strengthen physician care because the gap between private practice and academics is bridged within the same system. Because tumor boards provide multidisciplinary meetings but not necessarily multidisciplinary care, tumor boards may validate physician care but not necessarily strengthen it. A physical multidisciplinary clinic is not required to achieve this success. Instead, a solid team of engaged members focused on a specific disease will enrich the program. Routine meetings of a disease-specific section open to all interested provide a forum to review comprehensive needs for lung cancer patients. When a consistent message is issued from the group, physician care is strengthened. Telephone, video, and internet access to all disease-specific section meetings encourage participation. Communication facilitated by technology is the backbone to the success of this linked enterprise. The format of routine section meetings provides the venue to shift the “what” into the “how.” Announcements for lung cancer events are widely distributed. Consensus-driven standard algorithms of care are reviewed and updated. Finally, research options are reassessed. Integration of clinical trials in the community setting is necessary to strengthen care even in larger systems that may otherwise feel that care is already comprehensive. The best academic programs are often built on a reputation of offering research and clinical trial opportunities. Because the majority of patients with lung cancer are never seen in major academic centers, it is imperative that community programs become involved in clinical trials. Common protocol review (again maximizing participation with technology access) broadens interest. A centralized trials unit blends the team with appropriate system-wide delegation of resources. Utilization of a common internal review board allows for trials to open efficiently as well as simultaneously at multiple sites within the larger system. Local access obviates the need for travel, enhances program visibility, and provides ongoing relationships with the larger worldwide research community. Ultimately, a larger hospital system will benefit from restructuring the community. Physician care can be effectively strengthened not under the traditional hub-and-spoke model but instead as a cancer institute “without walls” (5). Regional councils, subspecialty sections, and multi-site clinical trial options under common review are all successful when system-wide participation is encouraged and when access is easily provided via advanced technology. Consider the large hospital organization as a system not a center. Aim to decentralize cancer care facilities by providing as many of the programs of a tertiary referral center throughout the region, limiting patient travel and lost time while still maintaining balanced quality (6). In order strengthen physician care in large hospital systems, growth measured as patient encounters is not as productive as reorganizing the care team. You can have “many” but still be “One.” 1. American College of Surgeons: Commission on cancer national cancer data base. Benchmark Reports v1.1 2. Fischel RJ, Dillman RO: Developing an effective lung cancer program in a community hospital setting. Clin Lung Cancer 10: 239-243, 2009 3. Dahele M, Ung Y, Meharchand J, et al: Integrating regional and community lung cancer services to improve patient care. Curr Oncol 14: 234-237, 2007 4. Carrier JM, Kendall I: Professionalism and interprofessionalism in health and community care; some theoretical issues. Interprofessional Issues in Community and Primary Health Care, 1995 5. Goldberg P: The Raghavan experiment. The Cancer Letter 39: 1-9, 2013 6. Raghavan D: Costs of cancer care: rhetoric, value, and steps forward. Semin in Oncol 40: 659-661, 2013

Abstract:
Minority populations often suffer disproportionately from lung cancer due to 1) lower levels of education 2) jobs with higher occupational hazards 3) housing in areas with higher environmental hazards and 4) economic disadvantage. Lower socioeconomic status leads to higher rates of uninsured or underinsured populations living in neighborhoods with less access to quality health care. The recently published “Neighborhood Deprivation Study of Lung Cancer”, demonstrated living in a social-economic depressed environment, defined as high rates of low education status (< 10 years formal education), low income (less than 50% of individual median income), high unemployment and high rates of social welfare assistance, leads to higher incidence and mortality from lung cancer[1]. The lung cancer mortality was 13 per 1000 in high deprivation neighborhoods vs 8 per 1000 (OR 1.6) in low deprivation neighborhoods. Minority communities also have more barriers to effective cancer care. Barriers include differences in culturally related health beliefs, (values and preferences that are not understood by health care providers and lead to decreased compliance with medical recommendations), language discordance, provider stereotypes that lead to health care disparities, limited clinic hours of service that do not account for community work patterns, etc. Health care disparities in lung cancer have been studied in treatment decisions for early-stage disease. Bach et al. studied the differences in survival of Medicare beneficiaries with stage I or II NSCLC based on race[2]. The five year survival of black patients was significantly less than white patients, 26 % vs. 34.1% (p < 0.001). The difference in survival could be accounted for by the lower number of black patients treated with surgery, 64.0 % vs. 76.7 % for white patients. Although the difference in treatment had an impact on survival, the authors could not determine if this was due to patient held health beliefs regarding surgery and/or black patients being offered surgical resection less often. A similar outcome was seen by Koshy et al. when examining the National Cancer Database for differences in radiation treatment modalities offered for early stage disease[3]. Socioeconomic factors, including insurance type and race/ ethnicity, were significant variables in determining if a patient received no radiation therapy, conventional radiation therapy or stereotactic body radiation therapy. Each of these barriers is important to study and overcome as efforts to improve the treatment of diverse patient populations will increase the lung cancer cure rate. Applying cultural competence to cancer care delivery will improve adherence to screening and prevention measures, improve compliance to medical treatment and necessary follow-up, and reduce health care disparities. Effectively treating diverse populations of lung cancer patients requires change on multiple levels within healthcare delivery. On an organizational level, the leadership and workforce must allow for greater minority representation, to remain connected to the communities they serve. For minority patients, racial concordance between patient and physician is associated with greater patient satisfaction and higher self-reported quality of care. Specific quality measures for diverse patient populations must be developed. For example, patient-reported health care quality surveys can be adapted to better evaluate culturally diverse populations. Ultimately, health care organizations benefit from establishing ongoing links for consultation with representatives from diverse communities. On a structural level, work-processes can be adapted to aid diverse patient populations. Often the intake process is difficult or cumbersome for minority patients to navigate. Lack of interpreter services or inappropriate health care education materials can limit the effectiveness of the clinic visit. Ngo-Metzger et al. studied the effects of language discordance between patient and provider within a Chinese and Vietnamese population in the US. Patients with language discordant providers reported receiving less health education compared to those with language concordant providers. This effect was mitigated with the use of a clinic interpreter[4]. This language barrier includes key signage and patient information documents. The Joint Commission has published guidance in establishing effective communication, both written and verbal, for diverse patient populations[5]. Finally the clinical (patient- provider encounter) level must be addressed. When cultural differences between provider and patient are not fully understood it becomes a barrier to effective care. Diverse patient populations have specific health beliefs; such as use of home remedies, attitude toward medical care and medical practices, level of trust in doctors and the health system. Each of these differences, if not understood, can interfere with effective care. The Witness Program is an example of a successful, culturally competent approach to health care delivery[6]. Although African-American (AA) women have high rates of breast cancer, screening with mammography was low in this population. To better understand the cultural barriers associated with breast cancer screening among this group, investigators performed multiple focus groups. By directly interviewing AA women in the community barriers to breast cancer screening were identified. The Witness Program® turned cultural barriers into culturally based interventions. Key to this project are Witness Role Models – African American breast and cervical cancer survivors who talk about their experiences with other AA women in a community setting. This approach has led to improved rates of breast cancer screening among the women who participated in this educational program. Training of medical providers in cultural competency is necessary to effectively treat diverse patient communities. Efforts to improve the care of diverse patient populations will increase the lung cancer cure rate. This begins by having a clear understanding of the community that is served, including health care values and beliefs, predominate language used, and any barriers to health care that are present. Training for staff in cultural competency and the ability to evaluate the perceived quality of health care of diverse populations is needed to provide the best care. References 1. Li et al. Journal of Thoracic Oncology, 2015; 10:256-263. 2. Bach PB et al. N Engl J Med. 1999; 341:1198-1205. 3. Koshy et al. Journal of Thoracic Oncology. 2015; 10:264-271. 4. Ngo-Metzger et al. J Gen Intern Med. 22(suppl 2):324-30. 5. The Joint Commission: Advancing Effective Communication, Cultural Competence, and Patient- and Family-Centered Care: A Roadmap for Hospitals. Oakbrook Terrace, IL: The Joint Commission, 2010. 6. Bailey et al. J Natl Med Assoc. 2000; 92:136-142.

Abstract:
The rapid changes in lung cancer treatment,with the development of new treatment modalities such as immunotherapy, coupled with the emergence of low-dose CT screening for lung cancer have made mutli-modality thoracic oncology programs even more vital than previously. Howerver, almost all of these programs are in urban areas, despite a great need in rural communities. Epidemiologic studies show that rural areas have higher lung cancer and all cancer mortality than urban areas (Singh et al J Ca Epidemiol 2011) with even greater disparity in minority and socio-economically disadvantaged rural populations. An analysis of the SEER database found that rural residence had no impact on stage-specific lung cancer survival with the exception of Stage I (Atkins et al, Am J Crit Care Med 191:2015;A3595). Tobacco use is more prevalent in rural communities and may account for much of the higher lung cancer mortality seen in these communities (ALS monograph, Cutting Tobacco's Rural Roots: Tobacco Use in Rural Communities, 2014). It does appear that rural residents are more likely to be diagnosed with an advanced stage of lung cancer than their urban peers (Wen et al, Ann Pub Health and Res 2015 2:1011 ; Johnson et al, Lung Cancer 2014 83:401-7). Survival was lower in rural areas with greater poverty and less educated residents. In addition, rural residents were less likely to receive radiotherapy and chemotherapy, and those in less educated areas were less likely to undergo surgery or chemotherapy (Johnson et al). Another study found poorer outcomes in Stage I lung cancer in rural areas, perhaps due to less access to surgical care (Atkins, op cit). Kim et al compared barriers to clinical trial participation in rural and urban areas of South Carolina (Kim et al, J Comm Health 2013). They found no significant difference between rural and urban residents in willingness to participate in clinical trials but found that rural residents perceived less access to less access to, and awareness and knowledge of, clinical trials. A study funded by the Rand Corporation found that physicians who participated in tumor boards weekly were more likely to enroll lung cancer patients in clinical trials (Kiehl et al, J Onc Practice 2015 11:E267-78). This suggests that rural thoracic oncology programs are likely to improve clinical trial participation by rural residents by improving access and physician particiapation. It is not just access to therapeutic modalities in lung cancer that differs between rural and urban areas; supportive/ palliative care is also different. An analysis of the SEER database found disparities in end of life care as well. Medicare beneficiaries in rural areas had more ER visits in the last 90 days of life than urban residents. Urban residents had more ICU days in the last 90 days of life and were more likely to be enrolled in hospice programs. Minority and lower socioeconomic patients were less likely to use hospice and had more ICU days, inpatient days, and ER visits in the last 90 days of life (Nayar et al, J Comm Health 2014 39:1012-9). These disparities are of particular note since several studies have shown that early palliative care improves survival in lung and other cancers. Greater prevalence of rural thoracic oncology programs may improve access to potentially curative modalities, particularly for early stage disease. Given the higher prevalence of tobacco use in rural populations, these programs should ideally include smoking cessation efforts. Since rural residents are more likely to be diagnosed with advanced lung cancer, the implementation of low-dose CT screening is likely to be particularly beneficial in these communities. It seems likely that rural areas with thoracic oncology programs will have better rates of clinical trial access and participation. Incorparation of early effective palliative care into these programs may improve outcomes and help reduce the disparities seen in end of life care and survival in rural areas. However, resources are often limited in small rural hospitals, so it may be difficult to provide all of these services.

Abstract:
Introduction and Rationale: Assessment and treatment of the cancer patient continues to increase in complexity. Some oncologists have subspecialized in their disease discipline, allowing for a greater depth of knowledge in that particular cancer but not having the breadth of expertise over numerous cancers. The majority of cancer treatment is delivered in the community-based setting where most oncologists practice general oncology. This has created a need for treatment guidelines which help oncologists manage patients in a standard approach. The evolution of treatment guidelines or pathways has several purposes. There has been much research in justifying the implementation of treatment pathways as they lead to consistent care, tend to lower healthcare costs overall, and influence outcomes of care[1-3]. However, each individual system, hospital, or physician will have their own purpose for utilizing pathways, ranging from education of assessment and treatment recommendations to providing evidence to payers for treatment. The development of clinical pathways requires a predetermined strategy. Reports have stressed the need for transparency, inclusiveness, disclosure and frequency of meetings[4][,][5]. This then requires a team to translate the results of these meetings into disseminated information for the clinical teams. The Institute of Medicine published recommendations in 2011 on how to develop these clinical pathways[4]. Various other organizations have published guidelines, such as the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), European Society of Medical Oncology (ESMO), Cancer Care Ontario, Cancer Council Australia, and Via Oncology. National Comprehensive Cancer Network (http://www.nccn.org/about/default.aspx) Clinical Practice Guidelines in Oncology The NCCN is the most comprehensive set of guidelines in the United States, covering 97% of all cancers. Guidelines cover the entire cancer spectrum, from prevention to survivorship issues, and are evidence-based and continually updated. Guideline content is consensus based and developed by one of 47 panels consisting of multidisciplinary and disease-specific oncologists and researchers. Within the guidelines, a variety of content can be utilized, including algorithms or decision pathways and discussion text summarizing historical and current data. American Society of Clinical Oncology (http://www.instituteforquality.org/practice-guidelines) Clinical Practice Guidelines ASCO currently has 11 topic areas in which clinical practice guidelines are available for both solid and hematologic malignancies (e.g. use of diagnostic testing and predictive assays, disease-specific treatment, supportive care and survivorship). Each year, ASCO solicits guideline proposals from its members. Expert panels, consisting of oncologists, nurses, pharmacists, and practice managers approve proposal topics and develop the guidelines. Anyone has the opportunity to comment on or provide new evidence for use in the guidelines through the ASCO Guideline Wiki page (https://pilotguidelines.atlassian.net/wiki/display/GW/ASCO+Guidelines). European Society of Medical Oncology (http://www.esmo.org/Guidelines) Clinical Practice Guidelines The ESMO Clinical Practice Guidelines consist of 60 guidelines on cancers of the breast, lung, gastrointestinal tract, head and neck, and more, as well as supportive care and bone health. The ESMO Guidelines Committee is comprised of a Subject Editor and other leading experts and they are charged with authoring, publishing, and disseminating the full clinical practices guidelines and Pocket Guides. Cancer Care Ontario (https://www.cancercare.on.ca/cms/One.aspx?portalId=1377&pageId=7582) Program in Evidence-Based Care (PEBC) The Cancer Care Ontario’s PEBC is a program of the Ontario provincial cancer system, with support from the Ontario Ministry of Health and Long Term Care. Guidelines focus on all stages of cancer, including prevention, screening, diagnostic assessment, treatment, palliative care and survivorship. The PEBC consists of multidiscipline panels (disease-specific and modality-specific guideline development groups) consisting of 200+ physicians, other healthcare providers, and methodologists. Cancer Council Australia (http://www.cancer.org.au/health-professionals/clinical-guidelines/) Clinical Guidelines Network Cancer Council Australia (CCA) is Australia’s national non-government cancer organizations. CCA has published full and condensed guidelines on cancer screening and treatment of lung, esophageal, endometrial, sarcoma, and prostate cancers. The CCA is currently working to transform these guidelines in to a web-based format Via Oncology, LLC (http://viaoncology.com/) Via Oncology Pathways Via Oncology is affiliated with the University of Pittsburgh Medical Center (UPMC) and University of Pittsburgh Cancer Institute (UPCI). The Via Oncology Pathways were developed in 2005 to ensure high quality and standardized care in medical and radiation oncology across UPMC/UPCI facilities and now has grown to include practices from 20 states. Disease committees, consisting of physicians from all participating practices, have developed guidelines covering more than 90% of cancers to demonstrate value to patients, payers and referring physicians. Guidelines are available to participating providers only. Overcoming Barriers and Resistance Many reasons for why physicians do not follow guidelines have been noted in the literature, including: lack of clarity; length of guidelines; guideline format; lack of awareness; lack of familiarity; lack of agreement with the evidence; lack of outcome expectancy; lack of self-efficacy; inertia of previous practice; organizational constraints; excessive frequency of revision; and external barriers[5-8]. Kaster et al recently published data on key domains (stakeholder involvement, evidence synthesis, considered judgment, implementation feasibility, message, and format) related to positive implementation of pathways[5]. These domains largely are nested within two, broad categories: content creation and communication of content[5]. Clinical Trials One aspect that is not as inclusive in all clinical pathways is access or information to clinical trials. This content is an entirely different aspect to clinical pathways as different groups value clinical trials access differently. National accrual rates to clinical trials are low[9][,][10]. Barriers to clinical trial participation are noted on the patient, physician and system level. Clinical pathways that incorporate clinical trials may benefit the patient by increasing physician knowledge of available trials and may benefit the overall clinical trial by increasing accrual rates. EAPathways, Levine Cancer Institute, Carolinas HealthCare System We have developed in-house clinical pathways which include not only treatment pathways to assist clinicians, but also have a number of additional features. These include access to documents, educational resources, clinical trials information and communication to colleagues. The pathways on this proprietary system are developed by our disease-specific sections and housed on our system intranet. Conclusions Clinical pathways are an integral part of patient management. Their utilization is increasing and additional groups are developing these. Functionality and adaptability will be key, especially in the oncology realm, as changes in molecular testing and treatment options are occurring at a faster than ever rate. Educating our practitioners and empowering their ability to accurately assess and treat patients with cancer will enable consistent and efficient care. References 1. Hall SF, Irish JC, Gregg RW, Groome PA, Rohland S. Adherence to and uptake of clinical practice guidelines: lessons learned from a clinical practice guideline on chemotherapy concomitant with radiotherapy in head-and-neck cancer. Current oncology (Toronto, Ont.). Apr 2015;22(2):e61-68. 2. Sullivan WJ. Demystifying pathways in oncology. Managed care (Langhorne, Pa.). Jun 2012;21(6):34-38. 3. Gesme DH, Wiseman M. Strategic use of clinical pathways. Journal of oncology practice / American Society of Clinical Oncology. Jan 2011;7(1):54-56. 4. Graham R, Mancher M, Miller Wolman D, Greenfield S, Steinberg E, eds. Clinical Practice Guidelines We Can Trust. Washington DC: 2011 by the National Academy of Sciences; 2011. 5. Kastner M, Bhattacharyya O, Hayden L, et al. Guideline uptake is influenced by six implementability domains for creating and communicating guidelines: a realist review. Journal of clinical epidemiology. May 2015;68(5):498-509. 6. Kastner M, Estey E, Bhattacharyya O. Better guidelines for better care: enhancing the implementability of clinical practice guidelines. Expert review of pharmacoeconomics & outcomes research. Jun 2011;11(3):315-324. 7. Cabana MD, Rand CS, Powe NR, et al. Why don't physicians follow clinical practice guidelines? A framework for improvement. Jama. Oct 20 1999;282(15):1458-1465. 8. Collins IM, Breathnach O, Felle P. Electronic clinical decision support systems attitudes and barriers to use in the oncology setting. Irish journal of medical science. Dec 2012;181(4):521-525. 9. Go RS, Frisby KA, Lee JA, et al. Clinical trial accrual among new cancer patients at a community-based cancer center. Cancer. Jan 15 2006;106(2):426-433. 10. Comis RL, Miller JD, Colaizzi DD, Kimmel LG. Physician-related factors involved in patient decisions to enroll onto cancer clinical trials. Journal of oncology practice / American Society of Clinical Oncology. Mar 2009;5(2):50-56.

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Abstract:
Background: From the moment of diagnosis, malignant mesothelioma (MM), decreases health-related quality-of-life (QOL) in patients and their caregivers. In addition to the symptoms of the disease itself, aggressive treatments options such as surgery, radiation, and chemotherapy can cause side effects which border on the intolerable. Specifically, chemotherapy is associated with side effects such as fatigue, nausea, vomiting, and systemic pain which has been described as unpleasant and stressful. The side effects of treatments can be burdensome enough to lead to noncompliance or outright refusal of continuation of care. Data from 13 frequently cited QOL studies conducted in the United States and Europe between 1990 and 2009 focus on chest pain and shortness of breath as the two chief symptoms of pleural mesothelioma. The largest QOL study to date, conducted across five continents, enrolled 495 patients in a multicenter study evaluating MM using the LCSS (lung cancer symptom scale). Investigators reported the most common symptoms as: fatigue (94%), dyspnea (89%), loss of appetite (86%), Chest pain (85%), cough (75%), and hemoptysis (24%). Ninety-two percent of patients experienced three or more above symptoms. Research on the psychological aspects of patients living with mesothelioma has shown their disregard for their exposure to asbestos in respect to their diagnosis. One such study investigated the reactions of 38 patients upon diagnoses with mesothelioma. Interestingly, although most patients had exposure to asbestos, only 17% of patients reported being concerned about their health prior to diagnosis, and, perhaps most interestingly, 65% of those with asbestos exposure denied anger towards the asbestos industry. Such studies’ preliminary findings suggest the need for better information about asbestos and mesothelioma, especially for high-risk individuals. Mesothelioma has a number of emotional consequences as well. A study conducted by the British Lung Foundation (BLF) reported significant impairment of emotional function and/or emotional state in patients with mesothelioma and their family members. The BLF’s study further reported a more positive response amongst patients versus caregivers in regards to supportive treatment to their emotional functioning. However, the authors did not provide a definition for significantly impaired emotional functioning, opacifying the results of such support. Recent psychological studies have demonstrated health benefits in cancer patients when sharing their illness experiences through online blogs. It has been suggested that blogging creates a survivor identity and facilitates a social support network for patients. Further, studies suggest that expressive writing increases self-management of chronic pain and lowers depressive symptoms. Methods: The platform for the support group was remote, consisting of both online and telephone domains. Each participant received an email a week prior to support sessions with an access code to the online and phone conference systems. Participants would utilize both online and phone systems during sessions, which were held once a week during evenings for a total of 6 weeks. Sessions were guided (by a team of healthcare professionals consisting of: a social worker, nurse, and community group leader) and kept closed, available only to those affected by mesothelioma – confidentiality was kept strong to encourage dialogue. The only non-patient participants were the group’s facilitators. The platform facilitated anonymity, should a patient have wished to remain so. Session summaries and follow-up information were provided online after support meetings. Conclusions: Active participation in a guided support group allowed participants to share their feelings and concerns about their diagnosis without feeling judged by their peers or healthcare providers while getting the emotional, mental, and post-active treatment support they needed facilitating the transition to follow-p care. The online portion of the platform was particularly helpful in assuaging common negative concerns like: fear of healthcare provider judgment, confidentiality, self-editing, emotional backlash from loved ones, and disapproval of lifestyle post-active treatment. Analysis of support session dialogue allowed facilitators to gauge information available to patients as well as to provide information about life after active treatment. Online space (on our blogs) gave participants a place to provide more communicative responses outside the main dialogue of support sessions.

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Multi-disciplinary care has become an essential part of medicine, especially in oncology. This care is not limited to the disciplines of medical, surgical and radiation oncology. We as providers must start, if we haven't already, expanding our thinking to involving other disciplines such as nutrition, social work, respiratory therapy, palliative care, physical therapy, psychiatry etc. Even though medicine is becoming more personalized with targeted therapies, we cannot allow this to narrow our focus of treating the patient as a whole. Our panel of experts from different disciplines will review and discuss lung cancer and mesothelioma cases highlighting the importance of a multi-disciplinary approach to patient care.

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Abstract:
Main point: Given the nonspecific nature of a GGO or multiple GGOs, a conservative approach to GGOs without a solid component is suggested. Ground glass opacity is a localized nodular lesion which appears as an undetermined finding ‘of hazy lung opacification, without obscuration of the underlying vascular markings’ on a CT scan. Any condition that decreases the air content of the lungs without totally obliterating the alveoli can produce ground glass opacity. GGOs, also known as nonsolid nodules, have been known to decrease or increase in size and/or disappear. There are benign and malignant causes of GGOs. A GGO can be indicative of inflammation, infection and fibrosis that are usually not fatal: pulmonary edema, alveolar proteinosis, many causes of alveolitis or interstitial pneumonitis, including idiopathic pulmonary fibrosis, sarcoidosis, hypersensitivity pneumonitis, early radiation pneumonitis, aspergillus infection, pneumonia, and bronchiectasis. GGOs can also be an early finding of neoplasms such as bronchioalveolar carcinoma (BAC). A recent study has shown that lung cancers appearing as nonsolid nodules were Stage I adenocarcinomas. Analysis of 57,496 participants in the International Early Lung Cancer Action program has shown a 100% survival rate regardless of the time from diagnosis to treatment and tumor size. There are methods to indicate malignancy without surgery: marginal characteristics, the size and development of the solid component or the attenuation on the CT scan, patient’s medical history of cancer, and fine needle aspiration. These are not without some controversy. A solid component is concerning because they are areas of collapsed alveoli or fibroplastic proliferation which signifies more invasive lesions. However, nonsolid nodules can be followed safely by CT screening annually to see if they transition to a part-solid component. Lung cancers diagnosed among nonsolid nodules tend to be slow growing and indolent in nature. The recent I-ELCAP study shows that until the identification of molecular markers, CT imaging can differentiate among different levels of lung cancer sufficiently early so delay in treatment did not change prognosis. A surgeon has to weigh the risks inherent to surgery while leaving the patient with as much lung as possible. Note that a patient’s desire to have the nodule removed may factor in. If feasible, follow the patient and if the GGO’s morphologic characteristics begin to change dramatically, proceed with surgical intervention, preferably VATS. In most cases, with a conservative approach, the patient has enough pulmonary reserve for aggressive action if required. Location of the lesions may make surgical resection challenging. The decision to perform a lobar versus sublobar resection is based on multiple factors and varies from patient to patient. REFERENCES Cho J, Ko SJ, Kim SJ, Lee YJ, Park JS, Cho YJ, Yoon HI, Cho S, Kim K, Jheon S, Lee JH, Lee CT1. Surgical resection of nodular ground-glass opacities without percutaneous needle aspiration or biopsy. BMC Cancer. 2014 Nov 18;14:838. Cho JH, Choi YS, Kim J, Kim HK, Zo JI, Shim YM. Long-term outcomes of wedge resection for pulmonary ground-glass opacity nodules. Ann Thorac Surg. 2015 Jan;99(1):218-22. Engeler CE, Tashjian JH, Trenkner SW, Walsh JW. Ground-glass opacity of the lung parenchyma: a guide to analysis with high-resolution CT. AJR Am J Roentgenol. 1993 Feb;160(2):249-51. Kim HK, Choi YS, Kim J, Shim YM, Lee KS, Kim K. Management of multiple pure ground-glass opacity lesions in patients with bronchioloalveolar carcinoma. J Thorac Oncol. 2010 Feb;5(2):206-10. Miettinen OS, Henschke CI, Smith JP, Yankelevitz DF. Is ground glass descriptive of a type of pulmonary nodule? Radiology. 2014 Jan;270(1):311-2. Mirtcheva RM, Vazquez M, Yankelevitz DF, Henschke CI. Bronchioloalveolar carcinoma and adenocarcinoma with bronchioloalveolar features presenting as ground-glass opacities on CT. Clin Imaging. 2002 Mar-Apr;26(2):95-100. Yankelevitz DF, Yip R, Smith JP, Liang M, Liu Y, Xu DM, Salvatore MM, Wolf AS, Flores RM, Henschke CI; As the Writing Committee for The International Early Lung Cancer Action Program Investigators Group. CT Screening for Lung Cancer: Nonsolid Nodules in Baseline and Annual Repeat Rounds. Radiology. 2015 Jun 23:142554. [Epub ahead of print]

Abstract:
Recent advances in diagnostic imaging and the use of low dose screening CT scans for high risk individuals has increased detection of ground-glass opacities (GGOs). These lesions are defined as hazy lung opacities on CT with preservation of bronchial and vascular markings, and are typically classified as pure, without a solid component, or mixed,with a solid component[1, 2]. While GGOs have historically been characterized by slow growth and indolent tumor biology, their pathogenesis is poorly understood, and progression can be variable. It remains unclear whether these lesions represent dissemination of malignant cells from a single primary tumor (intrapulmonary spread) or synchronous development of multifocal independent clones [3]. In addition, depending on their size and solid component, GGOs can exist anywhere along the histological spectrum from adenomatous hyperplasia (AAH) to invasive adenocarcinoma (AC). Histologic heterogeneity can be reflected in uncertain growth rates, making therapeutic decision making challenging. While historically GGOs have been managed surgically or with close surveillance, chemotherapeutic strategies have been employed. In addition, recent identification of relevant, driver mutations within GGOs has allowed for consideration of targeted therapies including tyrosine kinase inhibitors (TKIs). Given that GGOs frequently represent bronchioloaveolar carcinoma (BAC) (recently reclassified as adenocarcinoma in situ, lepidic predominant adenocarcinoma or mucinous adenocarcinoma), an overview of chemotherapeutic and targeted strategies for such lesions would require extrapolation from the BAC literature. Despite longstanding recognition of BAC as a distinct subclass of lung adenocarcinoma, few completed prospective trials are available to inform on therapy decisions. To date, only two, small phase II prospective studies evaluating cytotoxic chemotherapy for treatment naïve patients with multi-focal BAC have been published. Both trials evaluated single agent paclitaxel and resulted in disappointing response rates (RR) of 11% and 15%, respectively [4, 5]. Post hoc analysis from the sentinel ECOG 1594 study demonstrated a response rate of only 6% to platinum chemotherapy in patients with BAC [6]. In contrast, the French IFCT-0401 trial demonstrated a RR of 21% and PFS of 3 months in 43 patients with BAC who received chemotherapy (platinum doublet; N=38) after disease progression on first line gefitnib[7]. Experience with third-generation agents such as pemetrexed or gemcitabine has been described only in case reports or retrospective series; however, these agents have demonstrated acceptable outcomes and may be considered in systemic treatment plans Subgroup analysis of early studies evaluating the role of EGFR TKIs in NSCLC demonstrated disproportionate and often dramatic responses in those tumors formally classified as BAC. This observation led to several trials exploiting gefitinb or erlotinib as initial therapy for patients with BAC. While overall responses rates in these studies were similar to studies evaluating chemotherapy (RR: 15 to 25%) patients with EGFR mutations derived greater benefit. For example, in a study evaluating erlotinib as initial therapy for patients with advanced BAC, the RR for those with EGFR mutations was 87% compared to 7% for those without EGFR mutations [8]. The association of EGFR mutations with GGOs and the non-mucinous subtype of BAC is supported by multiple studies including a recent comprehensive analysis evaluating genetic alterations in 217 resected GGOs from 215 lung cancer patients[9]. In this study, EGFR mutations were detected in 119 (54.8%). Other relevant driver mutations, including ALK mutations (2.8% in the aforementioned study evaluating resected GGOs) and KRAS mutations in mucinous subtype of AIS, have also been identified. This allows for consideration of other targeted therapies including ALK directed therapies (crizotinib, certinib, alectinib) and those targeting KRAS (selumetinib). Despite the well-established paradigm of offering targeted therapy to molecularly characterized subgroups, the clinical scenarios for patients with multiple GGO’s can be unique in several ways. Should these patients, if confirmed to have EGFR mutations, be treated with TKIs if lesions are slow growing or not growing at all? Or, should the indolent biology of such lesions trump the actionable mutation when making a therapeutic decision? In addition, the notion that a mutation discovered on a biopsied or resected GGOs is representative of all GGOs within a patient may be incorrect. A recent analysis evaluating 72 resected GGO lesions from 35 patients, all with more than one GGO, demonstrated a high rate of mutation discrepancy. In this study, 80% of patients (24/30) who harbored at least one genetic alteration had a driver mutation discrepancy within another GGO supporting the hypothesis that multiple GGOs seem to arise from different primary clones [10]. Given that patients with GGOs represent a spectrum of tumor biology and clinical behavior, an individualized approach that affords flexibility should be employed when implementing treatment strategies (Figure 1). Management decisions need to factor in the potential for indolent disease with consideration of a watch and wait approach for stable or slow growing lesions. If the clinician identifies progressive disease, systemic options should be entertained and include both chemotherapy and TKIs for patients who harbor actionable mutations. Further studies are needed to better define the clonal relationship of GGOs in an effort to optimize targeted approaches for such patients.Figure 1 References: 1. Hansell, D.M., et al., Fleischner Society: glossary of terms for thoracic imaging. Radiology, 2008. 246(3): p. 697-722. 2. Godoy, M.C. and D.P. Naidich, Subsolid pulmonary nodules and the spectrum of peripheral adenocarcinomas of the lung: recommended interim guidelines for assessment and management. Radiology, 2009. 253(3): p. 606-22. 3. Chung, J.H., et al., Epidermal growth factor receptor mutation and pathologic-radiologic correlation between multiple lung nodules with ground-glass opacity differentiates multicentric origin from intrapulmonary spread. J Thorac Oncol, 2009. 4(12): p. 1490-5. 4. West, H.L., et al., Advanced bronchioloalveolar carcinoma: a phase II trial of paclitaxel by 96-hour infusion (SWOG 9714): a Southwest Oncology Group study. Ann Oncol, 2005. 16(7): p. 1076-80. 5. Scagliotti, G.V., et al., A phase II study of paclitaxel in advanced bronchioloalveolar carcinoma (EORTC trial 08956). Lung Cancer, 2005. 50(1): p. 91-6. 6. Schiller, J.H., et al., Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med, 2002. 346(2): p. 92-8. 7. Duruisseaux, M., et al., Chemotherapy effectiveness after first-line gefitinib treatment for advanced lepidic predominant adenocarcinoma (formerly advanced bronchioloalveolar carcinoma): exploratory analysis of the IFCT-0401 trial. J Thorac Oncol, 2012. 7(9): p. 1423-31. 8. Miller, V.A., et al., Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib. J Clin Oncol, 2008. 26(9): p. 1472-8. 9. Ko, S.J., et al., Epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangements in lung cancer with nodular ground-glass opacity. BMC Cancer, 2014. 14: p. 312. 10. Wu, C., et al., High Discrepancy of Driver Mutations in Patients with NSCLC and Synchronous Multiple Lung Ground-Glass Nodules. J Thorac Oncol, 2015. 10(5): p. 778-83.

Abstract:
Definition. Ground glass opacity (GGO) is a finding on thin-section CT that is defined as “hazy increased attenuation of the lung with preservation of bronchial and vascular margins”.[1]This is in contrast to consolidation that is defined as a “homogeneous increase in pulmonary parenchymal attenuation that obscures the margins of vessels and airway walls” (also called ‘solid´ component). Introduction. The resolution of the CT differs few orders of magnitude from the resolution of the microscope. Therefore, GGO is not one disease: pathological examination reveals several different diseases. The radiological GGO change is actually due to a reduction of air, while a certain amount of air remains present. At the microscopic level this may be caused by either i) partial filling of the alveolar airspaces, ii) thickening of the parenchymal interstitium and alveolar walls, iii) relative increase in perfusion, or iv) any combination of these factors.[1,2]Alveolar spaces may become partially filled by several ways, such as transudative fluid, blood, inflammatory cells or debris, or amorphous material as seen in cardiogenic pulmonary edema, diffuse alveolar hemorrhage, pneumonia, and pulmonary alveolar proteinosis. Alveolar walls and septal interstitium may become thickened secondary to edema, neoplastic proliferation, fibrosis, and noncaseating granulomatous deposition as seen in cardiogenic pulmonary edema, nonspecific interstitial pneumonia, and sarcoidosis. Partial alveolar filling and interstitial thickening coexist in many disease entities. Thus GGO is a non-specific finding that may be caused by various disorders, including inflammatory disease, pulmonary fibrosis, alveolar haemorrhage or neoplasms. GGO may be either (multi)focal (=localised GGO) or diffuse (present bilaterally in most of the lobes, nicely reviewed by El-Sherief et al.[1]), usually associated with inflammatory diseases. Localized GGO may be pure associated with a solid component (mixed GGO) or without (pure GGO). Localized GGO may contain benign[3,4](organising pneumonia, non-specific fibrosis, atypical adenomatous hyperplasia: AAH; aspergillosis) premalignant (adenocarcinoma in situ: AIS, formerly also called BAC)[5]and malignant diseases[3]((minimal) invasive adenocarcinoma with prominent lepidic component[4,5]). The clinical significance of localized GGO is its high incidence of malignancy compared with solid nodules. The reported range varies from 10-90%.[6–8] CT-guided thoracic needle biopsy is a useful tool for tissue diagnosis and may support the patient management with GGO lesions.[9]Fluoroscopic or image guidance has been studied as well.[10–12] The core biopsy procedure is preferred over aspiration.[13]As usual with biopsies underestimation/ underdiagnosis due to sampling variation is not excluded.[11,14]As GGO contains many diseases the term “Natural history of GGO” is a misnomer.[15,16] Radiology To distinguish GGOs with growth from those without growth, a 3-year follow-up observation period is a reasonable benchmark based on the data that the volume-doubling time (VDT) of pure GGOs ranges from approximately 600 to 900 days and that of part-solid GGOs ranges from 300 to 450 days.[7,8,17] AAH is often associated with malignancy and is shown on CT as persistent well-defined oval or round nodular GGOs without solid components, and it does not change on the follow-up CT.[18] Clinicoradiological characteristics of a benign course are smaller size (< 10 mm.), round/oval shape, lack of consolidation[18,19]or scattered consolidation.[20] Clinicoradiological characteristics of a progressive course are smoking history[21]and initial lesion diameter (> 1 cm) [5,19,22,23], lobulated or speculated margin,[4]growth[16], increase in attenuation,[24]greater irregularity of pixel texture (entropy).[5]Growth of localised GGO may be slow: for one case progression was reported within 10 years.[25] Biomarkers EGFR mutations may be present in pure and mixed GGO lesions, representing preinvasive and invasive cancer.[26–28]Interestingly, for p53 immunohistochemistry positive staining was seen in a small group (n=6) associated with growth or a solid component.[26]MIB1 (ki67) is higher in mixed GGO than in pure GGO.[29]CEA not relevant for the distinction of the progressive GGO.[30] Remarkably, with laborious cytogenetic analysis spontaneous metaphases appeared after 24-48 h. in 9 cases of pure GGO. Abnormal FISH was associated with poor outcome.[15] In case of multiple GGO synchronous BAC and/or ADC can have different EGFR or K-ras mutational profiles suggesting these lesions arise as independent events rather than intrapulmonary spread or systemic metastasis.[31] Management Surgical handling is hampered since AAH not or much less well easy palpable than AIS.[30] Since GGO may contain only AIS or minimal invasive adenocarcinoma partial resection may be the method of choice.[30]and systematic lymph node dissection may be avoided.[32] For multiple localized GGO wait and see is an option[33] Prognosis of mixed GGO invasive adenocarcinomas better for solid size than size including the GGO.[34,35]A larger solid component is worse than less solid component.[36] References 1. El-Sherief, A. H. et al. Clear Vision Through the Haze: A Practical Approach to Ground-Glass Opacity. Curr. Probl. Diagn. Radiol. 43, 140–158 (2014). 2. Hewitt, M. G., Miller, W. T., Reilly, T. J. & Simpson, S. The relative frequencies of causes of widespread ground-glass opacity: A retrospective cohort. Eur. J. Radiol. 83, 1970–1976 (2014). 3. Lee, H. J. et al. Nodular ground-glass opacities on thin-section CT: size change during follow-up and pathological results. Korean J. Radiol. 8, 22–31 4. Kim, H. Y. et al. Persistent Pulmonary Nodular Ground-Glass Opacity at Thin-Section CT: Histopathologic Comparisons 1. Radiology 245, 267–275 (2007). 5. Son, J. Y. et al. Quantitative CT Analysis of Pulmonary Ground-Glass Opacity Nodules for the Distinction of Invasive Adenocarcinoma from Pre-Invasive or Minimally Invasive Adenocarcinoma. PLoS One 9, e104066 (2014). 6. Ichinose, J. et al. Invasiveness and malignant potential of pulmonary lesions presenting as pure ground-glass opacities. Ann. Thorac. Cardiovasc. Surg. 20, 347–52 (2014). 7. Lee, H. Y. & Lee, K. S. Ground-glass Opacity Nodules. J. Thorac. Imaging 26, 106–118 (2011). 8. Kobayashi, Y. & Mitsudomi, T. Management of ground-glass opacities : should all pulmonary lesions with ground-glass opacity be surgically resected ? 2, 354–363 (2013). 9. Yang, J.-S. et al. Meta-analysis of CT-guided transthoracic needle biopsy for the evaluation of the ground-glass opacity pulmonary lesions. Br. J. Radiol. 87, 20140276 (2014). 10. Hur, J. et al. Diagnostic Accuracy of CT Fluoroscopy–Guided Needle Aspiration Biopsy of Ground-Glass Opacity Pulmonary Lesions. Am. J. Roentgenol. 192, 629–634 (2009). 11. Yamagami, T. et al. Diagnostic performance of percutaneous lung biopsy using automated biopsy needles under CT-fluoroscopic guidance for ground-glass opacity lesions. Br. J. Radiol. 86, 20120447 (2013). 12. Chavez, C. et al. Image-guided bronchoscopy for histopathologic diagnosis of pure ground glass opacity: a case report. J. Thorac. Dis. 6, E81–4 (2014). 13. Choi, S. H. et al. Percutaneous CT-guided aspiration and core biopsy of pulmonary nodules smaller than 1 cm: analysis of outcomes of 305 procedures from a tertiary referral center. AJR. Am. J. Roentgenol. 201, 964–70 (2013). 14. Lu, C.-H. et al. Percutaneous Computed Tomography-Guided Coaxial Core Biopsy for Small Pulmonary Lesions with Ground-Glass Attenuation. J. Thorac. Oncol. 7, 143–150 (2012). 15. Bettio, D., Venci, A., Cariboni, U., Di Rocco, M. & Infante, M. Fluorescent in situ hybridization (FISH) in the differential diagnosis of ground-glass opacities in the lung. Lung Cancer 71, 319–322 (2011). 16. Chang, B. et al. Natural History of Pure Ground-Glass Opacity Lung Nodules Detected by Low-Dose CT Scan. CHEST J. 143, 172 (2013). 17. Oda, S. et al. Volume-Doubling Time of Pulmonary Nodules with Ground Glass Opacity at Multidetector CT. Acad. Radiol. 18, 63–69 (2011). 18. Park, C. M. et al. CT findings of atypical adenomatous hyperplasia in the lung. Korean J. Radiol. 7, 80–6 19. Lee, S. M. et al. Invasive Pulmonary Adenocarcinomas versus Preinvasive Lesions Appearing as Ground-Glass Nodules: Differentiation by Using CT Features. Radiology 268, 265–273 (2013). 20. Matsunaga, T. et al. Lung cancer with scattered consolidation: detection of new independent radiological category of peripheral lung cancer on thin-section computed tomography. Interact. Cardiovasc. Thorac. Surg. 16, 445–449 (2012). 21. Kobayashi, Y. et al. The association between baseline clinical-radiological characteristics and growth of pulmonary nodules with ground-glass opacity. Lung Cancer 83, 61–66 (2014). 22. Kitami, A. et al. One-dimensional mean computed tomography value evaluation of ground-glass opacity on high-resolution images. Gen. Thorac. Cardiovasc. Surg. 60, 425–430 (2012). 23. Fan, L., Liu, S. Y., Li, Q. C., Yu, H. & Xiao, X. S. Multidetector CT features of pulmonary focal ground-glass opacity: Differences between benign and malignant. Br. J. Radiol. 85, 897–904 (2012). 24. Eguchi, T. et al. Tumor Size and Computed Tomography Attenuation of Pulmonary Pure Ground-Glass Nodules Are Useful for Predicting Pathological Invasiveness. PLoS One 9, e97867 (2014). 25. Min, J. H. et al. Stepwise evolution from a focal pure pulmonary ground-glass opacity nodule into an invasive lung adenocarcinoma: An observation for more than 10 years. Lung Cancer 69, 123–126 (2010). 26. Aoki, T. et al. Adenocarcinomas with Predominant Ground-Glass Opacity: Correlation of Morphology and Molecular Biomarkers. Radiology 264, 590–596 (2012). 27. Usuda, K. et al. Relationships between EGFR mutation status of lung cancer and preoperative factors - are they predictive? Asian Pac. J. Cancer Prev. 15, 657–62 (2014). 28. Yoshida, Y. et al. Molecular Markers and Changes of Computed Tomography Appearance in Lung Adenocarcinoma with Ground-glass Opacity. Jpn. J. Clin. Oncol. 37, 907–912 (2007). 29. Ohta, Y. et al. Pathologic and Biological Assessment of Lung Tumors Showing Ground-Glass Opacity. Ann. Thorac. Surg. 81, 1194–1197 (2006). 30. OHTSUKA, T., WATANABE, K., KAJI, M., NARUKE, T. & SUEMASU, K. A clinicopathological study of resected pulmonary nodules with focal pure ground-glass opacity. Eur. J. Cardio-Thoracic Surg. 30, 160–163 (2006). 31. Chung, J.-H. et al. Epidermal Growth Factor Receptor Mutation and Pathologic-Radiologic Correlation Between Multiple Lung Nodules with Ground-Glass Opacity Differentiates Multicentric Origin from Intrapulmonary Spread. J. Thorac. Oncol. 4, 1490–1495 (2009). 32. Ye, B. et al. Factors that predict lymph node status in clinical stage T1aN0M0 lung adenocarcinomas. World J. Surg. Oncol. 12, 42 (2014). 33. Kim, H. K. et al. Management of Multiple Pure Ground-Glass Opacity Lesions in Patients with Bronchioloalveolar Carcinoma. J. Thorac. Oncol. 5, 206–210 (2010). 34. Nakamura, S. et al. Prognostic impact of tumor size eliminating the ground glass opacity component: modified clinical T descriptors of the tumor, node, metastasis classification of lung cancer. J. Thorac. Oncol. 8, 1551–7 (2013). 35. Tsutani, Y. et al. Prognostic significance of using solid versus whole tumor size on high-resolution computed tomography for predicting pathologic malignant grade of tumors in clinical stage IA lung adenocarcinoma: A multicenter study. J. Thorac. Cardiovasc. Surg. 143, 607–612 (2012). 36. Shimada, Y. et al. Survival of a surgical series of lung cancer patients with synchronous multiple ground-glass opacities, and the management of their residual lesions. Lung Cancer 88, 174–180 (2015).

Abstract not provided

Abstract:
In EGFR-mutant lung cancer, acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) develops after a median of 9-14 months. The T790M gatekeeper mutation is the most common mechanism of TKI resistance, detected in >50% of tissue biopsies done after the advent of resistance. The recent clinical development of third-generation, irreversible EGFR TKIs that have preliminarily demonstrated durable tumor responses in patients who have developed the EGFR T790M mutation has generated a need for novel methods of T790M detection. Repeating tumor biopsies at the time of acquired resistance to help select second-line therapies is recommended in the NCCN guidelines. However, tissue biopsies do not always supply sufficient material for current sequencing strategies and thus may require multiple invasive procedures for adequate genotyping. Blood-based methods are more readily repeated when necessary and avoid the risks and discomfort of invasive tissue biopsies. As there may be heterogenous mechanisms of acquired resistance, a tissue biopsy of a single site of disease also may not capture the full spectrum of resistance. Blood-based methods theoretically have the potential of more comprehensively illustrating the principal mechanisms of resistance within a patient. Although there are multiple non-invasive sources of tumor-derived genetic material, circulating tumor cells (CTCs) and plasma circulating tumor DNA (ctDNA) are two that have received particular attention for blood-based genotyping. CTCs are cells shed into the bloodstream from primary and metastatic tumors that can be captured through multiple microfluidic platforms. Despite their rarity in the blood there is ongoing development of increasingly sensitive methods of CTC isolation. ctDNA is also shed into the bloodstream from tumor deposits. While more abundant than CTCs, ctDNA analysis is complicated by a high background of plasma DNA shed from normal cells. Techniques for genotyping from these blood-based sources of tumor-derived genetic material have proliferated rapidly, but there have been few studies directly comparing them. In this presentation, I will describe an exploratory study comparing T790M genotyping, using either CTCs or ctDNA versus concurrent tumor biopsies in patients with non-small cell lung cancer progressing on first line EGFR inhibitors.

Abstract:
Blood-based proteomics strategies for the early detection of lung cancer. Since the advent of the new proteomics era, large-scale studies of protein profiling have been exploited to identify the distinctive molecular signatures in a wide array of biological systems spanning areas of basic biological research, various disease states, and biomarker discovery directed toward diagnostic and therapeutic applications. Recent advances in protein separation and identification techniques have significantly improved proteomics approaches, leading to enhancement of the depth and breadth of proteome coverage. Proteomic signatures specific for invasive lung cancer and preinvasive lesions have begun to emerge. In this presentation, we will provide a critical assessment of the state of recent advances in proteomic approaches to the discovery and validation of blood based biomarker signatures for the early detection of lung cancer. Mass spectrometry and immuno-based detection methods will be reviewed including commercially available blood tests to aid the early detection of lung cancer. Much of this progress was driven by increasing knowledge of tumor-related aberrations that affect nucleic acids at genomic, transcriptional, and posttranscriptional levels. Proteins are the functional end product of genes that ultimately control vital biological processes via their expression level and posttranslational modifications. Moreover, the number of proteins produced by cells far exceeds the number of genes because proteins vary in their stability compared with mRNA and are subjected to many levels of posttranscriptional and posttranslational regulations, such as splicing variants, fusions, and posttranslational modifications. Therefore, to advance our understanding of the biology of lung cancer and to obtain a more integrated view of the disease biology, it is critical to capture the full spectrum of the variations in protein expression patterns, their posttranslational modifications, and their functions in cancer cells. Thus, we hope to take advantage of the molecular complexity of the proteome to improve early detection strategies for lung cancer. Proteomic analysis of blood represents an appealing choice to researchers addressing the discovery of biomarkers because it can be quickly and easily obtained noninvasively in large quantities over time. Several recent studies have investigated the extent to which proteomic technologies can unravel the complexity of the plasma proteome. In this regard, the Human Proteome Organization completed a comprehensive collaborative study to characterize the human serum and plasma proteomes. The rapid proteomic profiling of blood in particular has generated great enthusiasm but has been minimally successful at providing robust signatures to translate to the clinic. The major preanalytical challenges are related to the lack of standardized sample collection and preparation techniques, leading to the introduction of analytical bias and the lack of reproducibility. The extreme complexity of biofluids, such as blood, serum, or plasma, and the low abundance of most of the specific protein markers are among other factors that reduce the sensitivity of detection by proteomic technologies. After the discovery of new biomarkers, the next critical steps are to validate and evaluate their performance in clinically relevant patient populations. Multiple levels of validation have to take place before confirming the clinical utility of the biomarker. This includes confirmation of detected changes in protein level by different techniques and correlation with biological outcomes of lung cancer such as early detection, chemosensitivity, or survival. These phases of clinical validation will evaluate a biomarker's performance in relevant clinical context and how it may affect clinical management of risk or disease. Selected readings: 1. Zeng GQ, Zhang PF, Deng X, Yu FL, Li C, Xu Y, Yi H, Li MY, Hu R, Zuo JH, et al. Identification of candidate biomarkers for early detection of human lung squamous cell cancer by quantitative proteomics. Molecular & cellular proteomics : MCP. 2012;11(6):M111 013946. 2. Massion PP, and Walker RC. Indeterminate pulmonary nodules: risk for having or for developing lung cancer? Cancer Prev Res (Phila). 2014;7(12):1173-8. 3. Hassanein M, Callison JC, Callaway-Lane C, Aldrich MC, Grogan EL, and Massion PP. The state of molecular biomarkers for the early detection of lung cancer. Cancer Prev Res (Phila). 2012;5(8):992-1006. 4. Kikuchi T, Hassanein M, Amann JM, Liu Q, Slebos RJ, Rahman SM, Kaufman JM, Zhang X, Hoeksema MD, Harris BK, et al. In-depth proteomic analysis of nonsmall cell lung cancer to discover molecular targets and candidate biomarkers. Molecular & cellular proteomics : MCP. 2012;11(10):916-32. 5. Skates SJ, Gillette MA, LaBaer J, Carr SA, Anderson L, Liebler DC, Ransohoff D, Rifai N, Kondratovich M, Tezak Z, et al. Statistical design for biospecimen cohort size in proteomics-based biomarker discovery and verification studies. Journal of proteome research. 2013;12(12):5383-94. 6. Zhang B, Wang J, Wang X, Zhu J, Liu Q, Shi Z, Chambers MC, Zimmerman LJ, Shaddox KF, Kim S, et al. Proteogenomic characterization of human colon and rectal cancer. Nature. 2014;513(7518):382-7. 7. Neal JW, Gainor JF, and Shaw AT. Developing biomarker-specific end points in lung cancer clinical trials. Nature reviews Clinical oncology. 2015;12(3):135-46.

Abstract not provided