Virtual Library

Background:
The cholinergic anti-inflammatory signaling pathway allows the autonomic nervous system to modulate immunologic stimuli and inflammatory processes. α7 nicotinic acetylcholine receptor (α7-nAChR) is a major component in this pathway. GTS-21, a selective α7 nicotinic acetylcholine receptor agonist, has been demonstrated as a promising treatment for inflammation. So, the aim of this study is to determine whether treatment GTS-21 can mitigate the radiation induced lung injury.

Methods:
C57BL/6 mice were randomly divided into three groups: a control group, a 12 Gy thoracic irradiation group, a 12 Gy thoracic irradiation group treated with 4mg/kg GTS-21 immediately after irradiation. Each of group were sacrificed at 1,3,7,14,21d and 3m, 6m post-irradiation, and the sections were respectively stained with hematoxylin and eosin (HE) and Masson’s trichrome to assess the degree of inflammation and fibrosis. Serum concentrations of TNF-α, IL-1β and IL-6 were quantitatively measured by Cytometric Bead Array (CBA) kit. Real-time PCR and Western blot were used to detect the mRNA and protein levels of HMGB1, TLR-4, NF-κB, MyD88 and TGF-β in lung tissue from GTS-21 group and irradiation control group at different time after radiation.

Results:
The result from HE and Masson staining showed that GTS-21 could dramatically reduce radiation-induced lung inflammation and following mitigate lung fibrosis. Then, we found that radiation-induced TNF-α, IL-1β and IL-6 in serum were also inhibited by GTS-21. Comparing to the control group, the mRNA levels of HMGB1,TLR-4 and NF-κB were decreased at the early time of radiation pneumonitis, and the most significant difference was observed at 21d post-irradiation(P<0.05). the mRNA levels of TGF-β was decrease in GTS-21group at 3m and 6m post -irradiation when compared to control (P<0.05). However, there did not have any different on MyD88 between GTS-21and control groups. The result from western blot showed that the protein levels of HMGB1, TLR-4 and NF-κB in GTS-21 group were also significantly decreased at 21d after radiation. After 3m and 6m from radiation, the protein level of TGF-β was decreased dramatically at GTS-21 group.

Conclusion:
GTS-21 can reduce radiation pneumonitis and fibrosis by inhibiting HMGB1/TLR-4/NF-κB pathway which subsequently decrease TGF-β expression.

Background:
Radiotherapy is one of the major treatment methods for patients with non-small cell lung cancer (NSCLC). However the presence of radio-resistant cancer stem cells (CSC) may attribute to the relapse or poor outcome of radiotherapy. We previously identified calcium channel α2δ1 subunit (CACNA2D1) isoform 5 as a marker for CSC in hepatocellular carcinoma. This study aimed to investigate the radio-sensitivity of CACNA2D1+ cells in NSCLC cell lines.

Methods:
NSCLC cell lines A549, H1975 and PC9 were used. CACNA2D1-knockdown or overexpression cell lines were established by lentivirus infection. The proportion of CACNA2D1+ cells before and after radiation was analyzed by flow cytometry. Colony formation assay was performed to determine the radiosensitivity. Sphere formation assay in serum-free medium was performed to evaluate the self-renewal capacity. γH2AX foci were analyzed by immunofluorescence. The monoclonal antibody of CACNA2D1 was applied alone or combined with radiation to CACNA2D1+ cells and colony formation and sphere formation assays were performed to determine its effect on CACNA2D1+ cells.

Results:
CACNA2D1+ cells had higher sphere-forming efficiency, and were resistant to radiation compared with CACNA2D1- cells. In unsorted cells the CACNA2D1+ percentage was enhanced after radiation. These data suggest CACNA2D1+ NSCLC cells are relatively radio-resistant. Knockdown of CACNA2D1 in CACNA2D1-high A549 enhanced radiosensitivity, while overexpression of CACNA2D1 in CACNA2D1-low PC9 and H1975 reduced radiosensitivity, suggesting CACNA2D1 converts the radio-resistance. The number of γH2AX foci increased after radiation, and decreased more rapidly in CACNA2D1-overexpression cells than control group. Moreover, in CACNA2D1-overexpression cells, the baseline phosphorylation level of CHK2 and ATM was higher than control group, and were more activated after radiation, suggesting CACNA2D1 overexpression resulted in an increase in the DNA damage repair capacity. The monoclonal antibody of CACNA2D1 had a synergetic effect with radiation to block self-renewal of CACNA2D1+ A549 cells. The antibody also enhanced radiosensitivity in CACNA2D1+ cells in colony formation assay.

Conclusion:
CACNA2D1 marks radio-resistant cancer stem-like cells in NSCLC. CACNA2D1 converts resistance to radiation, partially by enhancing the DNA damage repair efficiency. The monoclonal antibody of CANCA2D1 enhances the radio-sensitivity of CACNA2D1+ cells, suggesting its potential to improve the treatment outcome when combined with radiation on NSCLC.

Background:
Hyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway has been associated with radioresistance. It is unclear whether such mutations also confer suboptimal local control for patients who receive lung stereotactic body radiation therapy (SBRT). Our objective was to examine whether mutations in the EGFR/AKT/PIK3CA signaling pathway are associated with local failure (LF) after lung SBRT.

Methods:
We retrospectively reviewed 134 patients who underwent SBRT to primary or metastatic lung lesions from 2007-2015 for whom molecular testing data was available for EGFR, AKT, and PIK3CA genes. For tumors of lung origin (n=122), molecular testing data was included from the lung tumor. For metastatic tumors to the lung (n=12), molecular testing data from either a primary or metastatic tumor site was used. Association between clinical factors, including molecular mutation status, and LF was evaluated with Cox regression analysis. The Kaplan-Meier method was used to assess differences in LF rates based on PIK3CA mutation status.

Results:
The most common histology was adenocarcinoma (90%) among all tumors. Six patients (4%) had PIK3CA mutation, 31 patients (23%) had EGFR mutation, and one patient (0.7%) had AKT mutation. Median lesion size was 2.0 cm (range, 0.6–5.6 cm), median dose was 48 Gy (range 30–70 Gy), and median number of fractions was 4 (range, 3–10). Median follow-up was 20 months (range, 0.2–70 months). LF was observed for 16 patients (12%). Median time to local failure was 15 months (range, 7–31 months). On univariate analysis, PIK3CA mutation presence was associated with LF (HR 5.3 [95% CI 1.1-25.0], p=0.03), while tumor histology (adenocarcinoma vs. other), tumor size (≤2cm vs. >2cm), primary tumor site (lung vs. other), and EGFR or AKT mutation presence were not. By multivariate analysis, PIK3CA mutation trended toward association with LF (HR 5.0 [95% CI 1.0-25.3], p=0.051). At one year, probability of LF in lesions with PIK3CA mutations was 12.4% vs. 5.7% in lesions without mutations (p=0.02). Lesions with PIK3CA mutations were associated with a decreased time to LF (mean 17.9 months [95% CI 12.7–23.2 months]) compared to those without PIK3CA mutation (mean 58.6 months [95% CI 52.6–64.7 months]).

Conclusion:
We explored EGFR/AKT/PI3KCA pathway mutations and found that patients with PIK3CA mutations are at higher risk for LF after lung SBRT. Due to the limitation of small numbers, this data needs to be validated in a larger patient cohort. Nonetheless, this is a novel finding and hypothesis-generating for future studies.

Background:
Radiotherapy is one of the main treatment modalities of lung cancer, but its effectiveness is often hampered because of dose dependent radiation toxicity. Aberration of apoptotic pathway after irradiation is another mechanism attenuating therapeutic effect of radiation. ABT-737, a ‘first-in-class’ of BH3 mimetics, disrupts the BCL-2/BAK complex and initiates BAK-dependent intrinsic apoptotic pathway. In this study, we sought that ABT-737 is able to maximize the therapeutic effects of radiation in experimental animal models.

Methods:
Kras:p53[fl/fl] double mutant mice were obtained by genotyping of offspring from LSL Kras G12D and p53[fl/fl ]mouse. Lung cancer was induced by inhalation of 5 X 10[7] PFU AdCre viral particles at 8 weeks age. After 12 (± 2) weeks of inhalation, the mice were randomized and treated with either vehicle or ABT-737 (50 mg/kg, i.p., daily) for 3 days. Then mice underwent microCT and were irradiated in the left lung at a dose of 20 Gy using X-rad 320. In 2 weeks, 2[nd] round microCT was performed and lungs were harvested for histological analysis.

Results:
When the changes in the expression of pro-apoptotic and anti-apoptotic molecules after 20 Gy of irradiation were evaluated by immunoblotting, the decrease of BCL2-like 11 (BCL2L11) was most prominent in the irradiated lung. The tumor area was decreased in the irradiated lung of both vehicle and ABT-737 pretreated mice and inhibitory effect was remarkable when the mice were pretreated with ABT-737. Disputed tumor structure with apoptotic bodies were most frequently observed in the irradiated lung of ABT-737 pretreated mice. To quantify the apoptotic effect of this combination, immunohistochemical analysis against activated caspase-3 was performed. Counts of activated caspase-3 were significantly higher in the irradiated lung with ABT-737 pretreatment, suggesting ABT-737 possesses radiosensitizing property.

Conclusion:
Decrease of BCL2L11 expression in the irradiated lung is one of prominent findings, which might compromise therapeutic effect of radiation. Pretreatment of ABT-737 enhanced anti-tumor effect of ionizing radiation in Kras:p53[fl/fl] lung cancer model, suggesting BH3 mimetics would be a good candidate of radiosensitizer in lung cancer. Further studies are warranted for identification of optimal dosing and schedule of this combination treatment.

Background:
EGFR T790M mutation accounts for more than 50% of acquired resistance to TKI. In pre-clinical, EGFR-TKI resistant cells with T790M exhibited enhanced sensitivity to radiation, suggesting the potential of radiotherapy in reduction and delay of T790M-mediated EGFR TKI resistance.

Methods:
Under different radiotherapy dose and times, we use droplet digital PCR to observe the emerging time of T790M and its proportion during chronic exposure to gefitinib in TKI-sensitivity cell lines, and to evaluate the anti-tumor effect of early radiation combined with gefitinib in xenograft model with different proportion of T790M. Furthermore, we performed miRNA microarray to screen miRNAs differentially expressed in the paired NSCLC gefitinib-sensitivity cell lines and gefitinib resistant cell lines and find potential molecular markers of T790M mutation.

Results:
Our data showed radiation combined with gefitinib delayed the occurrence of EGFR T790M mutation compared to gefitinib alone in T790M wildtype (TKI-sensitive) cell line and it also reduced the T790M mutation abundance in de novo T790M mutation (TKI-resistant) cell line. The phenomena was also confirm in mice xenograft model. In addition, our results showed TKI-resistant (induced T790M mutation) cells had higher radiosensitivity than TKI-sensitive cells. miRNA array showed miR-1275 was the one of the most significantly elevated miRNAs in TKI-resistant cells. Knockdown of miRNA-1275 significantly decreased the radiosensitivity of TKI-resistant cells. Western blot showed knockdown of miR-1275 affected proteins relating to cell proliferation and apoptosis. Bioinformatics showed SPOCK1 might be one of the targets of miRNA-1275.

Conclusion:
Our results contribute to understand molecular mechanisms of T790M-mediated EGFR-TKI resistance, but also provide a new therapeutic strategy for patients in advanced NSCLC to aid expansion of the effectiveness of TKI treatment through radiotherapy.

Background:
The factors affecting survival were evaluated in patients aged ≥ 70 years with non-small cell lung cancer (NSCLC) treated with definitive radiotherapy (RT).

Methods:
Between January 1996 and April 2012, 52 patients were treated. The median age was 73 (range: 70-80), 73% and 75% of patients with stage III according to AJCC 2002 and 2010, respectively. Radiotherapy was performed median 6160 cGy (range: 3600-6660) and chemotherapy (CHE) were given 75% of the patients as neoadjuvant, concurrent or adjuvant. Statistical analysis were calculated with Kaplan-Meier and Cox regression methods.

Results:
Median follow-up was 12.5 months (range: 2.5-103). Median overall (OS), disease-free (DFS) and locoregional-progression-free (LRPFS) survival were 22 (95% CI 12-31), 18.5 (95% CI 7-29) and 25 months (95% CI 15-34), respectively. Two-year OS, DFS and LRPFS rates were 50%, 47% and 52%, respectively. Acute ≥ Grade 3 esophagitis and neutropenia were seen 6% and 10% of patients. Whereas the mortality associated with CHE were seen of 5 (10%) patients, RT-related death was not observed. In univariate analysis; AJCC 2002 stage I-II (72.5 vs 20 months, p = 0.05), RT dose ≥ 60 Gy (27.5 vs 12.5 months, p = 0.01), RT duration >49 days (31 vs 11 months, p <0.001) for OS and RT dose ≥ 60 Gy (25 vs 11 months, p= 0.02), RT duration >49 days (26.5 vs 10.5 months, p <0.001) neoadjuvant CHE ≤ 3 cycles (mean 58 vs 19 months, p = 0.03), complete response (72.5 vs 18.5 months, p = 0.03), ≥ 4 cycles of CHE (25 vs 11 months, p = 0.05) for DFS were significant. In multivariate analysis, RT duration > 49 days were found a positive impact on OS (HR: 3.235, 95% CI: 1:25 to 8:32 p = 0.01).

Conclusion:
Definitive and pallliative RT plays an important role in elderly lung cancer patients have multiple co-morbidities with limited treatment options. In our study, elderly patients with NCSLC can be given ≥ 60 Gy without complications and was seen positively impact on survival.

Background:
Recently, excellent results of stereotactic body radiotherapy (SBRT), proton beam therapy (PBT) for stage I non-small-cell lung cancer (NSCLC) have been reported, however any phase III trial comparing SBRT and surgery have not been completed yet. The aim of this study is to compare outcomes between SBRT, PBT and wedge resection (WR) for patients with peripheral stage I NSCLC who intolerable for anatomical resection, and analyze prognostic factors in this population.

Methods:
We retrospectively compared overall survival (OS), local recurrence rate (LRR), relapse-free survival (RFS) and cause-specific survival (CSS) between WR (n=172) and SBRT / PBT (n=188) for pathologically proven clinical stage I NSCLC in our institute from 2002 to 2015. Patients underwent WR were all high risk patients who intolerable for anatomical resection and achieved complete resection without any adjuvant therapy. Of radiation group (RT: SBRT+PBT), 56% was medically inoperable, with 44% refusing surgery. SBRT; 60 Gy in 8 fractions, PBT; 60-80 GyE in 10-20 fractions was prescribed. Propensity score matching was used to adjust the confounding effects in estimating treatment hazard ratios. 59 WR patients and 59 radiotherapy (RT) patients (SBRT 27, PBT 32) were matched blinded to outcome (1:1 ratio). There are 70 men and 48 women, median age was 81, and median follow-up period was 39 months.

Results:
3, 5 - year overall survival (OS) of WR and RT was 84.5%, 70.8% vs 89.7%, 59.6% (p=0.802), respectively. 3-year LRR, RFS, CSS were 94.7% vs 95.9% (p=0.751), 87.5% vs 75.6% (p=0.151) and 91.2% vs 93.9% (p=0.875), respectively. Multivariate analysis of prognostic factors for OS demonstrated any factors including treatment modality were not significant.

Conclusion:
Our results suggest that the treatment outcome of SBRT / PBT was equivalent to that of WR, SBRT / PBT may be alternative treatment in stage I NSCLC high risk patients.

Background:
Metastasis from “radioresistant” histologies are commonly regarded as less responsive to SBRT. Almost no data are available in Literature to evaluate the impact of these histologies on the outcome of patients with lung metastases treated with Stereotactic Body Radiation Therapy (SBRT). Therefore, we conducted this analysis on patients with lung metastases from renal cell carcinoma, hepatocellular carcinoma, adenoid cystic carcinoma and melanoma treated with SBRT in our Institution.

Methods:
Oligometastatic patients with lung metastases from renal cell carcinoma, hepatocellular carcinoma, adenoid cystic carcinoma and melanoma who received SBRT and with a discrete follow up time were included in this analysis. Kaplan Meyer analysis was used to calculate Overall Survival, Progression Free Survival, Local Control. Crude rates were used to calculate the response and distant failure rates. Toxicity was scored according to CTCAE v. 4.03

Results:
Sixty patients were included in the study. Most common primary histologies were renal cell carcinoma and hepatocellular carcinoma. Most of patients had 1 or 2 metastatic sites. Half patents did not receive any systemic therapy during their history before SBRT. Different RT doses and number of fractions were utilized according to site, number and volume of lung metastases, 48 Gy in 4 fractions was the most commonly prescribed schedule. The best local responses obtained were complete response in 13 patients (21.7%), partial response in 28 patients (46.7%) and stable disease in 14 patients (23.3%). Five patients (8.3%) had a local progression. With a median follow up of 24.3 months (range 4.1-118.6 months), local control was 93.7% and 86.1% at 1 and 2 years respectively. OS and PFS at 1 and 2 year were 89.5%, 64.6%, 87.7% and 70.1%, respectively. None of the analyzed parameters showed a statistically significant impact on any outcome. Treatment was well tolerated. None but one patients experienced acute toxicity of any grade. During follow up in 10 cases G1-2 toxicity (mostly pneumonia) were recorded.

Conclusion:
SBRT for lung metastases is an effective treatment for oligometastatic patients with lung metastases from “radioresistant” histologies. The treatment is safe and well tolerated and the outcomes are equivalent to the results obtainable with SBRT for lung metastases from more favourable histologies.

Background:
Concurrent chemoradiation therapy (CRT) is standard for stage III non-small cell lung cancer (NSCLC). In our institute, patients undergo surgery after CRT if possible. We aimed to assess the efficacy and adverse event of CRT in patients with stage III NSCLC and investigate the risk of radiation pneumonitis (RP).

Methods:
Two hundred fifty seven patients received CRT for newly diagnosed stage III NSCLC from 2003 to 2013. Patient characteristics were as follows: 87.2 % male; median age, 67 years; 55.6 % stage IIIA; and 44.4 % IIIB. CRT was prescribed, with 40Gy to the primary tumor and mediastinum and a boost of 20Gy to all gross disease. All patients also received platinum based doublet regimen concurrently. After CRT, the patients were re-evaluated in the resectability and underwent surgery. We analyzed tumor volume reduction ratio near the end of radiation therapy. All patients were classified by their lung condition about emphysematous and interstitial changes with CT images before treatment into three degree (slight / moderate / severe). Patients with grade 2 or worse RP were ebaluated with their Dose-Volume Histofram(DVH) parameteres of both lungs.

Results:
The median follow up time was 73.9 months. The 3-year and 5-year overall survival rates were 44.8 % and 33.0 % in all patients, and 74.7 % and 64.7 % in patients with CRT followed by surgery. The 3-year and 5-year local control rates were 68.8 % and 49.0 %, respectively, in all patients. More than 50 % volume reduction was observed in 73.2 % of patients surviving over 2-years, but 32.3 % of these good responder had local failure. Grade 2 or worse RP were observed in 70 patients (27 %), grade3 in 11 patients (4 %), grade 5 in 3 patients (1 %). The median of V5Gy, V10Gy, V20Gy, V40Gy, and mean dose of group with grade 2 or worse RP were 32.1, 27.5, 22.5, 16.5 %, and 13.5Gy, respectively, and with grade 3 to 5 RP were 31.5, 27.9, 23.9, 19.0 %, and 12.8Gy, respectively. In patients with grade 3 to 5 RP, 8 of 14 patients had severe emphysematous lung and moderate or severe interstitial change, or had over 30 % lung V20Gy.

Conclusion:
CRT for stage III NSCLC was effective with acceptable toxicities. Even though patients had good early response to CRT, local control was not sufficient. Grade 3 or worse RP may relate not only to DVH parameters, but also pulmonary complication before CRT.

Background:
To evaluate SBRT for primary and metastatic lung tumors in elderly patients.

Methods:
Retrospective analysis of technique and results of SBRT for lung tumors in patients over 75 years old treated in a single institution. Simulation was made with CT, abdominal compression and stereotactic frame. Internal target volume (ITV) was covered according ICRU recommendations. Treatment delivery using planar or noncoplanar fields or VMAT-IMRT dynamic arc. The prescribed dose was either 3 fractions of 15 Gy each or a single 30 Gy fraction. Planar images or cone beam CT were used for verification. Toxicity and radiologic response were assessed using standardized criteria (RTOG and RECIST). Survival rates and toxicities were calculated by the Kaplan-Meier method.

Results:
Between 2002 and 2015, 86 patients had 103 SBRT procedures; of those 66 were for primary lung tumors (T1-2N0M0) and to 37 oligometastases (M1). Median patient age was 80 years (75-88). At the treatment all patients had good performance status (ECOG PS 0-1). The FEV1 was over 30 % of predicted. 10 % of the primary and 67 % of the M1 received systemic treatment before SBRT. 73 % of the patients had 18-FDG PET-CT previous to SBRT. Primary tumors histology included: 48 % epidermoid, 14 % adenocarcinoma, 19 % undifferentiated, 4 % neuroendocrine and 15 % PET positive tumors without histology. In lung M1 patients the origin was in: 53 % NSCLC, 24% colorectal adenocarcinoma, 8.5% urotelial tumors, 8.5% thyroid, 3% endometrial and 3% parotid. Median ITV was 11.6 cm3 (0.9-143). Biological Equivalent Dose BED>100Gy. Transient grade 1 or 2 acute toxicities (cutaneous erythema, esophagitis, rib pain or respiratory symptoms) occurred in 11 %. No grade > 3 acute or any chronic toxicities were identified. Median follow-up 22 months (4-65). Overall survival is 79.4 % at 1 year (78.7 % primary; 81 % M1) and 74.2 % at 2 years (65.9 % primary; 84.6 % M1). Global cancer-specific survival rates were: 80.5 % (78.8 % primary and 84.6 % M1). Local control in the irradiated volume is 97.2% in primary and 100 % in M1 tumors, the only failure was marginal/proximal, in a patient with neuroendocrine histology, rescued with second time SBRT.

Conclusion:
SBRT is an excellent treatment option for lung tumors and metastasis in elderly patients in whom other treatment options might be limited. Our encouraging results are similar or better than those reported for younger patients.

Background:
To investigate the current status of radiotherapy (RT) trends in the definitive treatment of lung cancer in Turkey.

Methods:
A questionnaire consisting of 46 questions about the technical facilities, and indications regarding the definitive radiotherapy of lung cancer was sent to 62 centers in Turkey, and was answered by 47 centers.

Results:
RT centers were mostly gathered in Marmara, Central Anatolia, and Aegean region (15, 12 and 8 centers respectively). The median number of patients with non-small cell (NSCLC) and small-cell lung cancer (SCLC) treated definitively in one year were 55 and 15 respectively. The cases are discussed in a multidisciplinary tumor board in 75% of the centers. All of the centers use at least the minimum technological standard which is CT-planned 3D conformal RT (3D-CRT) in the definitive treatment of lung cancer; 33% has 4D-CT simulation facility, 94% use PET/CT in RT planning, 75% apply RT under image guidance; 41% has stereotactic body radiotherapy (SBRT) facility, and 53% use SBRT routinely in early-stage NSCLC patients who are medically inoperable or who refuse surgery. Ninety-eight percent of the centers apply concurrent chemoRT (87% starting RT with the first chemotherapy course) in locally advanced NSCLC. Concurrent chemoRT dose is 60-66 Gy in 96%. Chemotherapy was given by the radiation oncologists in 34% of the centers. In stage IIIA(N2) potentially resectable disease 56% of the centers apply neoadjuvant treatment (chemoRT 67%, chemo 33%). Besides main postoperative RT indications 27% of the centers apply RT to patients with inadequate mediastinal dissection, 37% apply to patients with suboptimal surgery. Regarding definitive treatment of SCLC 17% of the centers apply 45 Gy bid, 50% apply 50-60 Gy, 28% apply 61-66 Gy concurrent with cisplatin-etoposide, starting with the first or second course in 87%. In extensive-stage SCLC 89% of the centers apply thoracic RT (50-66 Gy in 62%, 30 Gy in 26%) after chemotherapy. Prophylactic cranial irradiation doses were 25 Gy in 71%, 30 Gy in 22%. The patients are followed with 3-month intervals in 89% of the centers, however there is no consensus regarding follow-up workup among the centers.

Conclusion:
At least minimum world standards can be applied in the definitive RT of lung cancer in Turkey. The problems regarding optimal RT dose and fractionation and concurrent chemotherapy regimen, postoperative RT indications are similar, but as a developing country we need more multidisciplinary workup and develop our own guidelines taking into account our own resources and patient characteristics.

Background:
Lung Cancer is a major cause of cancer mortality around the world. Many patients are not fit for surgery or chemoradiation, and are treated with radiation therapy alone. There are few data on the outcomes of definitive radiotherapy in Brazil

Methods:
All patients AJCC I-III Stage undergoing definitive radiotherapy at the HCPA between 2010 and 2015 were assessed Only individuals unfit for chemotherapy were evaluated. We excluded patients that received surgery. All patients were treated with conformal radiotherapy (3DCRT) and curative intent Individual variables and outcomes were retrospectively evaluated through medical records Statistical analysis was performed with software SPSS 22.

Results:
Figure 1

Patient characteristics	N = 68 (%)
Age, (Mean)	60,22 years
Gender, No. (%) Men Women	43 (63,2%) 25 (36,7%)
Race, No (%) White	54 (79,4%)
AJCC stage, No (%) I II III	5 (7,3%) 26 (38,2%) 37 (54,4%)
PS ECOG, No (%) 0-2 3-4	44(64,7%) 24 (35,3%)

Between 2010 and 2015, 68 patients were treated with radiation therapy alone. Most of patients were male and white. The median age at diagnosis was 60,22 years. AJCC Stage III disease was the most prevalent one. The median survival for all stages was 8.055 months (95% CI 5.796 to 10.313 months). Overall survival at 5 years was 11.7 %



Conclusion:
Radiotherapy alone resulted in very poor survival in this cohort. Our data is original in Brazil. Most of lung cancer patients who may not tolerate surgery or a chemoradiation regim die. New alternatives for the management of these patients are neceessary.

Background:
Stereotactic brain radiosurgery (SRS) was demonstrated to provide good local control in patients with oligo-brain metastases (commonly defined as 4 or less). The discovery of different targeted therapies provided significant improvement in survival in the past decade. We reviewed the effectiveness of SRS in lung cancer patients with oligo-brain metastases and identified prognostic factors which potentially can aid better patient selection.

Methods:
Medical records of patients with brain metastases treated with SRS in Prince of Wales Hospital, Hong Kong in Jan 2010-July 2015 were reviewed. Outcomes including local control rate (LCR), distant brain control rate (BCR) and overall survival (OS) were analyzed. Prognostic factors were identified with univariate and multivariate analyses. Correlation with available prognostic scorings including RTOG Recursive Partitioning Analysis, Basic Score for Brain Metastases, the Score Index for Radiosurgery and Graded Prognostic Assessment was evaluated.

Results:
Forty-eight patients with 66 lesions were treated with LINAC-based SRS with single dose of 12-24Gy (mean dose 18.1Gy). The distribution of different subtypes is as follows: Non-small cell lung cancer (NSCLC)/adenocarcinoma NOS n=18 (37.5%), EGFR mutation n=17 (35.4%), ALK IHC+ n=3 (6.3%), adenocarcinoma of unknown subtype n=2 (4.2%), squamous cell carcinoma n=5 (10.4%), small cell carcinoma n=2 (4.2%) and unknown subtype n=1 (1.8%). The median follow up time was 11.0 months (0.4-71.4 months). Five patients (9.4%) were symptomatic with acute brain edema. Seven patients (14.6%) had delayed seizure after a mean time of 10.1month (2.0-33.5 months). Six patients (12.5%) became steroid dependent. The median OS was 13.0 months. One year actuarial LCR was 73% and distant BCR was 67%. OS correlated significantly with all four scoring systems. Among NSCLC patients, those with activating EGFR mutation (exon 19 deletion or exon 21 L858R mutation) (n=12) had superior OS compared with non-mutational group (p=0.036, HR 2.811 95% CI 1.072-7.369), but there was no statistically significant difference on local or distant brain control.Concomitant whole brain radiotherapy (WBRT) did not significantly affect OS, local and brain control in the whole group and in EGFR activating mutant subgroup.

Conclusion:
SRS provided good control in patients with primary lung cancer with oligo-brain metastases. Current available prognostic scores provide good estimation of survival. Patients with EGFR activating mutation had superior survival after SRS compared with non-mutational NSCLC group.

Background:
Concurrent radiochemotherapy (CCRT) is the standard treatment in locally advanced small cell lung cancer (SCLC) patients. Even though elective nodal irradiation (ENI) had been advocated, its use in routine clinical practice is still limited [1]. Therefore, the purpose of this study is to assess the sites of recurrent disease in SCLC patients and to evaluate the feasibility of selective nodal irradiation (SNI) versus ENI.

Methods:
A retrospective single-institution study was performed in stage I-III SCLC patients treated with CCRT. After state-of-the-art staging, all patients underwent three-dimensional conformal radiotherapy to a total dose of 45 Gy in twice-daily fractions of 1.5 Gy starting concurrently with the first or second chemotherapy cycle (etoposide, cisplatinum). The gross tumor volume (GTV) consisted of the primary tumor and SNI visualized on CT and/or FDG-PET, or confirmed by cytology. The clinical target volume (CTV) was obtained by expanding the GTV, adjusting it for anatomical boundaries, and electively adding the supraclavicular lymph node stations. Thereafter, the CTV was expanded to a planning target volume based on institutional guidelines. After CCRT, prophylactic whole-brain irradiation (WBI; 30 Gy in 15 fractions) was administered to patients with a (near-complete) response. Follow-up consisted of a CT-thorax 6-8 week after completing treatment, followed by a 3-monthly chest x-ray or CT-scan. For this retrospective analysis, we reviewed all imaging data used for radiation treatment planning and during follow-up. The site of loco-regional relapse was correlated to the initial site and dose delivered.

Results:
Between April 2004 and December 2013, 54 patients underwent CCRT (followed by WBI in 63%). After a median time of 11.5 months, 17 patients (31.5%) had relapsed locally or regionally: six within the initial primary tumor volume, five within the initially affected lymph nodes, three metachronously within the primary tumor and initially affected lymph nodes, and three inside and outside of the initial nodal disease. Only one patient developed isolated supraclavicular lymph node metastases in the electively treated volume. All sites of loco-regional recurrence had received 92%-106% of the prescribed dose. Thirty-seven patients (69%) developed distant metastases (37.8% liver, 35% brain).

Conclusion:
In this retrospective analysis, most patients recurred in the initially affected primary tumor or lymph nodes, or distantly. So, in order to reduce toxicity and potentially increase dose in GTV/CTV, one may consider omitting irradiation of the supraclavicular lymph node stations in those patients with affected lymph nodes in the lower hilar and mediastinal lymph node stations.

Background:
To evaluate the long-term efficacy, pattern of failure, and toxicity of stereotactic ablative radiotherapy (SABR) for recurrent or multiple primary non-small-cell lung cancer (NSCLC).

Methods:
Patients with histologically confirmed, [18]F-fluorodeoxyglucose ([18]F-FDG)-PET staged, recurrent or multiple primary NSCLC, suitable for SABR (<5 cm, not abutting critical structures, met with SABR dose volume constraints),were prospectively enrolled and treated with volumetric image-guided SABR to 50 Gy in 4 fractions (prescribed to planning target volume). Lobar recurrent disease was defined as recurrence in the same lobe with the same histology after definitive therapy from prior NSCLC (n=9); recurrent or oligo-metastatic disease (<3 lesions) was defined as recurrence with same histology within four years in different lobe (n=35). Multiple primary NSCLC was defined as secondary NSCLC with either different histology, or same histology but located in the different lobe with more than 4 years after initial definitive treatment of prior NSCLC (n=16); synchronous tumors was defined as with two early stage NSCLC in the different side (n=3). Four-dimensional computed tomography (4DCT) was used for simulation and planning. Patients were followed with CT or PET/CT every three months for two years, then every 6 months for three years and then annually.

Results:
From February 2006 to April 2013, 63 patients were enrolled and eligible for evaluation. The median age was 70 years (range 45-86) and median follow-up was 4.2 years (the interquartile range 3.0-7.3 years). A total of 5 (7.9%) patients developed cumulative actual local recurrence within PTV and 18 patients (28.6%) developed any cumulative actual recurrence (local, regional and distant) after SABR. Estimated total local failure rates in the same lobe at 3-, 5-year were both 11.2% (95% CI 6.8-15.6). Estimated 3-, 5-year PFS rates were 60.2% (95% CI 53.7-66.7) and 52.6% (95% CI 43.5-61.7), respectively; corresponding overall survival rates were 64.1% (95% CI 58.0-70.2) and 52.9% (95% CI 45.5-60.3). Three (4.8%) patients developed grade 3 treatment-related adverse events (one [1.6%] dermatitis, one [1.6%] chest wall pain, and one [1.6%] radiation pneumonitis). No patient had grade 4 or 5 event.

Conclusion:
This exploratory prospective study showed excellent 5 years local control, minimal toxicity and outstanding 5 years OS and PFS for recurrent or multiple primary NSCLC treated with SABR, indicating a potential cure for some patients. Close follow up and surveillance after initial definitive treatment should be considered to detect early recurrence in NSCLC.

Background:
The standard treatment for inoperable locally advanced non-small cell lung cancer (LA NSCLC) includes concurrent or sequential chemotherapy and radiation therapy (RT). RT with 60 to 66 Gy in 30-33 fractions represent a backbone of treatment in inoperable LA NSCLC and optimal radiation dose is essential for successful treatment. Long term survival rates with these approaches remains in the order of 15 - 20%.

Methods:
We evaluated the clinical significance of the RT doses in patients with inoperable LA NSCLC who underwent concurrent chemoradiotherapy in our institution between 2005 and 2010 and correlated the doses with outcome of treatment. All patients were treated with three 21-day cycles of induction chemotherapy with cisplatin and gemcitabine. Within 13 – 22 days after the last application of chemotherapy, all patients continued treatment with conventionally fractionated 3D-RT in 2 Gy fractions concurrently with cisplatin and etoposide. We evaluated the outcome of the patients treated with RT doses less or equal 62 Gy and treated with more than 62 Gy.

Results:
One hundred and five patients were treated with combined chemoradiotherapy between 2005 and 2010 in our institution, 82 males and 23 females. Most patients had surgically inoperable tumor in stages IIIA (50 patients) and IIIB (51 patients), 4 patients were medically inoperable. The most predominant histological subtype was squamous cell carcinoma (75%), followed by adenocarcinoma (15%). No statistical significant differences in patient characteristics, including age, smoking status, gender and histology were found according to the dose of RT. The dose intensity of induction and concurrent chemotherapy, expressed as a mean percentage of prescribed drug administered, was not statistically different for any drug used according to the dose of RT. Radical irradiation with doses of 54 - 62 Gy and 62.1 - 66 Gy was completed in 47 and 58 patients. After a median follow up of 103.4 months, 17 patients were still alive, 11 patients treated with > 62 Gy. Median overall survival (mOS) was 16.6 and 31.4 months for RT doses ≤ 62 Gy and > 62 Gy, respectively (p=.037) (Fig.1). 5-years survival was 19.1% and 29.3% for treatment with ≤ 62 Gy and > 62 Gy.

Conclusion:
RT dose may be an important factor for outcome of patients with LA-NSCLC. Our analysis confirms the importance of RT dose on outcome in patients with LA NSCLC, but since small number of patients were included, no firm conclusion could be made and further clinical investigation is warranted.

Background:
Tumor regression during chemoradiation (CRT) in stage III non-small cell lung cancer patients has been described. Our aim was to investigate whether the extent of the primary tumor shrinkage is associated with local control and survival.

Methods:
Changes in the volume of the primary tumor (GTV-T) of 41 patients treated with concurrent (cCRT) (n = 21) or sequential (sCRT) (n=20) CRT were analyzed using cone-beam CT (CBCT) at every fifth fraction (F5–F30). Only changes in the primary tumor (excluding the lymph nodes) were considered. Previous research revealed F15 and F20 as optimal timing for treatment adaptation for cCRT and sCRT respectively (Berkovic et al. Acta Oncol 2015). Local control and survival data were reviewed retrospectively. Impact of the tumor regression at the time of the optimal adaptation timing during treatment (higher or lower than median) and chemotherapy schedule (cCRT vs. sCRT) on local control and survival were evaluated using the Kaplan-Meier survival comparison (log-rank test, p<0.05 were considered significant).

Results:
Median local control (LC) and overall survival (OS) was 32.5 res. 29.9 months in the sCRT and 31.4 res. 23.3 months in the cCRT group. LC and OS did not differ significantly for the cCRT and sCRT cohort. The median GTV reduction was 35.0% (range 2.8–64.2%) at F15 for cCRT, while 21.9% (2.1-53.5%) at F20 for sCRT patients. Higher than the group median (for cCRT and sCRT) GTV-T reduction showed statistically significant impact only on disease specific survival (p=0.016, Figure 1).

Conclusion:
Higher gradient GTV-T reduction during RT significantly correlates with better disease specific survival. Additional tumor and patient characteristics should be studied in larger patient cohorts to further understand tumor behavior and to offer a validated predictive tool of therapeutic outcomes. Figure 1. Kaplan-Meier survival curve for DSS. Figure 1

Background:
Isolated intrathoracic relapse is common across distinct tumors and especially in lung cancer. Patients who received previous radiotherapy treatment (PRT) are not suitable for salvage surgery and chemotherapy provides poor local control. This study aimed to assess the toxicity and outcome of SBRT re-irradiation (reRT) in patients with solid tumors who developed an intrathoracic relapse.

Methods:
35p treated with PRT who received salvage SBRT were identified in our database and their medical records were retrospectively reviewed. All patients underwent complete pulmonary function tests (cPFTs) (including DLCO, FEV1 and FVC) and PET-CT scan was performed before and after receiving lung reRT. Treatment planning was based on image fusion with the previous treatment plan and calculating the cumulative total nominal dose. Survival estimations were performed using Kaplan-Meier and differences between PFTs prior and post-reRT were analyzed using Student T-Test. Early toxicity was defined when it occurred up to 6 months.

Results:
Median age: 68 (r53-81); 29p (83%) were male The previous treatments SBRT in 17p (49%), 3D-RT 4p (11%) and CT+RT 14p (40%) Mean RT dose 60,4Gy (r34-74). Primary tumors: lung 24 (69%), colorectal 9 (25%), oesophagus 2 (6%). For lung cancer p, the stage distribution was: IA 8 (23%), IB 2 (6%), IIA 2 (5.7%), IIB 1 (3%), IIIA 5 (4%), IIIb 4 (11%), IV 2 (6%). For other primaries, 8p (23%) were non metastatic at diagnosis and developed oligoprogressive disease in thorax which was treated with SBRT and 3 (8.5%) were oligometastatic. The location of reRT site: same lobe 17 (48%), ipsilateral different lobe 7 (20%), contralateral lobes 11 (32%). Median delivered dose of salvage SBRT was 50Gy (50-60) in 10 fractions (r3-10). Median accumulated dose in the lung was 81Gy (r60.10Gy-176Gy). With a median follow-up of 10m local control rate was 74% (IC95%; 0.59-0.9) and 1-year OS was 84% (IC 95%;0.67-1). The metabolic complete response rate was 23%. No differences in the baseline and post re-irradiation PFTs were observed: FEV1, FVC and DLCO difference and CI95% were 2.41 (-1.79-6.62); 65 (-125-257) and 12.5 (-95 - 121). Asthenia GII in 12p (31%) was the most frequent acute toxicity, no long-term toxicities were detected.

Conclusion:
Salvage SBRT for treating isolated intrathoracic relapses achieved an outstanding local control and overall survival in selected p . This treatment did not impair post-reirradiation PFT and long-term toxicities were not observed.

Background:
Stereotactic body radiotherapy (SBRT) for central lung tumors, defined as tumor within 2 cm or touching the zone of the proximal bronchial tree or tumors immediately adjacent to the mediastinal or pericardial pleura (Adebahr S. et al. BJR 2015) is debated because of toxicities to organs at risk. No evidences from phase III trial are available.

Methods:
From 2010 to 2015, 45 central lesions in 40 pts were treated with SBRT. 14 lesions were primary lung cancer (PLC), 31 were lymphoadenopathies (LAP). PLC were treated with volumetric arc Therapy (VMAT) in 9 cases and 5 with Cyberknife®. LAP were treated with VMAT in 12 cases, with IMRT (step and shoot) in 10 and with Cyberknife® in 9 cases. Prescribed doses varied between 18 and 60 Gy (1-8 fractions) with median BED of 65 Gy (37,5-105 Gy). We evaluated Overall Survival (OS), Progression Free Survival (PFS) and Disease Specific Survival (DSS) using Kaplan-Meier method and treatment related toxicities using CTCAE version 4.0.

Results:
Median age was 62 years (48-86), 26 male and 14 female. PS was 0 in 9 pts, 1 in 21, 2 in 10 pts. Histology was available in all series and consisted of primary NSCLC (32 adenocarcinoma, 12 squamous cell carcinomas, 1 neuroendocrine tumour). 41 PLC were less than 2 cm from proximal bronchial tree, 4 PLC were immediately adjacent to the mediastinal or pericardial pleura. Tumor diameter was 10 to 60 mm with a median of 31 mm. Median follow up was 14,5 months. OS and DSS were 86.5% at 1 year, 55.6% at 2 years, and 49,4% at 3 years. PFS was 48,6% at 1 year, 24,1% at 2 years, and 12% at 3 years. 35 pts showed no acute toxicity; in 5 pts we recorded grade 1-2 esophagitis, in 2 pts grade 2 cough, in 2 pts, grade 1 asthenia. Chronic toxicity was present in 2 pts as grade 2 esophagitis.

Conclusion:
SBRT is confirmed to be a safe and effective strategy for central lung tumors. The majority of patients in the first part of our series was treated with low doses compared to current doses. Nevertheless 23 patients had clinical benefit from the treatment without life-threatening toxicities. Further studies are needed to establish the efficacy and safety of SBRT in central lung lesions.

Background:
Stereotactic ablative radiotherapy (SABR) is a radiotherapy technique using ultra-hypofractionated treatment to deliver a high biological dose to early stage lung cancers. It is believed that SABR is more effective than conventional fractionated external beam radiotherapy (EBRT), however definitive evidence of superior survival outcomes from controlled trial comparisons is lacking. Across the UK access to SABR is not been uniform, with only certain centres delivering the technique. Before the introduction of a routine lung SABR service in 2013, patients from Northern Ireland were referred to English Centres to have SABR. We compare the outcomes of those patients who had SABR to those who had conventional fractionated radiotherapy for early stage lung cancer.

Methods:
Using our institutional electronic database, which includes all patients who had radiotherapy in the treatment of lung cancer, we identified those patients who had received SABR or who were eligible to receive it based on UK consortium guidelines (tumor size <= 4cm, tumor > 2cm from main airways, performance status 0-3). The time period of 2009 to 2015 inclusive was chosen as SABR treatment was funded from this time point onwards. Patient baseline demographics, lung function, tumor size, the reason for the treatment received, details of the treatment received (e.g. dose, use of respiratory compensation, IGRT and Type B planning algorithm) and survival outcomes were recorded for each patient.

Results:
Between 2009 and 2015, eighty patients received SABR and an additional 63 were eligible to have SABR but received conventional EBRT (62 patients received 55Gy in 20 fractions and 1 patient received 66Gy in 33 fractions). The main reason for eligible patients not receiving SABR was that the patient did not want to travel or was not fit to travel to another country to have treatment with SABR (43% of all non-SABR patients). The 2-year overall survival for those receiving SABR was 68% versus 43% for those receiving conventional radiotherapy (HR 2.3 (95% CI 1.4 – 3.8), p=0.0007). Both disease free survival and metastasis free survival rates were superior in the SABR group. On univariate analysis of the various patient and treatment factors, only tumor size remained significant between the groups.

Conclusion:
In this cohort of patients there is evidence of improved local control, disease free survival and overall survival for SABR compared to conventional fractionated radiotherapy. SABR should be available in all radiotherapy centres for the treatment of early stage lung cancer.

Background:
Stereotactic radiosurgery (SRS) has been introduced for small-sized single and oligo-metastases in the brain. The aim of this study is to assess treatment outcome, efficacy, and prognostic variables associated with survival and intracranial recurrence.

Methods:
This study retrospectively reviewed 123 targets in 64 patients with non-small cell lung cancer (NSCLC) treated with SRS between January 2006 and December 2012. All patients underwent SRS with 2000~3000cGy/1~3Fx for each brain metastasis as a initial treatment or salvage treatment for recurrence after whole brain RT. Median target number and size were 2 targets and 1cm in diameter. Every patient was evaluated according to Eastern Cooperative Oncology Group (ECOG) performance status, RPA class, number and size of brain metastasis and other systemic metastasisdisease staus before SRS. We evaluated overall survival (OS), local tumor control and intracranial progression free survival rate (IPFS) of patients. We also evaluated quality of life immediate after SRS.Treatment responses were evaluated using magnetic resonance imaging.

Results:
The median follow-up was 13.9 months. The median OS and IPFS were 14.1 and 8.9 months, respectively. Fifty-seven patients died during the follow-up period. The 5-year local control rate was achieved in 85% of 108 evaluated targets. The 1- and 2-year OS rates were 55% and 28%, respectively. On univariate analysis, primary disease control (p < 0.001), the Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 vs. 2; p = 0.002), recursive partitioning analysis class (1 vs. 2; p = 0.001), and age (<65 vs. ≥65 years; p = 0.036) were significant predictive factors for OS. Primary disease control (p = 0.041) and ECOG status (p = 0.017) were the significant prognostic factors for IPFS. Four patients experienced radiation necrosis and no other neurocoginitive deficit by SRS was reported within follow up duration.

Conclusion:
SRS is a safe and effective local treatment for brain metastases in patients with NSCLC. Uncontrolled primary lung disease and ECOG status were significant predictors of OS and intracranial failure. SRS might be a tailored treatment option along with careful follow-up of the intracranial and primary lung disease status. Omission of WBRT can be option for patient with primary disease controlled and better ECOG with close image follow up.

Background:
This study was conducted to investigate the pattern of intrathoracic failure regarding the radiotherapy (RT) target volume in patients receiving early or late thoracic RT for limited-disease small cell lung cancer (LD-SCLC).

Methods:
One hundred ten patients who were enrolled in previous randomized trial of concurrent TRT with either first cycle (early TRT) or third cycle (late TRT) of chemotherapy were analyzed. RT target volume was based on initial tumor volume in early TRT group, and post-chemotherapy tumor volume in late TRT group. Initially involved nodal regions were covered in late TRT group, whereas uninvolved nodal regions were not included electively. TRT dose was 52.5 Gy in 25 fractions per daily. Prophylactic cranial irradiation (PCI, 25 Gy in 10 fractions) was delivered to 79 (71.8%) patients who had complete response or very good partial response. We analyzed pattern of failure regarding TRT target volume.

Results:
Median follow-up duration was 28.5 months. Overall recurrence rate is 69.1% (n=76). Intrathoracic (locoregional) failure with or without distant metastasis was developed in 27.3% (n=30). Distant metastasis including brain metastasis was observed in 46.8% (n=46). Among early TRT group (n=56), 14 patients (25.0%) had intrathoracic failure; 13 within initial tumor volume, and one on the boundary of initial tumor volume. Among late TRT group (n=54), 16 patients (29.6%) showed intrathoracic failure; 15 within post-chemotherapy tumor volume and one on the boundary of initial tumor volume. There was no regional recurrence outside target volume in both groups. There were 30 patients who developed brain metastasis. Patients who receive PCI showed brain metastasis less frequently (n=19/79, 24.1%) than patients who did not receive PCI (n=11/31, 35.5%, p=0.033).

Conclusion:
Using post-chemotherapy tumor volume is feasible strategy in determination of TRT volume in patients with LD-SCLC. Development of new RT dose fractionation schedule to further improve in-field local control may be warranted.

Background:
This study was conducted to assess optimal radiation target volume in patients with locally advanced thymic epithelial tumor (TET) treated by surgery and postoperative radiation therapy (PORT).

Methods:
The records of 54 patients with Masaoka-Koga stage III TET, who received surgical resection at Samsung Medical Center, from Jan. 2000 to Dec. 2014, were retrospectively reviewed. The most common TNM stage was T3N0M0 (n=46, 85.2%) according to the new staging system proposed by the International Association for the Study of Lung Cancer and the International Thymic Malignancy Interest Group. The median PORT dose was 54 Gy in 27 fractions. Target volume was confined to the primary tumor bed only, while did not include the regional lymphatics nor pleuro-pericardial space electively. The clinical outcomes, prognostic factors and patterns of failure were analyzed.

Results:
After median follow-up of 62 months, there were 19 (35.2%) patients who had disease recurrence. Pure local failure within the PORT volume was founded in only one (1.9%) patient who had gross residual mass after surgery, pleuro-pericardial seeding in 5 (9.3%), distant metastases in 10 (18.5%), and regional recurrence in adjacent mediastinum or lymph nodes in 3 (5.6%) patients with WHO type B3 or C TET. Overall survival rate at 5 and 10 years was 83.0% and 43.6%, respectively. Recurrence free survival rate at 5 and 10 years was 62.3% and 57.9%, respectively. The age <60 years old, female gender, and tumor diameter <10 cm were favorable prognostic factors for overall survival on univariate analyses. Radiation toxicity was mild in most patients and no severe toxicity was registered.

Conclusion:
PORT confined to the primary tumor bed only is suggested to be optimal in patients with Masaoka stage III (T1b-4N0) TET considering excellent in-field control and minimal out-field regional recurrences. Development of effective systemic treatment strategy to reduce the pleuro-pericardial seeding may be warranted.

Background:
Stereotactic body radiotherapy (SBRT) is a technique, introduced in the late 1990s. SBRT is a method of using single 10-20Gy of high dose and hypofractionated radiotherapy. Recently, many papers have been published on its clinical results, especially in early stage lung cancer.

Methods:
To recognize the current status of SBRT in Japan, a nation-wide survey was conducted by the Japan Conformal External Beam Radiotherapy Group (J-CERG).

Results:
The questionaire was sent to 227 institutions. One-hundred and forty-nine institutions responded by the end of May 2015.The fixing apparatus, respiratory regulation, treatment planning and verification was surveyed. For regulation of respiratory movement, abdominal wall compression, breath-holding, respiratory gating and tumor chasing methods were used. For irradiation technique, 6 to 10 non-coplanar beams or multiple arc beams were mainly adopted.

Conclusion:
The current status of SBRT in Japan was recognized.

Background:
~In 2007, a EORTC study demonstrated a beneficial impact on overall survival with the use of prophylactic cranial irradiation in extensive disease small cell lung cancer. Nevertheless, there is ongoing debate over the role of PCI as patients in this trial did not undergo imaging of the brain prior to treatment, and a recent Japanese randomized trial showed a detrimental effect of PCI on OS in patients with a negative pre-treatment brain MRI. 87% of our patients received brain imaging prior to PCI.~

Methods:
We examined the medical records of 137 patients with extensive disease small cell lung cancer who initially responded to chemotherapy and received PCI between 2007 and 2015. The outcomes, including the development of brain metastases and OS following PCI were analyzed. Survival and correlations were calculated using log-rank, univariate, and multivariate Cox proportional hazards-ratio analyses.

Results:
Median OS after PCI was 12 months and the median nPFS after PCI was 19 months. There was no significant survival difference in patients who received an MRI prior to PCI compared to patients who received a contrast enhanced computer tomography (CT) (p=0.20). Univariate analysis for overall survival did not show a statistically significant effect for known cofactors. Figure 1 Figure: OS (A) and nPFS (B) in patients with ED SCLC treated with PCI. .



Conclusion:
We present the 9-year clinical experience with PCI in ED SCLC patients from one of Europe’s largest Lung Cancer Centres. PCI leads to a nearly doubled median OS compared to the irradiation arm of the EORTC trial with a 2-months prolonged median OS compared to the irradiation arm of the Japanese trial.　PCI should remain standard of care for all patients with SCLC who have a response to initial chemotherapy. Contrast enhanced brain MRI instead of CT for staging prior to PCI is recommended if possible.

Background:
The purpose of this study is to evaluate the long term outcomes of postoperative radiotherapy(PORT) in patients with NSCLC.

Methods:
A total of 130 patients with resected NSCLC who were treated with PORT between January 1994 and December 2014 were respectively evaluated. Among the whole group 86 patients(66%) were treated with Co60 machines till 2005, and 44 patients(34%) with 6-10 MV photons with linear accelerators. Median RT dose was 54 Gy(range, 48-66 Gy) with 2 Gy daily fractions. the treatment fileds covered the bronchial stump, ipsilateral hilum and mediastinum in 109patients(83.8%);bronchial stump,ipsilateral hilum, mediastinum and supraclavicular nodes in 15patients(11.5%);and bronchial stump and ipsilateral hilum in 6patients(4.6%).Cisplatinum-based chemotherapy was administered to 69(53%) patients. Chemoterapy was applied preoperatively in22 patients(17%), concomitantly in 27 patients(21%), and after PORT in 20patients(15%). Overall(OA) survival, locoregional-free(LRF) survival and distant-metastasis free(DMF) survival were calculated using the Kaplan-Meier method.

Results:
The median age of the patients was 59 years (range,35-75 years). The most frequently performed surgical procedure was lobectomy (64.6%), followed by pneumonectomy(19.2%), wedge resection (10%), and bilobectomy(6.2%). Stages included I(19.2%), II(42.3%), IIIA (30.8%), and IIIB(6,9%).Neoadjuvant chemotherapy was applied to 62% of stage III patients.The median overall survival was 48 months. The 5-year OA, LRF and DMF survival rates for whole group were 43%, 75%, and 63% respectively.Significant prognostic factors for OA survival were indicated in the table. Acute and subacute toxicities were Grade I to II esophagitis in 48 patients (37%), anemia in 11 patients(8%), pulmonary infection in 11 patients (8%),and Grade ≥II radiation pneumonitis in 11 patients(8%) Radiation-induced late toxicities including radiologic Grade I to II fibrosis were recorded in 22 patients (17%).

The Prognostic Factors for Overall Survival

Characteristics	5-yearOA survival	UnivariateAnalysis (Log-rank p value)	Multivariate Analysis(Cox regression p value)
Age(Years) <59 >=59	55 32	0.012	0.000
KPS 70-80 90-100	35 48	0.028	0.003
Laterality Left Right	31 54	0.011	0.005
Stage T1-T2 T3-T4	55 28	0.001	0.050
Dose <54 >=54	55 36	0.037	0.006

Conclusion:
Unfavorable prognostic factors for PORT were RT dose > 54 Gy, advanced T stage, poor Karnofsky performance status, advanced age, and left sided tumors. When irradiating left-sided tumors cardiac toxicity must be kept in mind.

Background:
The aim of this study was to investigated the effects of thermo-chemotherapy induced by nano-paclitaxel magnetic fluid for lung cancer A549 proliferation, apoptosis and cell cycle in vitro, and therapeutic effect of human carcinoma A549 xenograft in nude mice in vivo.

Methods:
In vitro, nano-paclitaxel magnetic liquid was synthesised by chemical coprecipitation and ultrasound emulsification. Lung cancer A549 cells were set up the control group (group A), thermal therapy group (group B), chemotherapy group (group C) and thermo-chemotherapy group (group D), which exposed to an alternative magnetic field (AMF) for 30 min. And then the optical density (OD) of viable cell, cytotocixity index, growth curve of cells, morphologic changes of cell, cell cycle and aposptosis were measured. When tumor length to diameter (6 ~ 8 mm), they were randomly divided into 4 groups: control group, magnetic heat treatment group, paclitaxel magnetic thermo-chemotherapy group and chemotherapy group, the tumor was heated in an AMF for 30 min. Tumor volumes were then measured every week. The therapeutic effect was assessed by measuring the tumor volume and weight. Pathological examination was performed with a light microscope following treatment. Immunohistochemical detecting tumor after treatment tumor cell apoptosis, calculate the apoptosis index to compare the efficacy of treatment.

Results:
In 43 ℃, with the increase of paclitaxel concentrations, are more obvious A549 lung cancer cell proliferation inhibition, the number of cells in living cells of optical density value, the killing rate (cytotoxity index, CI). Cell apoptosis rate increased. Heat treatment group the stagnation of the cell cycle in S phase, S phase cells and G2 phase increases, S phase decreased in the chemotherapy group, after heat treatment of lung cancer cells in electron microscope magnetic apoptotic changes. The temperature inside the tumor can be quickly rise to 43 ℃. Tumors in three experimental groups are suppressed, magnetic thermo-chemotherapy group tumor growth inhibition is more obvious, immunohistochemical confirmed the tumor cell apoptosis in change, apoptosis index increased.

Conclusion:
In vitro, with the increase of paclitaxel concentrations, are more obvious A549 lung cancer cells proliferation inhibition in 43 ℃. The number of cells in living cells of optical density value, the killing rate (cytotoxity index, CI), cell apoptosis rate increased. Thermo-chemotherapy induced by nano-paclitaxel magnetic fluid can inhibit the growth of A549 lung cancer nude mice transplantation tumor, nano paclitaxel magnetic thermo-chemotherapy can enhance the anti-tumor effect in vivo.

Background:
The role of adjuvant radiotherapy (ART) on stage IIIA-N2 NSCLC is still controversial especially in different status of lymph nodes invasion. We conducted this retrospective study here to evaluate the effect of adjuvant radiotherapy (ART) on non-small cell lung cancer (NSCLC) patients with resectable stage IIIA--single station N2.

Methods:
Between January 2010 and December 2013, 383 resectable NSCLC patients with stage IIIA-single station N2 were recruited in Shanghai Pulmonary Hospital. The patients received neoadjuvant therapy or no adjuvant chemotherapy (ACT) and those were mixed with small cell lung cancer components were excluded from the study. Their clinicopathological data were collected and their survival times were recorded. The last follow-up was finished on May 31, 2016. Kaplan-Meier survival method was used here to calculate the overall survival (OS) , disease-free survival (DFS) and Cox regression analysis was used to conduct multivariate analysis.

Results:
Overall 341 patients with median age of 59 yrs (25-79yrs) were included. There were 164 patients with adenocarcinoma (AD), 106 with squamous cell lung cancer (SCC) and 61 others (37 with adenosquamous, 26 with large cell carcinoma and 8 with sarcomatoid carcinoma). Totally 26 patients were lost of follow-up. One hundred and eighty-nine patients (55.4%) were confirmed recurrence and 152 patients (44.6%) died until the last follow-up. Among them, 79 patients received ART and ACT after operation and 262 patients only completed ACT. The patients’ baseline characteristics of these two groups were balanced. The median DFS for the whole group patients, ART+ACT group and ACT group were 30 (23.9-36.1), 31 (19.8-42.2) and 30 (21.8-34.2) months respectively. The median OS for the whole group patients, ART+ACT group and ACT group were 52 (39.4-64.6), 54 (NR) and 50(36.7-63.3) months respectively. Multivariate analysis showed no difference in DFS and OS between ART+ACT and ACT groups. In subgroup analysis, we found the significant benefit in favor of ART (n=44) regarding DFS (HR 0.55 , 95% CI 0.323-0.938, p =0.028), and a tendency in OS (HR 0.553, 95% CI 0.284-1.078, p =0.082) in AD patients. While in SCC patients, ART (n=18) seemed a poor prognostic factor. (HR 2.0 for DFS, 95% CI 0.935-2.485, p = 0.074 and HR 0.757 for OS, 95% CI 0.225-2.553, p =0.654).

Conclusion:
ART significantly decreased the risk of recurrence in Adenocarcinoma patients with stage IIIA-single station N2 and might improve these patients’ survival. The benefit of ART for SCC patients didn’t be proved here.

Background:
Hyperthermia has long been recognized as a modality in anticancer therapy. In present study, we provide an update on the recent knowledge about the molecular mechanisms of thermal radiosensitization on highly invasive NSCLC cells.

Methods:
In previous study, we isolated invasive subpopulations of cancer cells from established human non-small cell lung cancer (NSCLC) H460 cell lines. The subpopulation of highly invasive NSCLC cells (H460-INV) showed cancer cell stemness, increased DNA damage repair. H460-INV cells were exposed to hyperthermia and irradiation. Cell survival was determined by an in vitro clonogenic assay and growth curve for the cells treated with or without hyperthermia. Immunohistochemical staining assay was performed to detect the expression of Ki67、γH2AX foci. Cell apoptosis was performed by Flow cytometry. Cell-scratches and transwell invasion chamber experiments were performed to detect the ability of cell migration and invasion. Western blot assay was used to detect DNA damage repair related molecular changes.

Results:
Hyperthermia can significantly enhance irradiation-killing cells. SER was 1.823. Ki67 immunofluorescence results suggested that thermo-radiation can significantly inhibit cell proliferation (p < 0.01). Flow cytometry results showed that the apoptotic cells increased significantly in heat treatment group (p < 0.05). Compared with the control group, H460-INV cell migration and invasion ability significantly reduced. WB results suggested that thermal downregulated the expression of E cadherin, upregulated N-cadherin. Relative persistence of γ-H2A.X nuclear foci in the H460-INV cells after IR treatment was observed, when compared to the no treat H460-INV cells. WB results suggested that thermal combined with radiation inhibited the DNA repair by inhibiting expression of Ku70 and Ku80.

Conclusion:
Microwave thermal therapy can increase the sensitivity of highly invasive NSCLC cells to radiation and its mechanism may be related to inhibition of radiation induced DNA damage repair, promoting tumor cell apoptosis, and thermo- radiotherapy can inhibit tumor cell invasion ability. This study suggests a beneficial clinical impact of maicrowave thermal therapy as a radiosensertizer for benefiting highly invasive lung cancer patients.

Background:
Central nervous system (CNS) metastases are considered as a common cause of morbidity and mortality in advanced non-small-cell lung cancer (NSCLC). It is estimated that 20–40% of NSCLC develop CNS metastases during their disease course. Sensitivity of chemotherapy is limited in CNS metastases of NSCLC, because of restrict transit function of blood-brain barrier. The main treatment options based on whole brain radiation therapy (WBRT), stereotactic radiosurgery, neurosurgery or combination of them. Median overall survival (mOS) achieved in NSCLC with CNS metastases treated with irradiation methods is 6.5-7.5 months. Introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) – gefitinib, erlotinib, afatinib – improved the treatment possibilities in selected group of NSCLC patients harboring EGFR gene mutations. Also CNS metastatic lesions of NSCLC showed sensitivity to EGFR-TKIs (mOS to 15-17 months). Moreover, concurrent EGFR TKIs and WBRT may be used synergistic because potentially improve survival and delays intracranial progression. The main aim of the study was evaluation weather implementation of WBRT prior EGFR TKIs in NSCLC patients with CNS metastases might influence on their survival in comparison to patients without CNS metastases treated with EGFR TKIs monotherapy.

Methods:
The studied group included 178 NSCLC patients harboring EGFR gene mutation. 160 (110 female, 50 male; median age 67 years) patients with primary NSCLC received EGFR TKIs in first or second line of treatment. 18 patients (16 female, 2 male; median age 69 years), who had diagnosed CNS metastases, received WBRT prior administration of EGFR TKIs.

Results:
The treatment response was showed in both studied group. We did not observed a significant differences in survival in both studied groups. The progression free survival (PFS) in patients with primary NSCLC treated with EGFR TKIs and in patients with CNS lesions treated with WBRT prior EGFR TKIs was 10 vs. 9 months (p=0.785; HR=1.07; 95% CI=0,618-1.866), respectively. Also mOS did not show significance discrepancies in both studied group (26 vs. 32 months, respectively; p=0.32; HR=0.639; 95% CI=0.301-1.356). Implementation of WBRT prior TKIs did not lead to additional neurotoxicity.

Conclusion:
The following study showed that combination of WBRT prior TKIs in NSCLC patients with CNS metastases achieves similar benefit like treatment of primary NSCLC (without CNS metastases) with EGFR TKIs monotherapy. Based on overall data, patients with CNS metastases achieved better response rate when EGFR TKIs are administrated prior WBRT. It may be caused by EGFR TKIs feature which possess CNS penetrability for radiation.

Background:
Different chemotherapy regimen have different toxicity for lung. which regimen can improve the therapeutic effect and reduce the toxicity reaction have not reached a consensus. This was a retrospective study to evaluate the clinical toxicity reaction and therapeutic of different chemotherapy regimen combined with radiotherapy for the treatment of locally advanced non-small cell lung cancer (NSCLC).

Methods:
117 non-small cell lung cancer patients were randomly dividedinto 3 groups,(1) group A( the patients received concurrent chemotherapy consisting of gemcitabine /cisplatin combined with radiotherapy), (2)group B (the patients received concurrent chemotherapy consisting of paclitaxel /cisplatin combined with radiotherapy) and (3) group 3( the patients received the concurrent chemotherapy consisting of Changchun vinorelbine, irinotecan, pemetrexed or other chemotherapeuticdrugs/cisplatin combined with radiotherapy). All the patients received 2-4 cycles chemotherapy, and 2-2.2 Gy per fraction to a total of DT56-66 Gy thoracic radiotherapy 5 times per week.

Results:
The overall response rate (CR+PR) of the three group was86.7%, 78.7%, 81.5% (x[2]=1.626, P=0.653). The 1-year, 2-year and 3-year progressionfree survival ratesof the three group were: 57.3%, 30.1%, 18.3%; 49%, 33.3%, 18.4% and 39.2%, 27.8%, 16.5% (x2=0.581，P=0.748). The 1-year, 2-year and 3-year overallsurvival rates were 89.3%, 48.5%, 30.3%; 65.5%, 43.3%, 26.8% and 70.3%, 48.3%, 31.6% (x2=1.658，P=0.437). The 1-year, 2-year and 3-year distant metastasis rates were 68%, 38.2%, 21%; 50.3%, 35.3%, 28.1% and 56%, 35.3%, 29.6% (x2=0.559，P=0.756).The incidence of radiation pneumonitis of the 3 group were: 37.5%、24%、20%(x[2]=4.909，P=0.037). In addition, the incidence of radiation esophagitis and bone marrow suppression in the three groups were 26.7%, 18.7%, 14.8 (P=0.832) and 26.7, 50.6%, 33.3%, (P=0.024).

Conclusion:
The patients received concurrent chemotherapy consisting of gemcitabine /cisplatin combined with radiotherapycould significantly increase the incidence of radiation pneumonitis, the patients received concurrent chemotherapy consisting of paclitaxel /cisplatin combined with radiotherapyalso had a high incidence of radiation pneumonitis. The local control rate and survival rate of the three groups were not statistically different .

Background:
Image registration of paired inspiratory & expiratory CT is a potential method for generating surrogates of regional ventilation by assuming that local lung expansion & density changes of corresponding parenchymal voxels equate to ventilation. Potential lung cancer applications include functional lung avoidance radiotherapy planning and longitudinal assessment of treatment response. However, the physiological accuracy of the technique has yet to be validated. The aim of this study was to compare the spatial correlation of ventilation CT & [3]He MRI in a cohort of lung cancer patients.

Methods:
5 patients underwent expiration & inspiration breath-hold CT. [3]He & [1]H MRI were also acquired in the same breath and at the same inflation state as inspiratory CT. Expiration CT was deformably registered to inspiration CT for calculation of ventilation CT from voxel-wise differences in Hounsfield units. Registration accuracy was validated using a reference CT dataset for 6 patients with 100 expert anatomical landmarks defined on both images. Inspiration CT was registered to [3]He MRI via the same-breath anatomical [1]H MRI to enable direct comparison of [3]He MRI & CT ventilation in corresponding regions of interest located within the lungs as defined by a [1]H MRI lung mask (see figure). Spearman’s rank coefficients were used to assess voxel-level correlation. Figure 1



Results:
The mean registration error for the reference dataset was 1.1±0.2mm (mean±SD). Successful registration enabled computation of ventilation CT images at the inspiratory state and direct comparison of ventilation CT with MRI. The median (range) Spearman’s coefficient was 0.68 (0.45-0.76).

Conclusion:
This work demonstrates a method of acquiring CT & [3]He MRI in similar breath-holds to enable direct spatial comparison of ventilation maps. Initial results show moderate correlation between ventilation CT & [3]He MRI. Further large-scale clinical trials are required before clinical implementation of the technology.

Background:
Whole Brain Radiotherapy (WBRT) has been the standard of care for multiple brain metastases, but due to its toxicity and lack of survival benefit, its use in the palliative setting has started to be questioned. New clinical algorithms regarding the correct use of WBRT are needed.

Methods:
This was a retrospective, single institution cohort study, consisting of 280 patients with brain metastasized lung cancer who received WBRT at Karolinska University Hospital between 2010 and 2015. Information about RPA and GPA scores, demographics, histopathological results and received oncological therapy was collected. Predictors of Overall survival (OS) from the time of received WBRT were identified by Cox regression analyses. OS between GPA and RPA classes was compared by pairwise log rank test. A subgroup analysis was performed stratified by RPA class. Separate multivariate analyses were performed for RPA and GPA scoring systems, due to significant collinearity between them.

Results:
Median OS was 324, 130 and 41 days for RPA class 1(n=13), 2(n=165) and 3(n=101), respectively. Median OS for GPA groups 0 (0-1 points, n=168), 1 (1.5-2.5 points, n=98) and 2 (3-4 points, n=13) was 55, 166 and 110 days, respectively. Age>70 years was associated with worse OS. OS differed significantly between RPA class 1 versus 3 and 2 versus 3, GPA groups 0 versus 1 and age (p<0.0001 for all comparisons). Multivariate analyses are shown in table 1.Figure 1



Conclusion:
WBRT should be omitted for RPA class 3 patients. RPA class 1 patients should receive WBRT if clinically indicated. For RPA class 2 subgroup, patients with age≤70 years and GPA≥1.5 points should be treated as RPA 1, whereas patients with age>70 and GPA<1.5 points as RPA 3. WBRT is not recommended in patients older than 70 years and GPA≥1.5 points, and should be considered in younger patients with GPA<1.5 points.

Background:
Malignant lung lesions are commonly treated with stereotactic body radiotherapy e.g. Cyberknife®. However, a common problem of existing markers is migration which requires placement of several devices (usually 3). This study presents the results of a first animal evaluation of a new device that comprises several markers in a single implant device, which can be placed in a one-step bronchoscopic procedure.The purpose of the study was to demonstrate feasibility of a new « All in 1 » shape memory (Novatech[®]) Nitinol (Ni–Ti) device with Tantalum (Ta) markers, with safety and efficacy as key points, in a porcine model.

Methods:
Devices: 55 devices with 3 different shapes were used to determine the best design to reduce the migration risk. Animals: 2 series with a total of 8 Piétrain pigs, 5 animals for safety and 3 animals for efficacy evaluation using flexible bronchoscopy under general anesthesia. Follow-up period: 4 weeks. Image based analysis: CT scans pre- and post-procedure, after 2 and 4 weeks. Procedure: The markers where launched in different peripheral sub-segments using a radial EBUS guide sheath (Olympus® K-201) under fluoroscopy control. Evaluation: Procedure time, ease of placement, blinded CT scan analyses for evaluation of migration, complications and histological analysis.

Results:
All 55 devices were easily inserted into the peripheral bronchi. All devices could be visualized under fluoroscopy. The average procedure time was 5 min (+/- 2,6). 5 devices per animal were inserted in the first series and 10 devices per animal in the second series. During the 4 weeks clinical follow up and CT evaluation, no immediate or late complication occurred (pneumothorax, pneumonia, severe granulations or bleedings) in the first series. One partial (<20%) pneumothorax with spontaneous remission occurred in the second series due to forceful reintubation of the pig after accidental extubation. Migration has been seen in some pigs of the first series but not in the second series. No device related complications have been noted.

Conclusion:
In this pilot animal study the new « all in 1 » device for fiducial tumor marking was easy, quick and safe to use. It could be demonstrated that migration risk can be reduced with the right design.

Background:
This study is a phase II, prospective, pilot feasibility study designed to evaluate the safety of SBRT in selected patients with stage I NSCLC or metastatic lung cancer lesions using an ablative dose-adapted scheme with Free Flattening Filters (FFF) beams. An interim analysis was planned after enrollment of the first 27 patients. We present our results of this interim analysis.

Methods:
Medically inoperable patients or medically operable patients who refuse surgery with a life expectancy >12 months with lung lesions were candidates. All patients will be treated using FFF beams and the following schedule:

	Topographical Criteria
Dose	Distance to Chest Wall	Size	Distance to main Bronchus	Patients
A. 34Gy single fr.	>1cm	< 2cm	>2cm	5p (18.5%)
C. 50Gy (12 x 5 fr.s)Peripheral	<1cm	<5cm	>2cm	13p (48%)
D. 60Gy (7.5Gy x 8fr.)Central	>1cm	<5cm	<2cm	9p (33.3%)

Physical examination, toxicity and clinical response will been performed every three months for the first year and 6 months thereafter. Follow up will include Thoracic CT, pulmonary function, quality of life survey and blood test.

Results:
After median of follow up of 33 months (r 10-45) we analyzed 27p, with median age of 74y (r 83-58), 21 males (78%). Main reasons for inoperability were: 7 (26%) poor respiratory function, 10 (37%) with multiple comorbidities and 6 (22%) who refused surgery. Location was RUL 9 (33%), RLL 6 (22%), LUL 7 (26%), LLL 4 (15%). Lung primaries in 19p (70%) and the main histologies were Squamous Carcinoma (7, 26%) and Adenocarcinoma (7, 26%). T1a (9 , 33%), T1b (7, 26%),T2a (5, 18%) and T3 (2, 7%). Maximum grade of acute toxicity was GIII 1p(asthenia), and for chronic toxicity was GII (asthenia) 4p (15%). Local Control at 30 months was 84% (three local failures, two from metastasis) and overall survival was 100% at this time.

Conclusion:
FFF beams using dose risk adapted schedule seem to be a safe approach with a good response profile. Further analysis with the entire cohort of the trial is needed in order to confirm these early results.

Background:
Nowadays pulmonary oligometastatic disease it´s a common situation. SBRT for these patients is a feasible therapeutic choice. We present our experience using single fraction of 34Gy in solitary lesions in Lung. The main aim of this report is to show that single fraction of 34 Gy in lung lesions is feasible, without toxicity and good response profile.

Methods:
11 patients with 11 metastatic pulmonary lesions were prospectively treated with single dose of 34Gy. Inclusion criteria were: lesion size smaller than 2 cm, distance from the chest wall and main bronchus tree higher than 2 cm , in metastatic lesions primary tumour should be under control in PET scan. Patients were treated using True Beam machine (VARIAN). In 6 cases treatments were delivered without flattening filter beams. Median Age 68.7y (r51-82), Gender distribution 3 women and 8 men, Histology: 4 cases (36.4%) were metastasic lesions from rectum, 2cases (18.2%) were metastasic lesions from Colon), 3 (27.3%) were primary lesions from lung, 1 (9.1%) was metastasic lesions from sigma and another 1 (9.1%) was from lachrimal gland. All patients underwent 4DCT for contouring. Inmobilization was done by thermoplastic mask (Lorca Marin.S.A). Location: 4 cases (36.4%) were on the Right superior lobe (RSL), 3(27.3%) were on Left Superior Lobe (LSL), 2(18.2%) were on Medial Lobe (ML), 1(9.1%) was on the Lingula and another 1 (9.1%) on Left Inferior Lobe (LIL). Pulmonary function impact was annalyzed using pulmonary function tests performed before and after treatment .

Results:
After 45 months of follow up (r 8-45) no toxicity higher than grade 2 was detected. Dosimetric characteristics: mean volume of GTV 1.46cc (r 0.6-4.1), mean volume of PTV 10.85 (r7.1-22.2), D Max oesophagus 4.84 (r 2.7-8.3), D max Heart 8.63 (r0.22-30.07), D max trachea 6.09 Gy (r 0.3-11.1), Dmax skin 10.98(r7.0-14.4). Local control and distant control at 20 months were 77% and 54% respectively. Overall survival was 72% at this time . We detected a significant DLCO impairment of 18% r(2.82-35.13) p=0,027.

Conclusion:
To sum up, even this is a preliminary study with a small sample size, this fractionation scheme of SBRT is fast and well tolerated. However, we have detected an impairment of DLCO, so further study with bigger sample size is needed in order to stablish the magnitude of this impairment.

Background:
For limited stage small cell lung cancer (LSCLC), early thoracic radiotherapy (TRT) with chemotherapy and radiation dose more than 60Gy has been suggested as standard therapy. We aim to evaluate the survival outcomes in LSCLC patients with complete response (CR) to 50 Gy of TRT with chemotherapy.

Methods:
One hundred and fifteen patients with LSCLC who completed the TRT from August 2005 to March 2014 were reviewed retrospectively. We evaluated the age, gender, smoking status, AJCC stage, PET parameters, tumor volume, dose and timing of TRT, duration of treatment, and prophylactic cranial irradiation (PCI) as a prognostic variables. Gross tumor volume (GTV) was defined as the post-chemotherapy tumor volume at the time of the first TRT planning and the pre-chemotherapy involved lymph nodes. Clinical target volume (CTV) was defined as GTV with minimum 7mm margin including the first echelon drainage lymph node station. At the time of 50 Gy of TRT, follow up chest CT was performed to all patient and only patients who showed non-CR received 10 Gy or more radiation. Dose of TRT was median 50 Gy (range, 42 to 65 Gy). Ninety-seven (84.3%) patients received concurrent chemoradiotherapy (CRT) and PCI was performed in all eligible patients.

Results:
For all patients, median survival was 27.8 months. Two & 3-year OS were 60.7% and 38.58%, respectively. Sixty-five patients (56.5%) showed the complete response (CR) and fifty patients (43.5%) showed non-CR. There was correlation between tumor response to 50Gy of TRT and the ratio of GTV to CTV (p=0.008) or AJCC stage (p=0.036). With univariate analysis, AJCC stage (p<0.001), ratio of GTV to CTV (p = 0.005), tumor response to 50Gy of TRT (p = 0.004), the duration from the start date of induction chemotherapy to the end of TRT (SER, p = 0.003), and PCI (p = 0.035) were statistically significant predictor of OS. Multivariate Cox regression demonstrated that AJCC stage (p<0.001) and SER (p = 0.007) only were significant. In patients with SER <80days & CR to 50Gy TRT, median survival was not yet reached until now.

Conclusion:
LSCLC patients who showed CR to 50 Gy of TRT and completed TRT within 80days represented the outstanding survival outcomes. Based on these results, we need the further study evaluating whether dose escalation more than 50 Gy is promising for survival improvement in patients with CR at the time of 50 Gy of early TRT and chemotherapy.

Background:
Stereotactic body therapy (SBRT) has been widely used as a safe and effective treatment method for primary or metastatic lung tumors. Among new techniques for SBRT, utilization of flattening-filter-free (FFF) beams allows more rapid delivery of treatment doses and may enable to improve clinical stability and comfort. FFF techniques have been adopted to our volumetric modulated arc therapy (VMAT)-SBRT system since 2013.We evaluated the safety and availability of VMAT-SBRT using FFF techniques in a clinical field of treatment of primary and metastatic lung tumors.

Methods:
A total of 62 lung VMAT-SBRT cases treated at our institution using an Elekta-synergy system from 11/2013 to 11/2015 were reviewed. SBRT plans using VMAT with single partial arc (220 degree) were optimized in the pinnacle[3] treatment planning system with inhomogeneity correction. We targeted at 48 cases with 1) one or two targets; 2) tumor diameter<40mm; 3) dose prescription= 55Gy/4Fr for peripheral lesions or 56Gy/7Fr for central lesions (PTV-D95); 4) image diagnostic approaches performed after treatment. In each prescription dose, We compared between two groups (flattening filter; FF vs. FFF) in total monitor units (MUs), treatment time, dose for tumors (ITV-D5, D50, D98, etc.), dose for lungs (V5,V20,MLD etc.), local recurrence, radiation pneumonitis, the other adverse events.

Results:
Before November 2014, 24 patients (peripheral: central=19:5) were treated with conventional FF VMAT, and remaining 24 patients (peripheral: central=18:6) with FFF VMAT. There were T1 primary lung tumors in 29 patients (FF:FFF= 14:15) including 8 GGOs, T2- in 10 patients (5:5), and metastatic tumors in 9 patients (5:4). In the both prescription dose, significant differences were found in the average treatment times; FF: FFF=3.65:1.45(sec) for 55Gy/4Fr, 2.28:1.26(sec) for 56Gy/7Fr respectively, while no significant difference in the mean total MUs; FF:FFF respectively, while no significant difference in the mean total MU values; FF:FFF= 2128(range, 1099-2817):2100(range, 1505-2343). The dose for tumors and lungs did not show significant differences between two groups.Local recurrence occurred in 3 patients (FF: FFF=1:2), Grade2 radiation pneumonitis occurred in 5 cases (FF: FFF=3:2), and the other adverse events were within an allowance compared with past reports.

Conclusion:
The VMAT-SBRT using FFF techniques could shorten the treatment time of lungSBRT keeping the high local control rate and the low toxicity in the clinical field.

Background:
Moving lung tumours exceeding the observed motion from planning 4D computed tomography (4DCT) can result in reduced dose coverage in stereotactic ablative body radiation therapy (SABR). 4D cone-beam CT (4DCBCT) facilitates verification of tumour trajectories before each treatment fraction. Using implanted Calypso beacons in the lung as ground truth, this work aims to assess how well 4DCT and 4DCBCT represent the actual motion range during imaging and irradiation.

Methods:
4DCBCT was reconstructed for 1-2 fractions of 6 patients (three implanted Calypso beacons) receiving lung SABR from the projections acquired for treatment setup CBCT. Two reconstructions per projection set were created using the prior image constrained compressed sensing (PICCS) method based on the Calypso motion trajectories or an external respiratory signal (Philips Bellows). Calypso beacons were segmented for all 10 bins of the 4DCT and 4DCBCT sets and the centroid position calculated. Beacon centroid motion as seen on the 4DCT and 4DCBCT with respect to reference phase (end-exhale) was extracted and compared with the actual beacon centroid motion during CBCT acquisition and during irradiation.

Results:
Both methods for 4DCBCT reconstruction failed to capture sudden motion peaks during scanning (see Fig. 1), but performed similar to the 4DCT. In general, 4DCT and 4DCBCT underestimated the actual beacon centroid motion. In the SI direction 22-27% of the actual motion exceeded the motion range from 4DCT and 4DCBCT imaging. In AP and LR direction up to 39-58% of the motion exceeded the observed motion range from 4D imaging. Figure 1



Conclusion:
Both 4DCT and 4DCBCT failed to represent the full tumour motion range. For a safe treatment delivery this needs to be accounted for either by sufficient margins or more preferably real-time treatment adaptation directly tackling motion peaks and unpredictable motion.

Background:
Delineation variability is a major uncertainty in radiotherapy for lung cancer. As respiratory motion is an important part of this uncertainty, respiratory correlated computed tomography (4DCT) imaging is widely used. Several image reconstruction techniques are available to generate 3D data for delineation, such as the Maximum Intensity Projection (MIP) and the mid-ventilation (MidV) technique. The latter selects data at the time weighted mean tumour position. Both techniques are prone to motion artefacts. The new Mid-position (MidP) technique averages CT data after motion compensation to the mean position reducing such artefacts. The aim of this study is to evaluate interobserver variation for tumour delineation for these three image reconstruction techniques.

Methods:
4DCTS of 10 patients were reconstructed using MIP, MidV and MidP methods. Seven specialised radiation oncologists delineated the primary tumour (GTVp) and lymph nodes (GTVln) on each reconstruction with a minimum of 4 weeks interval between delineations, using a provided protocol. The interobserver variation in the delineation of the GTVs was evaluated by calculating delineated volumes, conformity index (CI), and local SD between delineated contours (SDlocal) for GTVp and GTVln.

Results:
The differences in delineation variability are small (Table 1), with the only significant differences in overall volume (Friedman test): the MidP volume is slightly smaller than the MidV volume indicating a larger confidence in delineation. Counter-intuitively the observer variation was higher on the Midp images for the GTVln which seems to be related to increased reliance on the PET-CT images when delineation on the lower quality MIP images.

Table 1: Interobserver variability in the delineation of the GTVp and GTVln

Image	Mean Volume (cc)	Mean CI	Mean SDlocal (cm)
			ALL	GTVp	GTVln
MIP	81.91	0.568	0.363	0.330	0.477
MidV	66.17	0.576	0.327	0.314	0.425
MidP	62.23	0.602	0.337	0.261	0.543
	MIP>MidV (p=0.000) MIP>MidP (p=0.000) MidP	p=0.354	p=0.655	p=0.648	p=0.834p

Conclusion:
Although not statistically significant, the MidP images had the highest CI, lowest volume and the lowest SD for the GTVp but not for the GTVln. Overall the MidP had the smallest interobserver variation. Adherence to delineation protocols for lymph nodes must be improved to benefit from the better image quality of MidP.

Background:
Radical radiotherapy (RT) regimens for NSCLC vary considerably. In routine practice our centre has predominantly used continuous hyperfractionated accelerated radiotherapy (CHART, 54Gy in 36 fractions over 12 days)) and accelerated hypofractionated RT (55 Gy in 20 fractions over 4 weeks) since 1997. This report updates previous data presentation [1] including patients treated between 2005 - 2011.

Methods:
Case notes and radiotherapy records for all patients receiving radical radiotherapy were retrospectively reviewed. Patient demographics, tumour characteristics, RT and survival data were collected. Descriptive statistical analysis and Cox regression analysis was performed using SSPS.

Results:
516 patients received radical radiotherapy, over 95% received CHART (237 patients) or hypofractionated RT (257). Median age was 70 yrs, and 60% percent were male. PET staging was performed in 81%, and 26%, 17% and 51% were stage 1, 2, 3 respectively. 81% were WHO performance status 0-1. 44% were squamous carcinomas, 21% non-squamous, 20% not otherwise specified ,with 14% without histological diagnosis. Prior chemotherapy was given to 36%, of whom 84% had stage III disease. 99.6% completed their prescribed radiotherapy treatment. 2 year survival was 47.5% and median overall survival from time of diagnosis was 23 months. Univariate analysis showed statistically significant association of survival with gender, stage and histology, but not age, PS or RT regime.

Conclusion:
Discussion: This single centre experience reflects the outcome of unselected consecutively treated NSCLC patients. Patient selection for the two radiotherapy regimens was largely down to patient preference for in- or out-patient treatment. Encouragingly, CHART outcomes seem a little better than those reported in the original CHART paper [2] and our previous cohort [1]. We feel this probably reflects improved patient selection following the introduction of PET staging into routine practice. Conclusions: The outcome for patients treated with accelerated radiotherapy fractionations in routine practice remains encouraging, and randomised trials comparing these approaches with conventionally fractionated chemoradiotherapy regimes are needed. 1. Pemberton LS, Din OS, Fisher PM, Hatton MQ. Accelerated radical radiotherapy for non-small cell lung cancer (NSCLC) using two common regimens: a single centre audit of outcome. Clinical Oncology 2009;21:161-7 2. Saunders M et.al. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. CHART Steering Committee. Lancet. 1997 Jul 19;350(9072):161-5

Background:
The ability to accurately visualize and delineate tumour and surrounding normal tissue is an essential component of radical radiotherapy treatment planning and in non-thoracic sites has been improved by integrating MRI. This early work investigated and optimized different MRI sequences for potential use in thoracic radiotherapy planning.

Methods:
15 patients with primary lung cancer were scanned using a 1.5 Tesla scanner (Magnetom Aera; Siemens) and radiotherapy planning scanner (Philips Brilliance CT Big Bore, Philips Medical Systems). An identical patient immobilisation board was used (Extended Wing Board; Oncology Systems Limited) for both scans. Multiple MRI sequences were investigated and optimised to give similarity to contrast CT scans (3- 4 mm slice thickness, whole thorax coverage and axial imaging). After reviewing the entire anatomic structure, ability to visualize the primary tumour, lungs, heart and oesophagus were scored using a 5-point system (1, unacceptable; 2, poor; 3, acceptable; 4 good; 5 excellent) and compared to CT (two tailed t-test).

Results:
Respiratory triggered T2w SPACE (n=12) and T2w TSE (n=3) sequences suggest improved visualization of primary tumour (mean score 4.2 and 4.0) in comparison to CT (3.9), p> 0.05. T2w TSE, T1w TSE (n=3) and T1w 2-point DIXON (n=5, breath hold) sequences may enhance oesophageal (4.3, 3.7 and 3.6) and cardiac (3.3, 4 and 3.4) visualisation, compared with CT (3.0), p>0.05). CT (n=15) was the optimal imaging modality for viewing lungs (p< 0.05). T1w Cartesian VIBE (n=12, breath hold) provided no clear benefit over CT and diffusion-weighted single-shot-planar images (n=8) remain problematic due to image distortion. Figure 1



Conclusion:
This preliminary study demonstrates the potential for MRI to improve the visualization of thoracic primary tumours, oesophagus and cardiac anatomy, all of which can be challenging to see on CT imaging, particularly in patients with collapse, consolidation or mediastinal tumour invasion.

Background:
Lung tumour positional uncertainty has been identified as a major issue that deteriorates the efficacy of radiotherapy. The recent development of the Kilovoltage intrafraction monitoring (KIM) which uses widely available gantry-mounted kilovoltage (kV) imager has been applied to prostate motion monitoring. This study reports the first clinical result of KIM for lung cancer radiotherapy with an Elekta machine.

Methods:
A locally advanced stage IIIlung cancer patient undergoing conventionally fractionated VMAT was enrolled in an ethics-approved study of KIM. A Gold Anchor fiducial marker (0.4 mm diameter x 20 mm length) was implanted in the tumour near the right hilum (Fig 1, left). kV images were acquired at 5.5 Hz during treatment. Post-treatment, markers were segmented and reconstructed to obtain 3D tumour trajectories. A Microsoft Kinect audio and depth sensing device was also mounted on the couch to get the external respiratory signal. Figure 1 Figure 1. kV image of the Gold Anchor marker (left) and the KIM measured lung tumour 3D motion and the external Kinect signal (right).



Results:
Our method was successfully applied for the first KIM lung patient. The fiducial marker was visible on 62.9% of the kV images. The average lung tumour motion (mean ± SD) in superior-inferior (SI), anterior-posterior (AP) left-right (LR), directions were 0.27±7.52, -0.09±3.37, and -0.64±4.55 mm respectively. Seven fractions of lung tumour 3D motion and Kinect external signal were acquired, with the representative result illustrated (Fig 1, right).

Conclusion:
This is the first time that KIM has been used for intrafractional tumour motion monitoring during lung cancer radiotherapy, and also the first implementation of KIM on an Elekta imaging platform. This clinical translational research milestone paves the way for the broad implementation of image guidance to facilitate the detection and correction of geometric error for lung radiotherapy, and resultant improved clinical outcomes.

Background:
Many technological and methodical advances have made stereotactic body radiotherapy (SBRT) more accurate and more efficient during the last years. This study aims to investigate whether technological innovations and experience in SBRT also translated into improved local control (LC) and overall survival (OS).

Methods:
The working group “Stereotactic Radiotherapy” of the German Society for Radiation Oncology established a database of 700 patients treated with SBRT for lung metastases in 20 German centers between 1997 and 2014. It was the aim of this study to analyze the impact of FDG-PET staging (fluoro-deoxy-glucose positron emission tomography), biopsy confirmation, image guidance, immobilization and dose calculation algorithm as well as the influence of SBRT treatment experience on LC and OS.

Results:
Median follow-up time was 14.3 months (range 0-131.9 months) with 2-year LC and OS of 81.2% and 54.4%, respectively. In multivariate analysis, all treatment technologies except FDG-PET staging did not significantly influence outcome. Patients who received pre-SBRT FDG-PET staging showed superior 1- and 2-year OS of 82.7% and 64.8% compared to patients without FDG-PET staging resulting in 1- and 2-year OS rates of 72.8% and 52.6%, respectively (p=0.012). SBRT treatment experience was identified as the main prognostic factor for local control: institutions with higher SBRT experience (patients treated with SBRT within the last 24 months) showed superior LC compared to less experienced centers (p≤0.001). SBRT treatment experience within the last 24 months was independent from known prognostic factors for LC.

Conclusion:
Technological and methodical advancements except FDG-PET staging prior to SBRT did not significantly improve outcome in SBRT for pulmonary metastases. On the contrary, LC was superior with increasing SBRT treatment experience of the individual center.

Background:
Radical radiotherapy (RT) regimens for NSCLC vary considerably and there is little data on outcomes for elderly patients, who are underrepresented in clinical trials. Our centre has routinely used continuous hyperfractionated accelerated radiotherapy (CHART, 54Gy in 36 fractions over 12 days) and accelerated hypofractionated RT (55 Gy in 20 fractions over 4 weeks) since 1997. We have examined outcomes for patients over the age of 80 treated between 2005 – 2011.

Methods:
Case notes and radiotherapy records for all patients receiving radical radiotherapy were retrospectively reviewed. Patient demographics, tumour characteristics, RT and survival data were collected. Descriptive statistical analysis and Cox regression analysis was performed using SSPS.

Results:
516 patients received radical radiotherapy: 73 were over 80 years old; 71 % were male; and 85% WHO performance status 0-1. PET staging was performed in 87%, with 41%, 22% and 32% being stage 1, 2, 3 respectively. 51% were squamous carcinomas, 18% non-squamous, 12% unspecified, and 19% without a confirmed histological diagnosis. 2 patients received primary chemotherapy. 40% received CHART, and 56% hypofractionated RT. All patients completed their prescribed radiotherapy treatment. 2 year survival was 67% and median overall survival from time of diagnosis was 22 months. Univariate analysis suggested stage was the only statistically significant variable associated with survival.

Conclusion:
Discussion: Our results confirm that accelerated radiotherapy schedules are deliverable in elderly populations with NSCLC who are generally not considered suitable for standard treatment with chemo-radiotherapy. The outcomes are similar to those reported in our younger patient cohorts [1] and appear to be as good as those reported in the original CHART paper [2]. Conclusions: The use of accelerated radiotherapy fractionations for the radical treatment of elderly patients with NSCLC is a feasible and well tolerated treatment for those patients not suitable for a chemo-radiotherapy approach. Outcomes are encouraging, but trials specific to this population are needed to define the optimal radiotherapy regimen. Ref: Pemberton LS, Din OS, Fisher PM, Hatton MQ. Accelerated radical radiotherapy for non-small cell lung cancer (NSCLC) using two common regimens: a single centre audit of outcome. Clinical Oncology 2009; 21:161-7 2. Saunders M et.al. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. CHART Steering Committee. Lancet. 1997 Jul 19; 350(9072):161-5

Background:
The main reason for a low progression-free survival rate in radiotherapy for NSCLC is that the lung is sensitive to radiation, and radiation-induced lung injury is closely related to the exposed volume of the lung tissues. A large irradiation field resulted in difficulty in increasing target dose, so clinically complete remission is very difficult in the primary lesion of the lung cancer. Therefore, as opinions are currently divided on whether it is necessary to delineate the CTV, this study aimed to study the impact of delineating CTV on the treatment of lung cancer.

Methods:
A total of 177 patients with medium and late stages of NSCLC diagnosed by pathology and/or cytology were selected. These patients received three-dimensional conformal radiation therapy (3-DCRT) or intensity modulated radiation therapy (IMRT) were divided into an undelineated CTV group (A group) and delineated CTV group (B group). Gross tumor volume (GTV) and planning target volume (PTV) were delineated in the A group, while CTV was additionally delineated in the B group. Dose was fractionated in pulmonary lesions in the two groups: 200-220 cGy/time, 5 times per week, and the radiation dose was DT5600- 6600 cGy.The mean lung tumor doses were comparable between the two groups.

Results:
The short-term overall response rate had a trend to be higher in group B, while the 1-year, 2-year and 3-year distant metastasis rates, progression-free survival and overall survival rates had a trend to be higher in group A, but none of the differences were significant. The incidence of radiation pneumonitis was higher in group B (33.33% vs. 16.30%, P=0.017), but none were Grade-4 or worse.

Conclusion:
Undelineating the CTV in radiotherapy of lung tumors tends to reduce the radiation field and significantly reduce the incidence of radiation pneumonitis, but it don’t reduce overall response rate, the progression-free survival and overall survival rate.

Background:
Lung cancer related mortality remains high after radiotherapy (RT) despite advances in treatment. The RTOG 0617 study (1) reported increased mortality within the higher radiation dose treatment arm, though toxicity was similar between the two study arms. One possible explanation was, increased radiation dose to the heart. Typically radiation induced heart disease (RIHD) is considered a late effect of RT in lymphoma and breast cancer. But RT dose prescribed in lung cancer is greater, and may result in acute effects in a population of patients with underlying cardio-pulmonary disease. Hence detailed dosimetric predictors are required for different cardiac morbidity endpoints. The CART study (2) was a prospective study investigating RIHD with serial cardiac MRI scans and the team involved developed a technique to analyse radiation dose of cardiac substructures without the MRI scan.

Methods:
CT planning scan was reformatted to develop a standardised method to outline in detail, cardiac substructures such as the left ventricular (LV) myocardium segments supplied by the Coronary Arteries (As). Other cardiac substructures such as cardiac chambers, conduction system and valves were contoured. This technique was applied to the planning scans of lung cancer patients and the dose to structures was calculated

Results:
Initially 5 patients who died within 3 months after radical RT were assessed. The RT treatment was 55Gy in 20 fractions over 4 weeks using 3D conformal RT technique. 3 patients had underlying cardiac or pulmonary comorbidities and pulmonary function as acceptable for all patients to proceed with radical RT. Dose to OARs were acceptable and all patients completed treatment. Radiation dose to the heart –mean heart dose range 158cGy-1910cGy, maximum heart dose range 1521-5669cGy and V20 dose range 0%-36% and V50 dose ranged from 0%-19%. Dose to left ventricular myocardium – LAD territory was maximum dose range (MaxDR) 71-2086 (cGy) and mean dose range (MeanDR) 112-802 (cGy); LCX territory was MaxDR 71-2549 (cGy) and MeanDR was 81-562 (cGy), and RCA territory was MaxDR 45-372 (cGy) and MeanDR was 44-178 (cGy) - demonstrated that anterior and lateral areas of LV myocardium received higher radiation dose. Dose to conduction system was high – SA node maximum dose ranged from 1140-5372 (cGy) and AV node maximum dose range was 103-1660 (cGy).

Conclusion:
It is feasible to use the CT planning scan to analyse retrospective patients for RT dose of coronary A myocardial territories, conduction system, and other substructures. An analysis of a larger sample of patients is planned.

Background:
Fiducial marker has been an effective and intuitive way to localize motion target for lung Stereotactic Body Radiotherapy (SBRT). However, due to the complexity for motion target imaging, the optimal target localization strategy still need to be developed to improve the efficiency and effectiveness of the clinical procedure. In this study, the golden marker moving in different directions was characterized in Conebeam CT images for optimal localization application.

Methods:
A Visicoil linear fiducial marker was selected for this study. The length and diameter of the marker were 5mm and 1mm. The motion was generated by Real Time Position Management (RPM) phantom from Varian Medical System. The motion was simulated to be about 2.3 seconds breathing period and about 1cm amplitude and phantom was positioned at three directions along the anterior-posterior (AP), left-right (LR), and In-Out (IO) of the couch. The CBCT images were taken in Truebeam On-board Imaging System. And targets were defined by auto-contouring with Hounsfield Unit(HU) setting from minus 900 to positive 4000 in Eclipse treatment planning system. The targets were post-processed with keeping the largest part, and converted to high resolution segment. Their characteristics were described by shape, volume, center of the volume and volume pixel information, which were attained by MIM Software.

Results:
In this CBCT study, for the given the contouring technique, the volumes of Visicoil fiducial maker were 0.28cc, 0.35cc, and 0.27cc as moving along AP, IO and LR direction. They were corresponding to 143%, 163% and 236% of the static volume. The maximum HUs inside each moving target were 3395, 343 and 3097, which were 49 %, 13% and 44% of those inside the static marker volumes. The center distances between the moving and static targets were 0.63cm in average with standard deviation at 0.02cm.

Conclusion:
When golden makers are applied for localization of treatment target in Lung SBRT, the geometric distance can be reflected in accurate level submillimeter; however, the directional motions could generate large HU difference, which is possibly a challenge to distinguish the boundary of moving tumor. And resolution limit around region of marker should be further investigated to understand the difference between marker tracking or soft tissue localization techniques

Background:
Radical radiotherapy is widely used in the treatment of non-small cell lung cancer (NSCLC) among patients ineligible for surgery. Although side effects of radical radiotherapy have been well documented in clinical studies there is little real world prospective data describing their course, severity and effect on patient experience following treatment.

Methods:
NSCLC patients from the Beatson West of Scotland Cancer Centre (a specialised cancer care centre serving a population of 2.4m), treated with radical radiotherapy between September 2014 to December 2015, were offered followed up by a specialist nurse led clinic. This consisted of a telephone consultation at 2 weeks and clinic attendance at 2 and 6 months. Patient and tumour demographics were collected. Side effects were recorded at each visit and graded using the Common Terminology Criteria for Adverse Events (CTCAE). Descriptive statistical analysis was performed using Stata 14.0

Results:
92 consecutive patients attended the clinic, 50% were male and the median age was 70 (IQR 63.5-78) years. 48 patients had squamous carcinoma and all were performance status 0 – 2. The breakdown was 16% 23% and 56% for stage I, II and III respectively. A total of 62 (67%) of patients received 55Gy in 20 fractions. Overall one-year survival was 59.7% (95%CI 47.0-70.3%). Information from 75% was obtained by telephone at 2 weeks and in clinic at 8 weeks post treatment. At 6 months 54% attended for assessment. The most commonly reported side effects at week 2 were fatigue (90%), dyspnoea (70%), oesophagitis (70%), anorexia (26%) and cough (21%). At week 8 side effects were similar except that oesophagitis had decreased to 23% (p<0.001), and cough increased to 30% (p=0.07). All side-effects were graded 2 or less with the exception of one patient with grade 3 oesophagitis at week 8.

Conclusion:
This study confirmed a high level of patient engagement with a nurse led follow up protocol which was able to capture detailed information about frequency and severity of side effects following radical thoracic radiotherapy. This confirmed that the side effects patients experience were temporary and manageable.

Background:
The purpose was to evaluate impact of systemic inflammation and sarcopenia on outcomes after stereotactic body radiotherapy (SBRT) for T1N0M0 non-small cell lung cancer (NSCLC) as a supplementary analysis of Japan Clinical Oncology Group (JCOG) study JCOG0403.

Methods:
Pretreatment serum C-reactive protein (CRP) was used as a marker for systemic inflammation. Patients were divided into high and low CRP groups with a threshold value of 0.3 mg/dL. Paraspinous musculature area (PMA) at a level of the 12th thoracic vertebra was measured on simulation CT with thresholding Hounsfield Units between -29 and 150. When PMA was lower than the gender-specific median, the patient was classified as sarcopenia. Toxicities, overall survival (OS) and cumulative incidence of cause-specific death were compared between groups. Kaplan-Meier method and cumulative incidence function were applied to estimate proportion of OS and cumulative incidence of cause-specific death, respectively.

Results:
Of 169 patients enrolled into JCOG0403, 60 operable and 92 inoperable patients were included into this study after excluding 5 patients ineligible for JCOG0403 and 12 patients whose simulation CT images were unavailable or unsuitable for the PMA measurement. Forty-two patients were classified as high CRP. Medians of PMA were 31.6 cm[2] (range, 12.6-52.9) and 25.1 cm[2] (range, 3.4-38.5) in male and female, respectively. Proportions of toxicities Grade 3-4 were 19.1% and 10.9% in the high and low CRP groups; and 17.1% and 9.2% in the sarcopenia and non-sarcopenia groups, respectively. In the operable patient cohort, OS significantly differed between the CRP groups (log-rank test P=0.009; hazard ratio of high CRP 2.43, 95% confidence interval 1.23-4.80; 3-year OS of 58.8% and 83.6% for high and low CRP, respectively). This difference in OS was mainly contributed by difference in lung cancer death (Gray’s test P=0.070; 3-year cumulative incidence of 29.4% and 7.1%, respectively). No impact of sarcopenia on OS was observed in operable patients. In the inoperable patient cohort, OS did not differ between the CRP groups (log-rank test P = 0.925). No significant difference was observed in OS between the sarcopenia groups, either.

Conclusion:
The present study suggests that systemic inflammation may provide prognostic information for operable patients receiving SBRT for early-stage NSCLC. Further studies are warranted to confirm these findings.

Background:
To evaluate toxicity of RTOG 0915 protocol’s constraints in lung SBRT for patients treated with 60Gy in 5 fractions.

Methods:
Between 2010 and 2015, 77 pts were treated with SBRT for single or multiple lung lesions, 43 pts. (55.8%) for primary tumor and 34 pts. (44.2%) for metastatic lesion. A total of 80 lesions were treated. Four dimensional CT images were acquired; maximum intensity CT reconstruction was used for ITV delineation and average CT reconstruction for OAR contouring and dosimetric calculation.We prescribed 57Gy to 95% of PTV volume and OAR constraints are reported in table 1. Figure 1 Dose calculation was performed in 70% of the cases with collapsed cone convolution algorithm and 7 fields 3D technique and the remaining 30% with Monte Carlo dose calculation and intensity modulated fields (dynamic MLC and VMAT tecniques). Treatments were delivered in 28% of the cases on Elekta-Precise accelerator with electronic portal films on-line setup verifications and the remaining 72% on Elekta-Agility accelerator with cone beam CT. We evaluated pre-treatment respiratory function and we treated only pts. with %FEV1 > 40%. We reported toxicity following CTCAE v3.0 score.



Results:
All the dose/constraints were respected except for the chest wall dose that was higher than 30 Gy in 8 pts. (10.3%). Toxicity was evaluated in all the patients except one that was lost in follow-up. We found only lung or chest wall toxicity: 11 pts. (14.2%) with a G2 dyspnea, one patient with a G3 dyspnea; 8 pts. with a G2 chest wall pain and 1 with a symptomatic rib fracture . We find more lung toxicity in patients with primary tumor because of more chronic lung disease prior to the treatment.

Conclusion:
The use of these SBRT constraints is safe in both metastatic and primary lung lesions, with a particular attention on pre-treatment respiratory function.

Background:
Purpose: SABR is popular because of the high rates of local control seen in lung cancer patients. However, prospective head to head trial data comparing the toxicity of SABR to conventionally fractionated radiotherapy are still awaited. We compare pneumonitis rates in SABR vs. non-SABR treatment for early stage lung cancer patients.

Methods:
Methods: A PUBMED search of all human, English language papers on SABR and on-SABR radically treated early stage lung cancer patients was performed until March 2016. The date range for the non-SABR patients extended back to January 1995, but the first 3D-CRT SABR papers assessed were found in 2003. Results of these searches were filtered in accordance to a set of eligibility criteria and analysed in accordance with the PRISMA Guidelines.

Results:
Results: The systematic search yielded a total of 184 SABR and 360 non-SABR articles, which were filtered down to 75 SABR and 23 non-SABR articles. SABR patients were older than non-SABR patients with 35/75 SABR papers and 0/23 non-SABR papers recording a median age >75 years. Meta-analysis did not demonstrate a significant difference in pneumonitis rates between patients receiving SABR [11.4% ( 95% CI of 9.7 to 13.3)] and non-SABR treatment [14.4% (95% CI of 10.6 to 18.8)].

Conclusion:
Conclusion: Although meta-analysis did not confirm that SABR had lower rates of pneumonitis, it appears that SABR patients are older, and thus potentially frailer than the non-SABR radically treated patients. SABR is safe and has justifiably become the treatment of choice for inoperable patients.

Background:
Stereotactic radiotherapy (SRT) for lung tumors and related pneumonitis have been increasing, associated with the widespread use of SRT. However, insufficient research on pneumonitis related to SRT has been reported. Therefore, we attempted to clarify the clinical features and risk factors for pneumonitis.

Methods:
Between October 2011 and 2014, 91 patients received SRT for thoracic tumors in our hospital. We carried out a retrospective analysis of their data based on medical records and chest images, and we summarized the clinical features and the presence or absence of pneumonitis.

Results:
Of 91 patients who received SRT, 62 (68.1%) were men and 29 (31.9%) were women, with a median age of 77 years. Fifty-seven (62.6%) patients were smokers and 34 (37.4%) were non-smokers. Furthermore, 17 (18.7%) patients had pre-existing pulmonary fibrosis and 48 (52.7%) had pre-existing emphysema. The target diseases treated with SRT were 62 cases of primary lung cancer and 29 cases of other diseases (e.g., metastatic lung tumor). Pneumonitis related to SRT was observed in 74 cases (81.3%). Their grades (CTCAE version 4) were as follows: 54 (59.3%) cases of grade 1, 15 (16.5%) cases of grade 2, 4 (4.4%) cases of grade 3, 1 (1.1%) case of grade 4, and no cases of grade 5. Grade 2 or more severe pneumonitis was significantly higher in patients who had pre-existing fibrosis (p=0.016). Grade 3 or more severe pneumonitis, clinically serious, was observed in 5 cases (5.5%), of which 4 were men and 1 was a woman, and 4 were smokers. In addition, 4 of them had both pre-existing fibrosis and emphysema. All were treated with steroid therapy and improved.

Conclusion:
Pneumonitis related to SRT, including mild cases, was observed frequently. Pre-existing pulmonary fibrosis is suggested to be an independent risk factor for pneumonitis caused by SRT, as well as by conventional radiotherapy. However, even severe pneumonitis was improved by steroid therapy. These observations highlight the importance of steroid therapy. We will analyze more cases, including patients under observation, and will report these data at the venue.

Background:
Radiotherapy (RT) alone or in combination with chemotherapy (CT) are essential in treatment of non small cell lung cancer (NSCLC). A limitation for those therapies is the radiosensitivity of the lung. The aim of this study was to evaluate the incidence of radiation pneumonitis as well to identify potential markers for its early detection and to determine changes in the BAL protein expression.

Methods:
Fourteen NSCLC patients diagnosed at Multidisciplinary Lung Cancer Unit treated with chemotherapy-radiotherapy (CT-RT) or RT alone were enrolled in this prospective study. The collected variables were anthropometric values, lung function, tumor features and RT dosimetric data. A fiberopticbronchoscopy for bronchoalveolar lavage (BAL) was performed in both lungs before RT and at the third week of treatment. Radiation pneumonitis was scored according to the “Common Terminology Criteria for Adverse Events v4.0”. One patient with grade 1 pneumonitis and one patient with grade 3 pneumonitis were selected to perform the protein analysis using “Human Cytokine Array Panel A” (R&D Systems). The normality was determined with the Kolmogorov-Smirnov test. Student’s t-test was used when variables had a normal distribution. Differences were considered statistically significant when p values were < 0.05.

Results:
All patients develop radiation pneumonitis, 35.75% of patients developed grade 1 pneumonitis, 20% grade 2, 35.75% grade 3 and 6.66% grade 5. Four patients developed pneumonitis in the lung without tumour. The decrease in lung diffusion capacity for carbon monoxide (DLCO) was the most sensitive parameter for determining the existence of early lung damage (p=0.04). Development of radiation pneumonitis was not associated with baseline lung function neither RT dosimetric data. The BAL protein expression profile was different between the two patients before RT. Expression of PAI-1, IL-1ra, MIF, and CXCL-1 in patient with pneumonitis grade 1 were increased only in the lung with tumor however these proteins were also increased in patient with pneumonitis grade 3 but in both lungs. It was significant that in the 2 cases, RT induced similar changes in BAL protein expression in both lungs.

Conclusion:
In this prospective study, the incidence of radiation pneumonitis was greater than previously reported in the literature. The DLCO decline was the most sensitive parameter for its early detection. The risk to develop radiation pneumonitis appeared to be independent of dosimetric parameters and might be related with the baseline inflammatory state. According to BAL protein expression analysis, RT produced comparable molecular changes in both lungs. Funded by SEPAR and IDIBELL.

Background:
The prognosis from non-surgical treatment of non- small cell lung cancer remains poor. Patients are often elderly with multiple comorbidities. Evaluating toxicity and patient outcomes is essential to guide appropriate patient selection for intensive treatment. In addition to overall survival (OS) and progression free survival (PFS), 90 day mortality is increasingly recognised as a metric of service quality in the delivery of radiotherapy and reporting is recommended by the National cancer reform Strategy UK 2011.

Methods:
Consecutive patients were included who commenced radical radiotherapy between January 2013 and December 2015. 90 day mortality was calculated from the last day of radiotherapy to the date of death. PFS and OS were estimated from Kaplan-Meier curves. Patients who developed a recurrence were reviewed to determine if this was within the radiotherapy field.

Results:
115 patients were included. The median age was 70 (range 43-96), recent trials such as RTOG 9410 have an age limit of 75-79. Median follow-up was 14 months (range 1-38). The majority (61.7%) were stage III. 57.4% were ex-smokers, 41.7% were performance status 1 and 86% had a co-morbidity score of 1 or above (ACE27). 45.2% received radiotherapy alone, the remaining received concurrent chemo-radiotherapy . 7 patients (6%) died within 90 days. The 1 year PFS and OS were 70% and 81% respectively. Of the 49 recurrences, 26 (22.6%) were within the radiotherapy field. There was a correlation between a high V20 figure (volume of lung receiving 20Gy) and worsening survival (p=0.0218), measured by cox proportional hazard model.

Conclusion:
The 90 day mortality is 6% in this series of unselected relatively elderly patients, likely to be representative of the population of patients presenting to clinical oncologists in many cancer centres in the UK. This is comparable to the recent series reported by the Christie hospital and helps build a bench mark for comparison. Further work to identify factors increasing the risk of early death and strategies to identify and proactively manage toxicity and comorbidities during and immediately after treatment are required. Patient selection for concurrent chemotherapy is challenging in the very elderly or those with multiple comorbidities and may have had an impact on our outcomes. The in-field recurrence rate of 22.6% emphasizes the need to improve radiotherapy delivery and support the need for further clinical trials in this area looking at acceptable methods of safe dose escalation, such as the soon to open ADSCAN trial.

Background:
Prior studies describe increased toxicity following stereotactic body radiotherapy (SBRT) for central lung tumors. We report our institutional experience treating central lung tumors with SBRT, stratifying as central (C), ultracentral (UC) or paramediastinal (PM), and report toxicity for each cohort.

Methods:
The charts of all patients with centrally located lung tumors treated with SBRT Sept 2009 -June 2015 were reviewed. Eligible tumors were located within 2 cm of the proximal bronchial tree (PBT) or the planning target volume (PTV) overlapped the mediastinum. Tumors were classified as UC if the PTV overlapped the PBT or esophagus, C if located within 2 cm of the PBT, and PM if abutting the mediastinum but not meeting criteria as C. Toxicity was scored with CTCAE V1.1.

Results:
We identified 42 patients treated to 46 centrally-located lung tumors (38 primary and 8 metastases) treated to a median dose of 50 Gy (range 40-60) over 5 fractions (range 4-8). Nine tumors (19.6%) were classified as UC, 25 (54.3%) as C, and 12 (26.1%) as PM. The median follow-up for living patients was 21.4 months (range: 11.5-63.5). Crude rates of grade 3+ toxicity for patients with UC, C, and PM tumors were 22.2%, 4.3%, and 0% respectively (p=0.11). Grade 3+ toxicity included 2 cases of grade 3 post-obstructive pneumonia and one case of grade 5 respiratory failure following SBRT for an UC tumor. PBT doses for UC tumors routinely exceeded standard constraints. Key dose volume metrics for each group are outlined in Table 1.

Maximum Point Dose in Gy: Median (range)
	Ultracentral	Central	Paramediastinal
Proximal Bronchial Tree	58.0 (46.5-67.9)	29.1 (2.1-51.2)	15.8 (2.3-28.6)
Esophagus	29.9 (11.1-41.2)	16.9 (4.3-37.9)	18.1 (9.7-33.2)
Heart	29.8 (5.2-37.8)	18.4 (0.3-62.6)	20.1 (1.4-61.1)
Great Vessels	59.7 (43.4-69.9)	41.1 (11.5-72.3)	51.9 (11.0-62.2)
Grade 3+ Toxicity	n=2 (22.2%)	n=1 (4.3%)	n=0 (0%)

Conclusion:
In our cohort, SBRT for UC tumors showed a trend toward increased high-grade toxicity, suggesting additional counseling regarding treatment risks for the subset of patients with UC lung tumors is warranted. Additional studies to optimize SBRT dose-fractionation schedules for patients with UC tumors are needed.

Background:
Dose-fractioned cisplatin and oral etoposide (mPE) +/- bevacizumab (mPEBev) is a metronomic treatment showed anti-tumor anti-angiogenic and immunological activity in non-small-cell-lung-cancer (mNSCLC) patients enrolled in BEV2007 trial. These effects could altogether contribute to final antitumor activity. Recent findings suggested that radiotherapy may induce immunological effects on this bases we investigated whether palliative radiotherapy could affect the survival of patients enrolled in BEVA trial. We therefore, carried out a retrospective analysis in the subset of 47 who received palliative radiation therapy after four courses of mPE +/- bevacizumab.

Methods:
All of the patients had received chemotherapy with cisplatin (30mg/sqm, days 1-3q21) and oral etoposide (50mg, days 1-15q21) (mPE) while thirty-five also received bevacizumab at the dosage of 5mg/kg on the day 3q21 (mPEBev regimen). Radiation therapy was delivered with a palliative intent to different target sites including bones (19 patients), brain (Whole brain) (18 patients), lung parenchymal lesions and nodes (7 patients), stereo-tactic ablative radiation therapy (3 patients).

Results:
Our statistical analysis found that the use of RT was associated to a much longer survival (RT vs no RT: 23.26 vs 16.05 months, P=0.003) months, with no difference in term of PFS 1.65 vs 13.12 P= 0.135). We found no differences with treatment (+/- bevacizumab), sex, grading, stage (IIIB versus IV). Log-rank tests revealed a much longer OS in those patients presenting serum levels of IL17 (p:0.046), c-reactive-protein (p:0.056) and ESR nome per esteso (p:0.014) lower than median value, after Mpe +/- bevacizumab and prior irradiation. We finally observed a longer survival in patients showing a CD4+/CD8+ T cell ratio higher than median value (p:0.050).

Conclusion:
These results suggest that palliative radiation therapy delivered after our metronomic regimen in mNSCLC is associated to a longer survival with a mechanism presumably driven by immunological effectors. These results represent a solid rationale to test our metronomic regimen and RT in sequential combination with immune-checkpoint inhibitors in mNSCLC patients.

Background:
There is an unmet need to develop non-invasive biomarkers that can be used to tailor radiotherapy and select patients for future mechanism-based therapy-radiotherapy combination trials. The aim of this study is to assess blood biomarkers of radiotherapy response and toxicity in patients with lung cancer.

Methods:
This is a prospective exploratory study conducted at the Christie NHS Foundation Trust (Manchester, UK). Blood samples were collected prior, during and post-radiotherapy and at the time of relapse. A panel of 26 biomarkers were evaluated; M30 and M65 (apoptosis/ cell death), CA-IX and Osteopontin (hypoxia), Ang-1, Ang-2, FGFb, IL-8, PDGFb, PIGF, Tie-2, VEGFA, VEGFC, VEGFR-1 and VEGFR-2 (angiogenesis), E-selectin, IL-1b, IL-6, IL-10, IL-12 and TNFα (inflammation), CYFRA 21-1, EGF, KGF and VCAM-1 (tumour burden, proliferation and invasion) and HGF (multiple processes). Clinical, demographic and treatment data as well as routine haematology and biochemistry test results were collected. Blood sampling and analysis were performed in a good clinical practice-compliant laboratory. Univariate analysis was performed on patients with small-cell and non-small cell lung cancer (NSCLC) while multivariate analysis focused on patients with NSCLC. All statistical analyses were performed in R v3.1.1.

Results:
Between March 2010 and February 2012, blood samples form 78 patients were analysed. Forty eight (61.5%) were treated with sequential chemo-radiotherapy, 61 (78.2%) harboured NSCLC while 66 (84.6%) had stage III disease. TNFα, IL-1b, KGF and IL-12 accounted for the bulk of the variability between patients at baseline. Of these, high TNFα (hazard ratio (HR); 2.27, 95% confidence interval (CI); 1.22-4.23, log-rank p=0.008) and IL-1b (HR; 4.02, 95% CI; 2.04-7.93, log-rank p<0.001) were the strongest covariates of survival. Of routinely-collected laboratory tests, neutrophil count was a significant covariate of survival (HR; 1.07, 95% CI; 1.02-1.11, log-rank p=0.017). A multivariate survival predication model for NSCLC was created by combining baseline IL-1b and neutrophil count. The addition of early-treatment (week 3) CYFRA 21-1 to this model modestly improved the survival prediction concordance probability (0.75; p=0.029 to 0.78; p=0.004). Chemotherapy was strongly correlated with acute oesophagitis (p<0.001) while KGF was weekly correlated (p=0.019). The addition of KGF did not improve a multivariate toxicity prediction model based on chemotherapy. None of the tested variables correlated with acute pneumonitis.

Conclusion:
Blood biomarkers of inflammation and proliferation and early-treatment tumour burden could provide additional information about radiotherapy response and toxicity in patients with lung cancer. Following independent validation, the proposed biomarkers could be integrated within future mechanism-based therapy-radiotherapy combination trials.

Background:
MGCD516 (Sitravatinib), is an oral, potent small molecule inhibitor of a closely related spectrum of RTKs including RET, the split RTKs (VEGFR, PDGFR and KIT), TRK family, DDR2, MET and AXL. RTKs inhibited by sitravatinib are genetically altered in NSCLC and other cancers, where they function as oncogenic drivers, promoting cancer development and progression. Alterations in these RTKs have also been implicated in tumor resistance mechanisms. Sitravatinib has demonstrated antitumor activity in nonclinical cancer models harboring genetic alterations of sitravatinib targets, including rearrangement of RET, NTRK, or CHR4q12 amplification. Phase 1 dose escalation has been completed, showing dose proportional increases in exposure. PK and preliminary PD data indicate inhibition of the targets at the 150 mg dose administered orally once per day.

Methods:
This phase 1b study includes enrollment of molecularly selected patients (pts) with unresectable or metastatic NSCLC or other advanced solid tumor malignancies in patient cohorts characterized by activating alterations in sitravatinib RTK targets (RET, KDR, PDGFRA, KIT, TRK, DDR2, MET, AXL) or by loss of function mutations in CBL, a negative regulator for MET, AXL and PDGFR/KIT signaling. Pts receive sitravatinib at 150 mg once daily in 21-day cycles. Study endpoints include safety and tolerability, PK/PD, and clinical activity assessed by objective disease response per RECIST 1.1, duration of response and survival. A two stage optimal Simon design of up to 24 pts (8 pts in first stage and 16 pts in second stage) will be applied to those cohorts defined by a specific tumor gene alteration assuming p~0~=0.15 and p~1~=0.35, with an additional expansion of a cohort up to a total of 70 pts in order to provide a more precise estimate of ORR. PD biomarkers, including sMET, sVEGFR2, VEGFA and sAXL, are being explored in plasma samples for prognostic potential and possible relationship with clinical outcome. The study is open for enrollment, and recruitment is ongoing. Clinical trial information: NCT02219711

Results:
Section not applicable

Conclusion:
Section not applicable

Background:
Oncogenic gene fusions of ROS1 or NTRK have been reported in various cancers. DS-6051b is an orally available small molecule receptor tyrosine kinase inhibitor with high affinity for the ROS1 and NTRK receptors. Non-clinical pharmacology studies demonstrated anticancer activity of DS-6051b against several types of human tumor harboring ROS1 or NTRK fusion gene in cultured cells and xenograft models.

Methods:
This is an ongoing phase 1 study in Japanese subjects with advanced solid tumors harboring either a ROS1 or NTRK fusion gene. Subjects receive doses of DS-6051b from 400mg to 800mg once daily (QD). Pharmacokinetics (PK) samples are collected from Day1 to Day22. Primary objective is to assess the safety profile and secondary objectives are to determine the maximum tolerated dose (MTD), the recommended phase 2 dose (RP2D), and to assess the PK profile. The efficacy of DS-6051b is an exploratory assessment performed by investigator judgment per RECIST v.1.1.

Results:
As of June 27, 2016, a total of 9 subjects were enrolled. Median age was 51 (43-69) years, 56% were female, all 9 subjects were ROS1 fusion positive non-small cell lung cancer patients, and 3 subjects had prior crizotinib treatment. Subjects received DS-6051b at doses of 400mg QD (n=6) and 800mg QD (n=3). There were no DLTs in the 400mg QD cohort, and 2 out of 3 subjects in the 800mg QD cohort experienced DLT with grade 3 AST/ALT increased. To evaluate the MTD and RP2D more in detail, 600mg QD cohort is planned. Common adverse events were AST increased, ALT increased, diarrhea, and constipation. Among 7 patients who had target lesion, 4 subjects showed partial response, 3 subjects showed stable disease. PK data indicated the plasma drug concentration increases as the dose increases.

Conclusion:
This study is categorized as “Clinical Trial in Progress”. This study was initiated from February 2016 and estimated primary completion date will be September 2018.

Background:
In non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine kinase inhibitors (TKIs), acquired resistance is attributed to the T790M mutation in exon 20 in approximately 50% of cases. Despite promising preclinical findings, afatinib did not improve survival of patients with the T790M mutation. In a recent preclinical study, we demonstrated that autocrine IL-6 induced JAK/STAT3 signaling pathway activation mediated adaptive resistance to afatinib in H1975 and PC9-GR cells harboring T790M mutations. Knockdown of STAT3 with siRNA or pharmacologic JAK1 inhibition increased the anti-tumor activity of afatinib in T790M-positive NSCLC cells. Based on the promising preclinical results, we conducted a phase Ib study to evaluate the safety and efficacy of the combination of afatinib and ruxolitinib, a selective JAK inhibitor, in NSCLC patients who had progressed on EGFR-TKIs.

Methods:
For dose escalation with the classical 3+3 design, patients with histologically diagnosed, EGFR mutant stage IV NSCLC were considered eligible. Patients should have documented disease progression on EGFR-TKIs with clinical definition of acquired resistance. Afatinib was administered alone once daily from day 1 through day 8 (run-in period), then ruxolitinib was orally administered twice daily concomitantly with afatinib until progression. The primary endpoint was to determine RP2D and DLT.

Results:
As of July 13, 2016, 15 patients (8 with exon19 deletion, 7 with exon21 L858R) were enrolled in the dose escalation cohort, 8 of which had T790M mutations. Patients were previously treated with erlotinib (n=5) or gefitinib (n=10). Patients received a median of 3 (range, 1-4) lines of chemotherapy. No DLT was observed at the highest dose level (afatinib 50 mg once daily plus ruxolitinib 25 mg twice daily). Frequent AEs included paronychia (G1 in 7 cases), diarrhea (G1 in 6 cases, G2 in 1 case), acneiform rash (G1 in 5 cases), and oral mucositis (G1 in 1 case, G2 in 3 cases). SAEs were reported in 4 patients, which were not related to the investigational products. Partial responses were observed in 6 patients (40%) with disease control rate (CR+PR+SD) of 86.7%. Median PFS was 8.8 months (95% CI, 1.8-15.8) and 6 patients remain on study. Dose expansion with pharmacodynamic study at the RP2D will be open for NSCLC patients with EGFR T790M.

Conclusion:
The combination of afatinib with ruxolitinib was well tolerated and had promising clinical activity with durable disease control in NSCLC with acquired resistance to EGFR-TKIs (NCT02145637).

Background:
Momelotinib (MMB) is a selective ATP-competitive small-molecule inhibitor of Janus kinases (JAK) 1 and 2. The JAK signal transduction pathway is hyperactivated in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Erlotinib, a tyrosine kinase inhibitor (TKI), is a standard of care treatment for EFGR-mutated NSCLC. However, patients eventually develop resistance to single agent EGFR TKI and thus this combination trial was designed. The primary objective of this phase 1b study (NCT02206763) was to determine the maximum tolerated dose and safety of MMB in combination with erlotinib. Other objectives included pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy.

Methods:
Eligible patients had metastatic EGFR-mutated NSCLC (exon 19 deletion or exon 21 [L858R] substitution). Oral erlotinib 150 mg was administered once daily. MMB was dose escalated in a standard 3+3 design as follows: MMB 100 mg once daily (Dose Level [DL] 1), 200 mg once daily (DL2A), and 100 mg twice daily (DL2B). Dose limiting toxicities (DLTs) were evaluated in the first 28 days. Plasma samples for PK/PD analyses were serially collected up to 24 hours postdose.

Results:
Eleven patients enrolled: 3 in DL1, 3 in DL2A, and 5 in DL2B. Seven were female and median age was 55 years. DLTs of grade 3 diarrhea (n=1) and grade 4 neutropenia (n=1) without fever were seen at DL2B, and trial enrollment was halted. Decreased neutrophil count was recorded in 4 additional patients (grade 1-3; only one grade 3). The most common treatment-emergent adverse events were diarrhea and fatigue, each reported by 7 patients. One patient reported grade 1 peripheral neuropathy (sensory). No deaths were reported. Mean MMB systemic exposure was dose proportional between DL1 and DL2A, and comparable between DL2A and DL2B (200 mg total daily dose). MMB did not affect erlotinib PK. Mean blood pSTAT3 was maximally decreased by 34.9% at 1 hour postdose and was not dose dependent. As observed for MMB in myelofibrosis, inflammatory cytokines such as CRP, IL-10 and IL-12/-23p40 were reduced, whereas IL-8 was increased. The overall response rate was 54.5% (n=6; all partial responses).

Conclusion:
MMB administered in combination with erlotinib had more toxicity than expected at DL2B, including one grade 4 neutropenia. However, grade 2-3 neutropenia without fever was seen in 2 additional patients. The response rate was similar to previous reports with erlotinib, but it is too early in the study to provide progression-free survival with this treatment combination.

Background:
Despite the likelihood of an initial response to 1st or 2nd generation EGFR-TKI, EGFR mutant patients develop disease progression. The most frequent mechanism of acquired resistance is the EGFR T790M gatekeeper mutation. Novel treatment options are needed in this treatment resistant patient population. Osimertinib, a third-generation EGFR TKI targeting mutant EGFR including T790M, is an oral, irreversible, selective inhibitor. Ramucirumab and necitumumab are human IgG1 monoclonal antibodies to VEGFR-2 and EGFR, respectively. This phase 1, open-label, multicenter study with expansion cohorts (JVDL; NCT02789345) is designed to evaluate the safety and preliminary efficacy of ramucirumab or necitumumab in combination with osimertinib in patients with advanced EGFR T790M-positive NSCLC who have progressed after EGFR TKI therapy.

Methods:
This study includes patients with advanced or metastatic EGFR T790M-positive EGFR activating mutant (exon 19 deletions or L858R) NSCLC, with measurable disease and ECOG performance status 0-1 who have experienced disease progression on one prior EGFR TKI regardless of prior chemotherapy. Patients previously treated with an EGFR antibody or 3rd generation EGFR TKI for NSCLC are not eligible. In the phase 1a dose de-escalation portion (3+3 design), all patients (n=6 to 24) will be administered daily oral osimertinib (80 mg) with either an initial dose of 10 mg/kg IV ramucirumab on day 1 of every 2-week cycle or 800 mg IV necitumumab on days 1 and 8 of every 3-week cycle. One level of dose de-escalation is planned for each arm. A dose reduction (level -1) to 8 mg/kg IV ramucirumab or 600 mg IV necitumumab is planned if 2 or more patients have DLTs in either arm. After the DLT evaluation, the study will open a dose-expansion portion (phase 1b) and 25 patients in each Arm will receive study treatment until disease progression or a criterion for discontinuation is met. The primary objective is to assess safety and tolerability of ramucirumab or necitumumab in combination with osimertinib. Secondary endpoints include preliminary efficacy and pharmacokinetics. An exploratory biomarker objective includes the assessment of correlations between EGFR-mutations in tissue and serial blood samples with clinical outcomes. Primary analyses will be conducted approximately 6 months after the last patient receives initial dose.

Results:
Section not applicable

Conclusion:
Section not applicable

Background:
L DOS47, a cancer therapeutic designed to exploit the acidic tumour extracellular environment, is a protein conjugate consisting of a urease conjugated to a camelid monoclonal antibody (AFAIKL2) that is targeted to the CEACAM6 antigenic tumour marker. The AFAIKL2 antibody serves as a targeting agent to deliver the enzyme to the tumor sites while the urease enzyme converts urea, an abundant natural metabolite, into ammonia and generates a local pH increase. The combined effect of ammonia toxicity and pH increase is cytotoxic to cancer cells in culture and in xenograft models. This first in human study of L DOS47 was designed to define the maximum tolerated dose of multiple doses of L-DOS47 administered intravenously to patients with non-squamous NSCLC when given as a monotherapy.

Methods:
Stage IIIb or IV histologically confirmed non-squamous NSCLC patients (aged ≥18 yrs, ECOG PS ≤2) receive multiple cycles of L-DOS47 during the study treatment period. L-DOS47 is administered once weekly over 14 days followed by 7 days rest in each treatment cycle. Patients are recruited into cohorts and received the same dose of L-DOS47 on Days 1 and 8 of each treatment cycle. Dose levels of L-DOS47 are escalated in further cohorts following a review of safety data by the Trial Steering Committee.

Results:
Fifty-five (55) pts (median age 61, 53% male) were enrolled in sixteen cohorts (dose levels: 0.12 to 13.55 µg/kg) in four Polish centers. L-DOS47 was well tolerated at the dose levels reviewed. One (1) DLT was reported in a cohort 13 patient (spinal pain). None of the patients treated to date have had a partial or complete response as defined by RECIST v1.1. Thirty-two (32) patients had an overall response of stable disease after completing two cycles of L-DOS47. Thirteen (13) of the 32 patients had a decrease in the sum of diameters of target lesions. One (1) patient in cohort 9 was dosed for 10 cycles without disease progression.

Conclusion:
L-DOS47 monotherapy is well tolerated at dose levels up to 13.55µg/kg.

Background:
Approximately 4%–9% of EGFR-mutated NSCLC tumors have EGFR exon 20 insertion mutations, and no targeted treatment options are currently approved for patients with these mutations. In addition, approximately 2%–4% of patients with NSCLC have HER2 mutations, the majority of which are exon 20 insertion mutations. The irreversible EGFR/HER2 inhibitor AP32788 was designed to selectively inhibit EGFR or HER2 kinases with EGFR/HER2 exon 20 mutations. In preclinical studies, investigational agent AP32788 had potent inhibitory activity against all EGFR and HER2 mutants tested, including exon 20 insertion mutants, while sparing wild-type EGFR.

Methods:
This phase 1/2 trial is a first-in-human, open-label, multicenter study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of orally administered AP32788 (NCT02716116). The study will be conducted in 2 parts: a dose-escalation phase with a 3+3 design and an expansion phase of 4 histologically and molecularly defined cohorts after the recommended phase 2 dose (RP2D) is determined. Patients (≥18 years) must have locally advanced or metastatic NSCLC. In phase 1, the dose-escalation phase, patients refractory to standard available therapies will be enrolled. The primary endpoint of phase 1 is identification of the RP2D of AP32788. Secondary endpoints include safety, dose-limiting toxicities, maximum tolerated dose, and plasma pharmacokinetics. Expected phase 1 enrollment is 20–30 patients. In phase 2, the expansion phase, 4 cohorts will be enrolled, patients with: 1. EGFR exon 20 activating insertions, without active, measurable CNS metastases; 2. HER2 exon 20 activating insertions or point mutations, without active, measurable CNS metastases; 3. EGFR exon 20 activating insertions or HER2 exon 20 activating insertions or point mutations and active, measurable CNS metastases; 4. other targets against which AP32788 has demonstrated preclinical activity (eg, EGFR exon 19 deletions or exon 21 substitutions [with/without the T790M mutation] and other uncommon activating mutations in EGFR). The primary endpoint of phase 2 is investigator-assessed objective response rate (ORR) per RECIST v1.1 for all expansion cohorts except Expansion Cohort 3, for which the primary endpoint is intracranial ORR. Phase 2 secondary endpoints include safety, pharmacokinetics, and additional efficacy assessments (ORR per independent review committee, best overall response, best target lesion response, duration of response, disease control rate, progression-free survival, and overall survival; for Expansion Cohort 3: duration of intracranial response and intracranial progression-free survival). Expected phase 2 enrollment is 80 patients (total). The first patient was enrolled in phase 1 in June 2016.

Results:
Section not applicable.

Conclusion:
Section not applicable.

Background:
Immune checkpoint inhibitors produce durable clinical responses in a subset of patients, however strategies are needed to improve clinical efficacy of these agents and overcome innate or acquired resistance to therapy. Growing evidence suggests that tumors evade immune detection through modulation of intrinsic immunogenicity and inhibition of both innate and adaptive anti-tumor immune responses. Mocetinostat, a class I histone deacetylase inhibitor, has multiple potential immunomodulatory features including: 1) induction of tumor associated antigens and major histocompatibility complex Class I and Class II expression on tumor cells, 2) induction of immunogenic cell death via activation and cross-presentation of tumor antigens by antigen presenting cells, 3) enhanced function of T effector cells, and 4) decreased function of immunosuppressive cell subsets including regulatory T cells and myeloid derived suppressor cells. Given these pleiotropic immune activating effects, combination therapy of mocetinostat and PD-L1 blocking mAb, durvalumab, is a rational approach to restoring or enhancing the clinical activity of immune checkpoint blockade in patients with NSCLC.

Methods:
This open-label Phase 1/2 study is evaluating the tolerability and clinical activity of mocetinostat in combination with durvalumab. Secondary objectives include pharmacokinetics, incidence of anti-drug antibodies, and changes in tumor PD-L1 expression. Exploratory objectives evaluate changes in circulating and tumor cell PD-L1, circulating and tumor infiltrating immune cell populations and cytokines. Phase 1 explores increasing doses of mocetinostat administered orally (50, 70, 90 mg three times weekly [TIW]) in combination with durvalumab in patients with advanced solid tumors. The regimen begins with a 7-Day Lead-in Period of mocetinostat single agent TIW followed by the combination regimen with durvalumab (1500 mg intravenously every 28 days). Phase 2 evaluates the clinical activity of mocetinostat and durvalumab, as assessed by Objective Response Rate (ORR) by RECIST 1.1., in patients with NSCLC who have previously received at least one platinum containing doublet chemotherapy regimen for advanced disease. Four population cohorts are included: 1) immunotherapy naïve, no/low PD-L1 expression, 2) immunotherapy naïve, high PD-L1 expression, 3) prior clinical benefit with PD-L1 or PD-1 inhibitor treatment followed by progression, 4) prior treatment with PD-L1 or PD-1 inhibitor with progression within 16 weeks of initiation of treatment. Tumor PD-L1 expression will be determined by the SP263 assay. The sample sizes for the populations are based on two-stage Simon Optimal Designs. Status: Enrollment into the study opened in June 2016. Clinical Trial Information: NCT02805660

Results:
Section not applicable

Conclusion:
Section not applicable

Background:
Cancer stem cells may be responsible for initiation, maintenance, progression and metastatic spread of lung cancers and may contribute to native or acquired drug resistance. We (APF, VJ) showed that PKCι is an oncogene for NSCLC and is amplified in many NSCLC including in most squamous lung cancer cells (LSCC). PKCι is required for LSCC cell proliferation in vitro and tumorigenicity in vivo and for maintenance of the lung cancer tumor initiating cell (TIC) phenotype. The PKCι-Rac1-Ect2-MMP10 signaling axis is activated in LSCC TICs and PKCι knock down impairs soft agar growth, clonal expansion and tumorigenicity. The gold salt auranofin (ANF) reproduces the effects of PKCi knock down on the PKCι-Rac1-Ect2-MMP10 signaling pathway and on clonal expansion and tumorigenicity by potently and selectively inhibiting oncogenic PKCι signaling. Combined PKCι and mTOR inhibition synergistically reduces lung cancer cell proliferation and tumor growth in vivo and in vitro.

Methods:
A phase I/II clinical trial is accruing patients to evaluate safety and preliminary efficacy of combined inhibition of PKCι and mTOR in lung cancer patients. Adults with confirmed diagnosis of lung cancer (squamous, RAS-mutated adenocarcinoma or small cell lung cancer), PS 0-2, adequate organ function, no significant comorbidities and completion of at least one prior course of platinum doublet chemotherapy were enrolled. Patients received oral ANF 3mg (dose level 0) or 6mg (dose level 1) once daily + sirolimus 5 mg once daily in 28 day continuous cycles. Primary endpoints are to establish the maximum tolerated dose (phase I) and to assess progression free survival at 4 months (phase I/II). Tumor biopsies for biomarker assessment focus on the PKCι-Rac1-Ect2-MMP10 pathway. Secondary endpoints are safety, survival, response rate and duration, and biomarker development.

Results:
6 patients were enrolled in the phase I portion of the trial, 3 each at dose level 0 & 1. All pts were evaluable. No DLTs were seen during the dose escalation phase. On dose level 0, 1 pt died with pneumonia during cycle 5. On dose level 1, 1 pt had grade 4 hyponatremia during cycle 4. At median follow up of 7.1 months (1.8 - 23.9) and median 6 cycles (2-25), responses were: PR 1 (16.7%), SD 3 (50%), PD 2 (33%). The phase II trial is ongoing at dose level 1.

Conclusion:
Phase I analysis suggested safety of auranofin plus sirolimus at doses that were effective against NSCLC in preclinical models. Biomarker analysis is ongoing. NCT01737502, funding R21 CA153000 (APF)

Background:
Osimertinib (AZD9291) is a selective and irreversible pyrimidine-based inhibitor of the primary activating and the secondary EGFR mutation, T790M, which is the most common mechanism of acquired resistance to 1st and 2nd-generation EGFR tyrosine-kinase inhibitors (TKIs). Progression-free survival (PFS) with osimertinib was 9.6 and 2.8 months (m) for EGFR mutated (EGFR+) NSCLC patients progressing to prior EGFR TKI therapy with and without EGFR T790M mutation, respectively, indicating that the T790M is a predictive biomarker for osimertinib efficacy. Sixty patients from two expansion cohorts of the same study, received 1st-line osimertinib and obtained a PFS of 19.3m. T790M, arising in cis with the primary activating mutation, confers resistance to EGFR TKIs, even in the absence of drug selection. The coexistence of the pretreatment T790M mutation has been under appreciated, in spite of accumulative evidence that is present in a frequency of 35-60% using different detection methods. In our experience, pretreatment T790M mutation is frequently detected by three specific aspects of the method: tumor microdissection, examination of two separate tumor areas, and the use of a peptic nucleid acid clamp that inhibits wild-type allele amplification. Thus, we designed the first phase IIa study to evaluate the safety and efficacy of osimertinib as 1st-line therapy for patients with metastatic EGFR+ NSCLC and concomitant pretreatment T790M mutation.

Methods:
This is a multicenter, single-arm, open-label, non-controlled phase IIa clinical study in Spain. Eligible patients are aged ≥18 years with metastatic EGFR+ NSCLC and by central testing documented presence of pretreatment T790M mutation. Seventy-three patients will receive continuous treatment with osimertinib 80 mg daily until disease progression, intolerable adverse events, consent withdrawal or noncompliance with the study protocol. The primary endpoint is the objective response rate (ORR) assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The trial is designed to detect a ≥70% ORR in this patient population. Secondary objectives include PFS, overall survival, time to treatment failure, duration of response and disease control rate. Additional pre-specified secondary objectives of the study are the longitudinal analysis of EGFR mutations (including the T790M and the C797S mutations) in plasma and serum and the expression analysis of a panel of biomarkers with possible predictive value for osimertinib treatment.

Results:
Not applicable

Conclusion:
Not applicable

Background:
The role of the HER3 receptor and its ligand heregulin (HRG) in the progression of multiple cancers has been well established. Seribantumab (MM-121) is a fully human, monoclonal IgG2 antibody that binds to the HRG domain of HER3, blocking HER3 activity. The correlation between the level of HRG mRNA in tumor tissue and progression free survival (PFS) were retrospectively analyzed in three completed randomized Phase 2 studies of seribantumab plus standard of care (SOC) versus SOC alone (NSCLC, breast cancer and ovarian cancer). In each of these studies, high levels of HRG mRNA predicted shortened PFS for patients who received SOC treatment, while the addition of seribantumab to SOC improved PFS for patients with HRG-positive (HRG+) tumors. This is consistent with the hypothesis that HRG expression defines a drug tolerant cancer cell phenotype shielded from the effects of cytotoxic or targeted therapies and that blockade of HRG-induced HER3 signaling by seribantumab counters the effects of HRG on cancer cells, with the potential to improve outcomes for HRG+ patients. It is estimated that up to approximately 50% of cases of all solid tumor indications are HRG+. This HRG expression may contribute to rapid clinical progression in a subset of patients with poor prognosis.

Methods:
In the ongoing randomized, open-label, international, Phase 2 study, NSCLC patients with HRG+ tumors are being prospectively selected using a HRG RNA in situ hybridization assay performed on a recent tumor tissue sample collected via fine needle aspiration, core needle biopsy or excision. Approximately 560 patients will be screened to support enrollment of 280 HRG+ patients, who will be randomized in a 2:1 ratio to receive seribantumab plus investigator’s choice of docetaxel or pemetrexed, or docetaxel or pemetrexed alone. Patients will be wild-type for EGFR and ALK and will have progressed following one to three systemic therapies, one of which must be an anti-PD-1 or anti-PD-L1 therapy, for locally advanced and/or metastatic disease. Overall survival (OS) is the primary endpoint of the study and secondary endpoints include PFS, objective response rate and time to progression. Safety and health-related quality of life will also be assessed. An interim analysis is planned when 50% of final OS events have been reported. Enrollment has been initiated with approximately 80 sites expected to participate worldwide. Clinical Trials Registry number: NCT02387216

Results:
Section not applicable

Conclusion:
Section not applicable

Background:
Stage IV non-small cell lung cancer (NSCLC) harboring KRAS mutations remains a treatment challenge. Abemaciclib, a small molecular inhibitor of both cyclin-dependent kinase (CDK) 4 and CDK6, demonstrated acceptable safety, tolerability, and single-agent activity for patients with different tumors, including NSCLC. Preclinical evidence suggests a lethal interaction between CDK4 inhibition in lung cells and KRAS oncogenes. Pembrolizumab, a humanized monoclonal antibody against PD-1 protein, is approved in the US for patients with metastatic PD-L1+ NSCLC. Both compounds demonstrated manageable toxicities. We thus aim to study the combination of abemaciclib and pembrolizumab in pretreated patients with NSCLC.

Methods:
This open-label phase 2 study will evaluate safety and preliminary efficacy of abemaciclib 150 mg given orally every 12 hours on a continuous schedule on days 1-21 in combination with intravenous pembrolizumab 200 mg on day 1 of a 21-day cycle to patients in 1 of 3 disease cohorts: KRAS mutation, PD-L1+, stage IV NSCLC (Part A); stage IV NSCLC with squamous histology (Part B); or hormone receptor+, HER2- metastatic breast cancer (Part C). Total target accrual is approximately 75 patients (25 per cohort). Only the 2 NSCLC cohorts will be presented here. Patients eligible for Part A have a confirmed KRAS mutation, PD-L1+ expression score of ≥1%, and are chemotherapy-naïve for metastatic NSCLC. Part B includes patients with predominately squamous NSCLC who have received 1 prior platinum-based chemotherapy for advanced NSCLC. Patients must provide tumor tissue before and after treatment (cycle 3, day 1); have measurable disease, adequate organ function, an ECOG PS ≤1, and a life expectancy ≥12 weeks; and be ≥18 years of age and able to swallow oral medications. The primary objective is to characterize the safety profile of abemaciclib plus pembrolizumab. Secondary objectives include objective response rate (ORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), characterization of pharmacokinetics, and health outcomes. Patients who receive any study drug will be included in the analyses. Analyses of ORR, DCR, DoR, and PFS will be evaluated according to RECIST v.1.1 and irRECIST. Time-to-event variables will be estimated by Kaplan-Meier methodology. An interim analysis of safety and preliminary efficacy may occur after all patients have completed (or discontinued from) approximately 24 weeks of treatment. The final OS analysis will occur based on data collected for approximately 12 months after the last patient receives treatment.

Results:
Section not applicable

Conclusion:
Section not applicable

Background:
Afatinib, an irreversible ErbB family blocker, inhibits signalling from all homo- and hetero-dimers of ErbB family members (EGFR [ErbB1], HER2 [ErbB2], ErbB3 and ErbB4). Based on the results of two large Phase III trials (LUX-Lung 3 [LL3] and LL6), afatinib is approved in many countries for first-line treatment of patients with advanced EGFRm+ NSCLC. More recently, following results of the Phase III LL8 trial, afatinib was also approved for treatment of squamous cell carcinoma of the lung after platinum-based chemotherapy. Overexpression/amplification of HER2 has been identified in NSCLC and may have a role in acquired resistance to reversible EGFR tyrosine kinase inhibitors. Afatinib has demonstrated preclinical activity in HER2m+ lung cancer models and clinical activity in HER2m+ NSCLC patients (de Greve et al. Lung Cancer 2012; Mazieres et al. Ann Oncol 2015). This Phase II trial investigates the efficacy and safety of afatinib in patients with advanced NSCLC harbouring HER2 mutations, previously treated with chemotherapy (NCT02597946).

Methods:
In this Phase II, open-label, single-arm trial, eligible patients are aged ≥18 years, with ECOG PS 0/1, histologically or cytologically confirmed stage IV NSCLC, confirmed HER2m+ tumour tissue, and measurable disease (RECIST v1.1), following failure of one or two prior chemotherapy regimens, of which one is platinum-based. Prior radiotherapy (except palliative treatment), chemotherapy or immunotherapy within 4 weeks, hormonal therapy within 2 weeks, or EGFR/HER2-targeted therapy is not allowed. In Part A of this two-part trial, patients will receive continuous oral afatinib monotherapy at the approved starting dose of 40 mg/day. The dose may be escalated to 50 mg/day after 4 weeks in patients with minimal drug-related adverse events (AEs); dose reduction by 10-mg decrements to a minimum of 20 mg/day will occur in case of drug-related grade ≥3 or selected grade 2 AEs. In Part B, patients with ECOG PS ≤2 experiencing >12 weeks of clinical benefit with afatinib monotherapy before disease progression will continue treatment with afatinib plus weekly intravenous paclitaxel 80 mg/m[2]. In Parts A and B, treatment will continue until disease progression or intolerable AEs. The primary endpoint is objective response in Part A. Secondary endpoints include: disease control, progression-free survival, time to progression, and duration of response in Part A; and overall survival. Safety will also be assessed. Target enrolment is 40 patients, and participating countries will be listed in the full presentation.

Results:
Section not applicable.

Conclusion:
Section not applicable.

Background:
Combination therapy with agents that target the molecular and cellular mechanisms of resistance to checkpoint inhibitor therapy (CIT) is a rational approach to restoring or improving the efficacy of CIT in patients with immunotherapy resistant NSCLC. Glesatinib, a tyrosine kinase inhibitor (TKI), which targets Axl, MER and MET RTKs expressed on macrophages and antigen-presenting-cells within the tumor microenvironment (TME), may reverse the immunosuppressive TME and enhance anti-tumor T and NK cell responses by enhancing antigen presentation and T cell effector function. Sitravatinib, also a TKI, which targets VEGFR2 and KIT as well as Axl, MER and MET, may further enhance anti-tumor activity by VEGFR2 and KIT inhibition mediated reduction of regulatory T cells and myeloid-derived suppressor cells (MDSCs). Given these pleiotropic immune activating effects, the combination of glesatinib or sitravatinib with nivolumab is a rational approach to restoring or enhancing the clinical activity of CIT in patients with immunotherapy resistant NSCLC.

Methods:
This open-label Phase 2 study evaluates the tolerability and clinical activity of the investigational agents, glesatinib or sitravatinib in combination with nivolumab in separate cohorts of patients with non-squamous NSCLC who have experienced progression of disease on or after treatment with CIT. The study begins with a limited dose escalation evaluation of each investigational agent in combination with nivolumab to determine the dose levels to be used in Phase 2. The primary objective is to assess the clinical activity of the combination regimens using the Objective Response Rate (ORR) by RECIST 1.1. Other objectives include safety, tolerability, pharmacokinetics and changes in circulating and tumor cell PD-L1, circulating and tumor infiltrating immune cell populations, cytokines and gene expression signatures. Enrollment into each Phase 2 treatment arm is stratified by prior outcome of CIT (e.g., clinical benefit versus progression of disease in ≤12 weeks). The investigational agents are administered orally in continuous regimens; nivolumab is administered intravenously, 3 mg/kg every 2 weeks. The sample sizes for the treatment arms are based on two-stage Simon Optimal Designs. Status: The US IND opened in June 2016.

Results:
Section not applicable

Conclusion:
Section not applicable

Background:
The standard chemotherapy for advanced NSCLC after the failing of second or third line chemotherapy has yet to be established. In these salvage setting patients the acceptable safety and efficacy of solvent-based paclitaxel (sb-P) monotherapy have been previously reported as one possible treatment option (Anticancer Res 2005). Compared with sb-P, nab-paclitaxel(nab-P) yielded a higher mean maximal circulating concentration of free paclitaxel and delivered higher drug concentration to tumors in preclinical xenograft models (Clin. Cancer Res. 2006). Moreover, a large multicenter international phase III study (CA031) of nab-P + carboplatin (C) vs sb-P + C, nab-P + C produced a significantly higher overall response rate (ORR) compared with sb-P + C, and had an acceptable safety profile as a first line chemotherapy (J. Clin. Oncol. 2012) .These results suggest that nab-P monotherapy have possibility to be more efficacious and tolerable compared to sb-P monotherapy. KTOSG trial 1301 has recently revealed weekly nab-P as a second line chemotherapy is associated with acceptable toxicity and a favorable ORR in patients with advanced NSCLC (Lung Cancer 2016).　However, there are no reports of nab-P monotherapy after the failing of second or third line chemotherapy. We therefore planned this study aiming to assess the efficacy and safety of nab-P monotherapy for patients in the salvage setting.

Methods:
This multicenter single arm phase II study assesses the efficacy of nab-P in pts with PS 0-2 and aged < 75 years with advanced non-small cell lung cancer. Pts must have failed two or three prior lines of therapy including at least a platinum- containing chemotherapy. Pts pretreated with sb-P or nab-P, or tumors harboring EGFR mutation or ALK fusion gene are excluded. Pts receive nab-P 80 mg/m2 on days 1,8 and 15 of a 28-days cycle. The primary endpoint of the trial is progression-free survival in an intent-to-treat analysis using the Kaplan-Meier method and log-rank test. Secondary endpoints include overall survival, ORR, disease control rate, efficacy according to prior docetaxel, quality of life, and safety. The study is powered to detect a 1.5-month improvement in median PFS in this investigational arm beyond the 2.0-month median PFS estimated from historical data. Assuming a one-sided 0.10 level of Type I error and 80% power, the sample size was calculated to be 35 pts based on the Brookmeyer-Crowley method. The target sample size is established as 38 pts. As of June 2016, 14 pts were registered and recruitment is ongoing (UMIN000016173).

Results:
Section not applicable

Conclusion:
Section not applicable

Background:
Ramucirumab, a human IgG1 monoclonal antibody, binds to vascular endothelial growth factor (VEGF) receptor 2, competing with VEGF-A, -C and –D and thereby preventing receptor activation and angiogenesis. The phase 3 REVEL trial demonstrated the addition of ramucirumab to docetaxel improved survival in patients with stage IV NSCLC following progression after platinum-based chemotherapy, independent of histology. The approved dose of docetaxel in NSCLC patients after progression on prior platinum-based chemotherapy is 75 mg/m2 every 3 weeks. The most common toxicity associated with this dosing regimen is myelosuppression, specifically neutropenia. In order to reduce the incidence of myelosuppression, various weekly docetaxel dosing regimens have been evaluated. These studies have suggested that weekly docetaxel can provide better tolerability with at least similar efficacy. This phase 2, single arm, open-label study (JVDN; NCT02831491) is designed to assess a potential reduction in the rate of grade ≥3 neutropenia and febrile neutropenia with weekly docetaxel in combination with ramucirumab, as compared to historical safety data from the REVEL trial. This study will also assess safety and efficacy of ramucirumab with weekly docetaxel in patients who received prior immunotherapy for NSCLC.

Methods:
Study JVDN includes patients (n=50) with stage IV NSCLC, with measurable disease and ECOG performance status 0-1 who have experienced disease progression from one prior platinum-based therapy which may have included bevacizumab. Prior immunotherapy for NSCLC is permitted. Patients will receive the approved ramucirumab dose regimen for NSCLC (10mg/kg IV) on day 1 every 3 weeks, followed by weekly docetaxel (35 mg/m2 IV) on days 1, 8 and 15 every 4 weeks. Treatment may continue until disease progression or a criterion for discontinuation is met. The primary endpoint is to assess safety, as measured by the rate of grade ≥3 neutropenia (CTCAE v4.0). Secondary endpoints for all patients include the rate of treatment-emergent febrile neutropenia, overall safety, pharmacokinetics (ramucirumab), and efficacy. Additional secondary endpoints of safety and efficacy will be assessed in patients who did or did not receive prior immunotherapy. An exploratory endpoint is to assess the association between biomarkers with safety and clinical outcomes. The primary and final analyses will occur after 31 and 50 patients, respectively, have completed ≥12 weeks of treatment to determine if grade ≥3 neutropenia and febrile neutropenia are reduced with the investigational weekly docetaxel treatment as compared to historical safety data from REVEL.

Results:
Not applicable

Conclusion:
Not applicable

Background:
MGCD265 is a potent, orally available, small molecule RTK inhibitor of MET and Axl, both of which mediate signals for cell growth, survival, and migration. The Amethyst NSCLC trial is designed to evaluate the activity of MGCD265 in patients with NSCLC exhibiting genetic alterations involving MET. Alterations in MET, including gene amplification and/or genetic mutations, occur in approximately 7% of NSCLC cases converting MET to an oncogene capable of driving cancer development and progression. Amplification of MET has been associated with a poor prognosis in NSCLC. In addition, various genetic mutations result in the deletion of exon 14 in MET mRNA (METex14del) and the subsequent loss of the Y1003 regulatory binding site for CBL ubiquitin ligase, required for MET degradation and signal attenuation. Loss of the Y1003 binding site of MET results in sustained MET signaling, which has been implicated as an oncogenic driver in a subset of NSCLC. The importance of MET as a driver is demonstrated in xenograft models of NSCLC with METex14del and MET amplification, and where MGCD265 induces tumor regression. Additionally, confirmed partial responses have been observed in pts with NSCLC characterized by METex14del who were treated with MGCD265 in the Phase 1 setting.

Methods:
Pts with platinum pre-treated NSCLC characterized by activating genetic MET alterations identified in tumor tissue or circulating tumor DNA (ctDNA) are eligible for this multi-center, global, Phase 2 trial. Pts are assigned to one of four cohorts based on the type of MET dysregulation and detection method: 1) mutations in tissue, 2) amplification in tissue, 3) mutations in ctDNA, and 4) amplification in ctDNA. The primary endpoint is Objective Response Rate (ORR) in accordance with RECIST 1.1; a Bayesian Predictive Probability Design is applied independently to each cohort. Secondary objectives include safety, tolerability, response duration, survival, correlation between tissue and ctDNA testing, and PK/PD. This study is currently open globally, and recruitment is ongoing.

Results:
Section not applicable.

Conclusion:
Section not applicable.

Background:
No standard of care exists for ECOG Performance Status (PS) 2 patients with advanced non-small cell lung cancer (NSCLC) and therefore clinical practice ranges from supportive care to combination chemotherapy. It was first reported that the combination therapy with carboplatin (CBDCA)/pemetrexed significantly improved survival for PS2 patients with advanced non-squamous NSCLC (J Clin Oncol 31:2849-2853.2013). However, due to the limited utilities of this regimen, establishment of other combination therapy is warranted in PS2 patients with especially squamous NSCLC or unfavorable renal function. On the other hand, in CA031 trial, CBDCA/nab-paclitaxel (PTX) demonstrated a significantly higher response rate (RR) compared with CBDCA/PTX in PS0-1 patients with advanced NSCLC, especially squamous histology (J Clin Oncol 30:2055-2062.2012). Furthermore, in elderly patients over 70 years old, CBDCA/nab-PTX tended to show superior PFS and OS on the basis of better tolerability compared with CBDCA/PTX. Thus, CBDCA/nab-PTX could be a valid treatment option for PS2 patients whose PS is exacerbated due to mass effect of NSCLC despite appropriate organ function.

Methods:
This phase 2 trial is enrolling untreated PS2 patients with NSCLC and appropriate organ function under 75 years old. Patients are included if they had histologically/cytologically confirmed stage IIIB/IV NSCLC unfit for surgery or radiotherapy, whereas they are excluded if they had uncontrolled symptomatic brain metastasis or uncontrolled pleural effusion. The primary endpoint is PFS rate at 6months. Achievement of more than 50% is considered worthy of further development of this combination therapy, whereas that of less than 30% is considered insufficient for further investigation. The estimated power of this design is 80% with a type I error of 0.05, resulting in 35 patients needed. Considering that about 20% of patients are likely to be excluded from the trial, we planned to enroll 45 patients. Patients are treated with nab-PTX (70 mg/m[2] on day1, 8, and15, q4w) and CBDCA (AUC 5 on day1, q4w), up to 6 cycles. Concurrently, Quality of life and Charlson Comorbidity Index are planned to be checked about the patients treated with this regimen. This study is open for enrollment and recruitment is ongoing. Clinical trial information: UMIN000019458.

Results:
Section not applicable

Conclusion:
Section not applicable

Background:
There is no curative treatment for patients with NSCLC who develop metastatic disease after resection. Trials of neoadjuvant and adjuvant chemotherapy have demonstrated an absolute survival benefit of 5% for patients with stages IB, II, and IIIA disease. Clearly, developing new treatment strategies to improve survival following resection is critical to improving outcomes for this patient population. Immunotherapy with checkpoint inhibitors such as antibodies to PD-1 and PD-L1 has demonstrated superior survival compared to chemotherapy in randomized clinical trials. PD-L1 expression is being investigated as a predictive biomarker for these therapies, but its ability to predict response has varied in published trials. Atezolizumab is a humanized IgG1 monoclonal PD-L1 antibody that was recently evaluated in the POPLAR trial (NCT01903993), a phase II randomized trial of patients with NSCLC who progressed on platinum based chemotherapy. Atezolizumab therapy improved overall survival compared with docetaxel (12.6 months vs. 9.7 months, HR 0.73 [95% CI 0.53 – 0.99]) with a manageable safety profile. Improvement in survival correlated with PD-L1 immunohistochemistry expression of tumor and tumor-infiltrating immune cells.

Methods:
Trial design: This phase II, open-label, single-arm study is designed to evaluate the efficacy and safety of atezolizumab as a neoadjuvant therapy in patients with Stage IB, II, or IIIA NSCLC prior to curative-intent resection. Approximately 180 patients with NSCLC will be enrolled in this study at 15 academic medical centers in the United States. There are two parts to this study: the first/primary part will evaluate the ability of neoadjuvant atezolizumab to produce objective pathologic responses in patients with early stage NSCLC. Atezolizumab 1200 mg IV will be given every 3 weeks for two doses. Surgical resection of tumors following treatment will allow determination of pathologic response rates and potential predictive biomarkers. Part 2 is exploratory and will evaluate atezolizumab adjuvant therapy for up to 12 months in patients who demonstrate clinical benefit (evidence of pathologic response or absence of radiographic progression) in Part 1. After surgical resection, patients may receive SOC adjuvant chemotherapy (with or without radiation) before starting atezolizumab adjuvant therapy in Part 2. The primary objectives are safety and major pathologic response based on surgical resection. Secondary objectives include overall response rate based on PD-L1 status, mutational load, antigen burden, and RNA-sequencing. This trial presents a unique opportunity to evaluate exploratory biomarkers, including pre- and post-treatment biopsy assessment of evolution of immune related markers associated with response.

Results:
Section not applicable

Conclusion:
Section not applicable

Background:
Genexol-PM is a novel Cremophor EL(CrEL)-free polymeric micelle formation of paclitaxel.This multicentre study was designed to compare Genexol-PM and CrEL-based paclitaxel in combination with cisplatin in terms of efficacy and safety as first-line therapy in advanced non-small cell lung cancer.

Methods:
Chemonaive patients aged from 18 to 70 years with histologically or cytologically confirmed, locally advanced, metastatic or recurrent advanced NSCLC and an ECOG performance status of 0–1 were randomised 2:1 to the treatment group (Genexol-PM+ cisplatin ) and the controll group (paclitaxel+cisplatin) .Patients were treated with Genexol-PM 230mg/m2 intravenously without premedication or paclitaxel 175mg/m2 intravenously with premedication plus cisplatin 70mg/m2 on day 1 of a 3-week cycle for up to six cycles. Intrapatient dose escalation of Genexol-PM to 300mg/m2 was carried out in treatment group from the second cycle if the prespecified toxic effects were not observed after the first cycle.

Results:
170 patients were randomised into the study. PFS and OS data are not yet mature.

Conclusion:
This multicentre study is in progress.

Background:
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown antitumor efficacy and prolonged progression-free survival (PFS) in patients with non-small cell lung cancer (NSCLC) harboring EGFR activation mutations; however, acquired resistance often develops limiting clinical efficacy. ASP8273 is an irreversible, once-daily (QD), orally available TKI with activity against both activating and resistance EGFR mutations (ex19del, L858R, T790M). Preliminary findings from Phase 1 and Phase 2 trials in the US, Japan, Taiwan, and Korea have demonstrated antitumor activity and overall tolerability of ASP8273 at doses of 100mg–300mg.

Methods:
This global, multicenter, open-label, randomized, Phase 3 study will enroll ~600 adult subjects with Stage IIIB/IV NSCLC with EGFR-activating mutations (ex19del or L858R, with or without T790M) who have not been treated with an EGFR inhibitor TKI (NCT02588261). Subjects will be randomized 1:1 to treatment with either 300mg oral ASP8273 QD or erlotinib/gefitinib. Each site will select a comparator drug (150mg erlotinib QD or 250mg gefitinib QD) at the beginning of the study. Randomization will be stratified by ECOG status (0, 1, and 2), EGFR mutation (ex19del, L858R), comparator selected (erlotinib vs gefitinib), and race (Asian vs non-Asian). Subjects will not be enrolled if they harbor both ex19del and L858R. All subjects will begin treatment on Day 1 Cycle 1 and will continue on 28-day continuous dosing cycles until the subject discontinues (eg, due to radiologic progression as determined by RECIST or unacceptable toxicity). Dose reductions will be allowed for ASP8273 and erlotinib, but not for gefitinib. The primary study objective is PFS as assessed by independent radiological review (IRR); secondary study objectives are overall survival, best overall response rate, disease control rate and duration of response by IRR, safety/tolerability, and patient quality of life. An independent Data Monitoring Committee will oversee trial safety and the interim futility analysis. Enrollment for the trial began 26 February 2016; 46 subjects have been randomized as of 17 May 2016.

Results:
Section not applicable

Conclusion:
Section not applicable

Background:
Current first-line therapy for advanced EGFR and ALK wild-type NSCLC is associated with poor survival and there remains a significant need for more effective treatments in this population. Blockade of immune checkpoints programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) represents a promising anticancer therapeutic strategy. In preclinical models, targeting both PD-1 and CTLA-4 provides for non-redundant pathway blockade and potential synergy. Durvalumab (MEDI4736) is a selective, high-affinity, engineered human IgG1 mAb that blocks programmed cell death ligand-1 (PD-L1) binding to PD-1 (IC~50~ 0.1 nM) and CD80 (IC~50~ 0.04 nM). Tremelimumab is a selective human IgG2 mAb inhibitor of CTLA-4. A Phase 1b study of durvalumab + tremelimumab demonstrated encouraging clinical activity and a manageable tolerability profile in advanced NSCLC, with activity observed in patients with high and low/no tumour PD-L1 expression (NCT02000947).

Methods:
NEPTUNE (NCT02542293) is a randomised, open-label, multicentre, global, Phase 3 study. Immunotherapy- and chemotherapy-naïve patients with advanced/metastatic EGFR and ALK wild-type NSCLC (with either PD-L1 high expression [≥25% tumour cells staining for PD-L1 at any intensity] or PD-L1 low/negative expression [<25% tumour cells staining for PD-L1 at any intensity] ) will be randomised (1:1) to durvalumab (20 mg/kg i.v. every 4 weeks [q4w] for up to 12 months) + tremelimumab (1 mg/kg i.v. q4w for up to 4 doses); or standard-of-care platinum-based doublet chemotherapy. The primary endpoint is overall survival (OS). Secondary endpoints are progression-free survival (PFS), objective response rate (ORR), duration of response and proportion of patients alive and progression free at 12 months by investigator assessment (RECIST v1.1); time from randomisation to second progression; OS, PFS and ORR in patients with PD-L1 low/negative NSCLC; safety (CTCAE v4.03) and tolerability; pharmacokinetics; and immunogenicity. Exploratory outcomes include potential biomarkers of response to treatment and impact of subsequent anticancer therapies on OS. Recruitment is ongoing. Figure 1



Results:
Not-applicable

Conclusion:
Not-applicable

Background:
Overcoming and prevention of acquired resistance to EGFR-TKIs in the treatment for patients with EGFR-mutated non-small cell lung cancer (NSCLC) is a critical issue. Although third-generation EGFR-TKIs, such as osimertinib, which are potent against EGFR carrying the T790M mutation, have been developed, they are insufficient to overcome other resistance mechanisms. We hypothesized that the insertion of platinum-doublet chemotherapy with EGFR-TKIs might prevent the emergence of acquired resistance to EGFR-TKIs and prolong the patient survival. An early phase II study of inserted cisplatin and docetaxel with gefitinib showed promising outcomes, including a median progression-free survival of 19.5 months and median survival time of 48.0 months.

Methods:
Figure 1 This study (JCOG1404 / WJOG8214L: AGAIN study) is an intergroup, multicenter, randomized phase III study conducted by the Japan Clinical Oncology Group (JCOG) and the West Japan Oncology Group (WJOG). The objective of this study is to confirm the superiority, in terms of the overall survival, of the study treatment, described below, over gefitinib monotherapy. As the study treatment, gefitinib are administered on days 1-56. Then, after a two-week drug-free period, three cycles of cisplatin and pemetrexed are administered on days 71, 92, and 113. Thereafter, gefitinib is re-started on day 134 and continued until disease progression. The secondary endpoints are progression-free survival, response rate, adverse events, severe adverse events and proportion of EGFR T790M mutation positive in the tumor samples at disease progression. The key eligibility criteria are: patients with advanced or recurrent non-squamous NSCLC harboring EGFR activating mutations (exon 19 deletion or exon21 L858R), age 20 to 74 years, and PS 0 or 1. This study was started in December 2015, and a total of 500 patients will be enrolled over a period of 3 years. This trial has been registered at UMIN-CTR[umin.ac.jp/ctr/] as UMIN000020242.



Results:
Section not applicable

Conclusion:
Section not applicable

Background:
HLA-A2 is expressed in 40 to 50% of NSCLC patients. TEDOPI is a combination of neoepitopes that generates cytotoxic T lymphocytes responses. It consists of nine HLA-A2 supertype binding epitopes covering five tumor-associated antigens overexpressed in advanced NSCLC and the universal helper pan-DR epitope. In a phase II trial (NCT00104780, Barve et al. JCO 2008), TEDOPI showed a promising median overall survival of 17.3 months with a manageable safety profile in pre-treated HLA-A2 positive patients with advanced NSCLC. ATALANTE-1 (NCT02654587) is a randomized, open-label, phase 3 study comparing the efficacy and safety of TEDOPI with standard treatment in HLA-A2 positive patients with advanced NSCLC, as second- or third-line therapy.

Methods:
Section not applicable

Results:
Trial design: Patients with advanced NSCLC without EGFR-sensitizing mutations or ALK rearrangements, with progressive disease to first-line platinum-based chemotherapy or second-line immune checkpoint inhibitors (IC) are eligible if they have HLA-A2 positivity and ECOG PS 0-1. Treated and asymptomatic brain metastases are allowed. Patients are randomized 1:1 to receive 1 ml TEDOPI subcutaneously Q3W for 6 cycles, then every two months for the reminder of the year and finally every three months or standard treatment with: 75 mg/m[2] docetaxel Q3W or 500 mg/m[2] pemetrexed Q3W (in non-squamous histology and pemetrexed-naïve patients). In both arms, treatment continues until progression, intolerable toxicity, consent withdrawal, or investigator decision. In TEDOPI arm, treatment may continue beyond initial radiographic disease progression in case of clinical benefit. Randomisation is stratified by histology (squamous vs. non-squamous), initial response to first-line chemotherapy (partial or complete response vs. stabilization or progression), and previous treatment with IC (yes vs. no). Tumor assessment is performed every 6 weeks and adverse events are collected throughout the study and for 60 days and 90 days thereafter and graded per NCI CTCAE v4.0. Archival biopsies samples are required for assessing PD-L1 status (IHC22C3 pharmDx from Dako). Primary endpoint is overall survival; and secondary are progression free survival based on RECIST 1.1 criteria, objective response rate, disease control rate, duration of response, and quality of life measured by QLQ-C30 and QLQ-LC13 global scores. This is a superiority study with a hazard ratio of 0.7391, two-sided alpha 5% and power 80%, after 356 events are observed over 500 patients. The first patient was enrolled on 25th January 2016. Enrolment is ongoing in Europe and the US. Clinical trial identification: NCT02654587 Legal entity responsible for the study & Funding: OSE Immunotherapeutics, France

Conclusion:
Section not applicable

Background:
Immunotherapy is active in malignant pleural mesothelioma (MPM). Durvalumab is a human monoclonal antibody directed against the programmed cell death ligand 1 (PD-L1). We hypothesize that the addition of durvalumab to first-line chemotherapy improves 6-month progression free survival (PFS6).

Methods:
DESIGN: Open-label, single arm, multi-centre, phase 2 trial with a safety run in. ELIGIBILITY: Adults with MPM starting first-line cisplatin and pemetrexed. ENDPOINTS: PFS6 (primary) and objective tumour response rate using modified RECIST for MPM and modified immune-related response criteria; adverse events and overall survival. Tertiary correlative objectives include associations between potential predictive/prognostic biomarkers and clinical outcomes. TREATMENT: Durvalumab 1125mg (dose to be confirmed in safety run-in), cisplatin (75mg/m[2]) and pemetrexed (500mg/m[2]) 3-weekly for a maximum of 6 cycles, followed by durvalumab alone until progression or for a maximum of an addition of 12 cycles. STATISTICS: 6 participants in an initial safety run-in using a 3+3 design, will be included in the total sample size of 54 evaluable participants, consisting of 31 recruited in stage 1, and another 23 in stage 2. The null hypothesis is that the true PFS6 rate is 45%, in keeping with standard therapy and would be considered not worthy of further evaluation. The two-stage design provides greater than 90% power with a one-sided type I error rate of 5% if the true PFS6 rate is 65% (alternate hypothesis). ASSESSMENT: CT scans 6-weekly for the first 30 weeks, then 9-weekly until disease progression. Translational research blood collections: baseline, cycle 2 and 3.

Results:
Central ethics submission has been completed and recruitment will be updated.

Conclusion:
DREAM is an investigator-initiated cooperative-group trial led by ALTG, in collaboration with NHMRC Clinical Trials Centre, University of Sydney, with support from Astra-Zeneca.

Background:
Dysregulation of the fibroblast growth factor (FGF) pathway is observed in a variety of cancers, including mesothelioma. FGF-9 is significantly over-expressed in mesothelioma and our pre-clinical data demonstrates that inhibition of FGF receptor (FGFR)-mediated signalling in vitro results in anti-proliferative and pro-apoptic activity. FGFR-targeted tyrosine kinase inhibitors strikingly reduce tumour burden in three separate murine models of mesothelioma. AZD4547 is a potent and selective oral FGFR-1,2, and 3 tyrosine kinase inhibitor that inhibits FGFR-related signal transduction pathways which makes AZD4547 appropriate to test in MPM in the context of strong preclinical rationale.Common side effects include dry mouth, mucositis and dermatological toxicity. Serious side effects include ophthalmological toxicity, such as Retinal Pigmented Epithelium Detachment (RPED), conjunctivitis and corneal atrophy, hyperphosphatemia leading to cardiac mineralisation and renal failure.

Methods:
The study is an open-label single centre phase II trial of single-agent oral AZD4547 in patients with confirmed, measurable MPM who have progressed after 1[st] or 2[nd] line chemotherapy. Key inclusion/exclusion criteria include ECOG performance status 0-1; adequate organ function; and drug-specific ophthalmological and cardiac exclusion criteria. The primary endpoint is 6 month progression-free survival (PFS-6), with secondary end points of objective tumour response (modified RECIST), PFS, overall survival, toxicity and treatment duration. We will enrol 26 patients in the first of 2 stages (Simon 2-stage design). If more than 7 of the first 26 have PFS >6 months, we will continue to a total of 55 patients. Observing a total of 50 progression events will provide 90% power to identify a 6 month PFS of >45%. Correlative biomarkers including immunological biomarkers from blood and pleural fluid will also be collected. These will be correlated with disease activity, effects of study drug and clinical outcomes to detect any biomarkers and potential predictive biomarkers.

Results:
As of 1[st] July 2016, 7 patients have been enrolled and recruitment is ongoing. There have been no grade 3 or 4 toxicities and no cardiac or ophthalmological toxicities. Main toxicities are grade 1 mucositis and dry mouth. 1 patient had hyperphosphatemia which resolved with dietary modification.

Conclusion:
AZD4547 is well tolerated with no grade 3 or 4 toxicities shown at this stage in a small number of patients. Recruitment commenced in April 2016 and stage 1 is projected to be completed by April 2017.

Background:
Mesothelioma is a rare but aggressive cancer with a poor prognosis. Mesothelin is a cell surface protein that is highly expressed in mesothelioma and other epithelial cancers. Anetumab ravtansine (BAY 94-9343), a novel fully human anti-mesothelin IgG1 antibody conjugated to the maytansinoid tubulin inhibitor DM4, has shown encouraging efficacy in mesothelioma patients in a phase I study. To further explore the possible benefit of antibody-drug conjugate therapy for mesothelioma, we initiated a randomized, open-label, active-controlled, phase II trial to evaluate the efficacy and safety of anetumab ravtansine in patients with metastatic pleural mesothelioma (MPM) overexpressing mesothelin and who have previously progressed on platinum/pemetrexed-based first-line chemotherapy (NCT02610140).

Methods:
Patients (≥18 years) with unresectable locally advanced or metastatic MPM are eligible. Patients should have recurrent or relapsing disease after having previously receiving first-line treatment with pemetrexed-based chemotherapy, with or without bevacizumab. Obligatory biomarker sampling will be performed on all patients at pre-screening and mesothelin-positivity as determined by Ventana MSLN (SP74) companion diagnostic assay as a requirement for entry. The primary objective is to test the superiority of anetumab ravtansine monotherapy over vinorelbine in progression-free survival (PFS) per modified RECIST criteria for MPM per central review. The secondary objectives of this study include overall survival, patient-reported outcomes (PRO), tumor response, and safety. Exploratory objectives include immunogenicity of anetumab ravtansine, pharmacokinetics, and biomarkers of response. Approximately 210 patients will be randomized in a 2:1 ratio to receive anetumab ravtansine 6.5 mg/kg Q3W or vinorelbine 30 mg/m[2] QW. Novel study methods include a grading system for AEs of special interest and the PRO instruments.

Results:
This trial is open and currently accruing patients globally.

Conclusion:
Section not applicable.

Background:
Checkpoint kinase 1 (CHK1), plays a role in cell cycle regulation and DNA damage repair. Prexasertib monomesylate monohydrate (prexasertib, or LY2606368) inhibits CHK1 and induces replication catastrophe. As monotherapy, it demonstrated an acceptable safety profile and preliminary evidence of efficacy in Phase 1. Replication stress, together with defects in cell cycle checkpoints and/or DNA damage repair pathways may sensitize tumors to CHK1 inhibitors. Small cell lung cancer (SCLC) tumors have high levels of replication stress through mechanisms such as MYC amplification and high rates of TP53 mutations, RB1 loss, and genomic rearrangements. Preclinical models of SCLC demonstrate sensitivity to prexasertib monotherapy. As a result, prexasertib is an attractive agent to evaluate in patients with SCLC.

Methods:
This is a parallel cohort, non-randomized, open-label, multicenter Phase 2 study (NCT02735980) in patients with extensive disease (ED)-SCLC. Cohort 1 includes patients with platinum-sensitive disease (objective response to prior platinum-based therapy with subsequent progression ≥90 days after last platinum dose). Cohort 2 includes patients with platinum‑resistant/refractory disease (patients who either did not have an objective response to prior platinum-based therapy or had progression <90 days after last platinum dose). The primary objective is best overall response rate per cohort as determined per RECIST v1.1. Secondary objectives include evaluation of safety/toxicity, pharmacokinetics, and efficacy measures; which include overall survival, progression-free survival, duration of response, and disease control rate. Safety will be assessed by collecting and grading AEs as per CTCAE v4.0. Exploratory biomarkers associated with efficacy and safety of prexasertib may also be assessed. Key inclusion criteria include: patients ≥18 years having histologic or cytologic diagnosis of ED‑SCLC who received prior platinum therapy; ≥1 measurable lesion per RECIST v1.1; ECOG performance status of 0 or 1; discontinued prior therapies ≥14 days before first dose of prexasertib. Key exclusion criteria include: received ≥2 prior therapies for ED-SCLC; symptomatic CNS metastases, prior treatment with CHK1 inhibitor; or serious cardiac conditions. Prexasertib will be administered as intravenous infusion every 14 days. Disease will be assessed by radiographic imaging every 6 weeks. Approximately 116 patients (58 per cohort) are planned for enrollment in 10 countries (>60 sites). An interim futility analysis will be conducted in each cohort after 29 patients have completed cycle 3 and, if required, the response is confirmed. Enrollment began in May 2016.

Results:
Section not applicable.

Conclusion:
Section not applicable.

Background:
Although PD-1 inhibitors have demonstrated significant activity in MPM (Alley, WCLC 2015; Kindler, WCLC 2016), not all patients benefit. About 1/3 of MPM have high PD-L1 expression and a CD8+ infiltrative pattern with a gamma-interferon gene expression profile; this phenotype has been employed in tumors such as melanoma to predict for benefit from immune checkpoint blockade (Ribas, ASCO 2015; Seiwert, ASCO 2015). The mechanisms of anti-tumor response in a disease with a low mutational burden and a distinct macrophage-dominant immune microenvironment remain poorly understood. Due to the anatomy of MPM, access to tumor tissue for correlative studies can be problematic without surgery. We therefore initiated a window-of-opportunity study of pembrolizumab in patients with resectable MPM (NCT02707666) to better understand the dynamic changes occurring with PD-1 checkpoint blockade.

Methods:
Eligible patients have previously untreated, histologically confirmed, epithelial or biphasic MPM amenable to maximal surgical debulking via extended pleurectomy/decortication. Measurable or evaluable disease, PS 0-1, no extra-thoracic disease, adequate pulmonary and cardiac function, and a free pleural space for video-thoracoscopy (VATS) are required. PET/CT and VATS to obtain tissue for correlative studies are performed at baseline. Patients receive 3 cycles of pembrolizumab, 200 mg IV Q21 days followed by repeat PET/CT. Extended pleurectomy/decortication is performed at least 4 weeks later. Adjuvant cisplatin/pemetrexed x 4 cycles is administered 6-8 weeks after surgery, followed by optional adjuvant pembrolizumab x 1 year. The primary objective is to assess an increase in gamma-interferon, measured via a gene expression profile (GEP), comparing matched pre- and post-treatment samples (IFN-G GEP response), and to identify additional candidate biomarkers that may predict benefit or constitutive resistance to pembrolizumab. Correlative studies include: a) multi-color immunofluorescence (CD8, CD4, PD-L1, FOXP3), b) evaluation of immune-related gene expression signatures (using Nanostring/RNAseq), c) evaluation of alternative immune checkpoints, d) determination of mutations in antigen presenting machinery, and e) assessment of activation of immunosuppressive signaling pathways. Radiologic correlatives use image-based texture analysis on PET/CT scans to evaluate therapy-induced changes in tumor composition. This is an exploratory trial. Fifteen patients will be enrolled, which provides a standard error for the estimated IFN-G GEP response rate of approximately 10% (assuming the true response rate is close to 20%). This will also provide 80% power to detect a 0.8 standard deviation change in pre-post treatment biomarker levels, using a paired t-test at the 0.05 alpha level.

Results:
Section not applicable.

Conclusion:
Section not applicable.

Background:
Pemetrexed, an anti-folate drug, is the preferred chemotherapeutic agent for non-squamous NSCLC histology. Addition of vitamin B12 and folic acid (folate; 350–1000μg PO daily) supplementation to pemetrexed containing regimens reduces the incidence and severity of myelosuppression without diminishing antitumor efficacy. Folate supplementation and vitamin B12 (1000μg intramuscular every nine weeks) should be started one week before the first cycle of chemotherapy and continued for atleast three weeks beyond the last cycle. However, observational and prospective single arm studies have not shown any increase in toxicity when pemetrexed was started prior to completion of the recommended duration (one week) of supplementation.

Methods:
The current study is an open-label, randomized trial (PEMVITASTART; NCT02679443) to evaluate differences in pemetrexed-related hematological toxicity amongst patients initiated on chemotherapy following 5-7 days of vitamin B12 and folate supplementation (Delayed Arm) compared to those in whom the above supplementation is started simultaneously with (within 24 hours of) chemotherapy initiation (Immediate Arm). Eligible patients are chemo-naïve WITH cytologically/histopathologically proven non-squamous NSCLC AND locally advanced/metastatic (Stage IIIB/IV) disease (OR Stage IIIA not scheduled for upfront surgical resection) AND ECOG PS 0-2. Prior molecular targeted therapy is an exclusion but previous radiation therapy is permitted if completed atleast four weeks before enrollment. Other important exclusion criteria include hemoglobin <9 gm/dL, administration of erythropoiesis stimulating agents (ESAs) or packed RBC (PRBC) transfusions in the past four months and symptomatic untreated brain metastasis. Randomization is 1:1 into delayed and immediate arms. All enrolled patients will receive pemetrexed in standard dose of 500 mg/m2 in combination with either cisplatin (65 mg/m2) or carboplatin (AUC 5.0mg/mL/min) each drug being given on day 1 of a 3-week cycle. Primary Outcome: Incidence of any grade hematological toxicity (NCI-CTC AE v3.0); Secondary Outcomes: a) Incidence of grade 3/4 hematological toxicity b) Number of granulocyte colony stimulating factors (G-CSFs), ESAs and PRBCs administered c) Relative Dose Intensity (RDI) delivered d) Number of Inter-Cycle Delays (≥ 7 day duration). Other Pre-specified Outcomes: Changes in serum levels of folic acid and homocysteine after third/sixth cycle. Enrolled patients will be followed up till three weeks beyond completion of pemetrexed-platinum doublet chemotherapy (average 18 weeks). Radiological Responses will be assessed by RECIST v1.0. IEC approval has been obtained and patients are enrolled after giving informed consent. The single centre study was opened to accrual in July 2015 and will continue till atleast 128 patients are enrolled. Clinical trial information: NCT02679443

Results:
Not Applicable

Conclusion:
Not Applicable

Background:
The development of resistance to chemotherapies in cancer leads to disease progression resulting in impaired survival. RRx-001, an epi-immunotherapeutic agent, may resensitize patients to previously effective, now refractory therapies, potentially improving survival. This study (NCT02489903) explores the potential of RRx-001 to sensitize patients who previously responded and now have failed a platinum based doublet to the previously effective therapy.

Methods:
In this 4-arm, 3-stage study, subjects with SCLC, NSCLC, HGNEC and ovarian cancer (EOC) in each arm receive RRx-001 weekly until progression followed by platinum therapy. Each cohort will initially enroll 3 patients to assess for safety (Stage 1) then 7 patients (Stage 2) for a total of 10 patients per cohort. If any arm has > 1/10 subjects that has stable disease or better, then additional patients would be enrolled in that arm (Stage 3) for totals of 31 (NSCLC), 26 (SCLC), 26 (HGNEC) and 26 (EOC). Eligibility criteria include: evaluable, progressive disease; previous response to platinum doublet therapy; ECOG PS ≤2. Primary endpoint is Overall Survival with ORR, DCR, PFS and rate of toxicity for reintroduced platinum therapy as secondary endpoints. Exploratory pathologic assessments, including oncogenic mutation expression and infiltrating tumor lymphocyte analysis, will be performed on tumor samples before and after starting the study regimens.

Results:
Stage 1 for all arms except EOC has been completed with no unexpected AEs. RRx-001 treatment to date resulted in a 45% (5/11) DCR including one Partial Response in HGNET. Reintroduction of platinum therapy in evaluable patients with SCLC and NSCLC resulted in an ORR of 75% (3/4), and 67% (2/3), respectively (HGNET and EOC: 0 evaluable). Median OS for all patients is 7.0 mo. (7.8 mo. median f/u). One patient with resistant SCLC had a confirmed Partial Response to cisplatin/etoposide and his treatment free interval post platinum was >180 days. To date, serial on-treatment biopsies have demonstrated an increase in T-cell tumor infiltration over time. Recruitment to this study is continuing.

Conclusion:
Although the trial is ongoing, early data suggest that RRx-001 appears to increase the sensitivity of SCLC and NSCLC to subsequently reintroduced carboplatin or cisplatin (to date no HGNCEC and EOC patients have been rechallenged with platinum). In addition, data from one patient indicates a conversion of resistant to sensitive SCLC phenotype. These data suggest that RRx-001 priming may lead to a new treatment strategy resulting in renewed sensitivity to chemotherapy and prolongation of survival.

Background:
Clinical Trial with Data Analysis in Progress

Methods:
Subjects (n=90) were selected for the trial if they met one the following criteria: current or former smoker (> 10 pack years); biopsy proven endobronchial dysplasia; airflow obstruction (FEV1/FVC < 0.70); or at least mild sputum cytologic atypia. Fluorescent bronchoscopy was performed at trial entry with biopsy of 6 standard endobronchial sites and all other abnormally appearing areas. Subjects also had pulmonary function testings and quantitative high resolution CT scans at the start and completion of the trial. Subjects were then randomized to oral pioglitazone or placebo for 6 months, followed by a second fluorescent bronchoscopy with repeat biopsy of all the central airway areas sampled on the first bronchoscopy. The endobronchial biopsies were scored on a 1-8 scale based on WHO criteria. The primary endpoint for the study is change in maximum (worst) endobronchial histology.

Results:
Final data analysis is pending

Conclusion:
clinical trial with data analysis in progress

Background:
Darbepoetin alfa (DA) is an erythropoiesis-stimulating agent (ESA) that has been shown to increase hemoglobin levels and reduce the rate of transfusions in patients with chemotherapy-induced anemia (CIA). Most studies have not shown an association between ESA use and poor outcomes, but some clinical trials have reported increased mortality and/or tumor progression. This trial was therefore designed to address the safety of DA for CIA in patients with non-small cell lung cancer (NSCLC).

Methods:
Study 20070782 is a randomized, double-blind, noninferiority trial to compare DA with placebo, and is enrolling patients with NSCLC with CIA. Eligible patients are ≥ 18 years old with Eastern Cooperative Oncology Group (ECOG) status ≤ 1, stage IV NSCLC, no prior adjuvant/neoadjuvant NSCLC therapy, ≥ 2 cycles first-line chemotherapy planned (≥ 6 weeks total), and screening hemoglobin ≤ 11 g/dL. Approximately 3,000 patients from up to 500 global sites will be randomized 2:1 to DA (500 mcg) or placebo every 3 weeks (Q3W) until disease progression or end of chemotherapy. At hemoglobin > 12 g/dL, study drug is withheld until hemoglobin ≤ 12 g/dL. Transfusions are allowed when necessary. Endpoints include overall survival (OS; primary) and progression-free survival (PFS; secondary), and will be analyzed when ~2,700 deaths have occurred. Additional safety endpoints include tumor response and rate of thromboembolic events. Superiority of DA to placebo in transfusion rates will be tested if noninferiority is achieved for OS and PFS.

Results:
As of April 15, 2016, a total of 2,215 patients have enrolled. The independent data monitoring committee has conducted 9 reviews of unblinded data (which included a planned formal interim analysis at 40% of planned total number of 2,700 deaths to test for harm), and has recommended continuation of the trial without changes.

Conclusion:
Study 20070782 is the largest clinical trial in NSCLC to date, and will provide comprehensive data on the safety and efficacy of DA in patients with CIA.

Background:
Tumor Treating Fields (TTFields) are non-invasive regional anti-mitotic treatment modality, based on low intensity alternating electric fields. Efficacy of TTFields in non-small cell lung cancer (NSCLC) has been demonstrated in multiple in vitro and in vivo models, and in a phase I/II clinical study. TTFields treatment to the brain was shown to be safe and to extend overall survival in newly-diagnosed glioblastoma patients.

Methods:
270 patients with 1-10 brain metastases (BM) from NSCLC will be randomized in a ratio of 1:1 to receive stereotactic radio surgery (SRS) followed by either TTFields or supportive care alone. Patients are followed-up every two months until 2[nd] cerebral progression. Patients in the control arm may cross over to receive TTFields at the time of 2[st] cerebral progression. Objectives: To test the efficacy, safety and neurocognitive outcomes of TTFields in this patient population. Endpoints: Time to 1[st] cerebral progression based on the RANO-BM Criteria or neurological death (primary); time to neurocognitive failure based on the following tests: HVLT, COWAT and TMT; overall survival; radiological response rate; quality of life; adverse events severity and frequency (secondary). Main eligibility criteria: Karnofsky performance status (KPS) of 70 or above, 1 inoperable or 2-10 brain lesions amenable to SRS, optimal standard therapy for the extracranial disease, no brain-directed therapy, no signs of significantly increased intracranial pressure, no electronic implantable devices in the brain. Treatment: Continuous TTFields at 150 kHz for at least 18 hours per day will be applied to the brain within 7 days of SRS. The treatment system is a portable medical device allowing normal daily activities. The device delivers TTFields to the brain using 4 Transducer Arrays, which may be covered by a wig or a hat for cosmetic reasons. Patients will receive the best standard of care for their systemic disease. Statistical Considerations: This is a prospective, randomized, multicenter study for 270 patients. The sample size was calculated using a log-rank test (based on Lakatos 1988 and 2002) and has 80% power at a two sided alpha of 0.05 to detect a hazard ratio of 0.57.

Results:
Trial in progress

Conclusion:
Trial in progress

Background:
The SABRTooth trial aims to assess the feasibility of recruiting patients with stage I non-small cell lung cancer (NSCLC) to a study comparing surgery to stereotactic ablative radiotherapy (SABR). Both trial treatments were available outside of the trial. An embedded qualitative study aimed to explore reasons for non-participation or refusal to take up the randomised treatment arm in the SABRTooth trial to help identify factors that affect recruitment.

Methods:
Using in-depth qualitative interviews we aimed to interview sixteen patients not taking part in the trial across five sites using a pre-defined topic guide. The data were thematically analysed using a compare and contrast approach, identifying similarities and differences.

Results:
Fifteen patients have been approached so far for interview, ten opted out, five were interviewed. Although, from a limited sample there were three key themes affecting patients decision making that are similar to those reported in the literature. These were 1) treatment preferences 2) influence of personal contacts 3) influence of professionals. We interviewed patients about their experience of being offered the trial and reasons for their treatment preference. Patients described existing treatment preferences that were amenable to change in some cases. Their choice of treatment was subject to change throughout the process of being of being offered the trial and treatment options and was shaped by previous experience and knowledge. Treatment decisions were influenced by people in their close personal networks. Those that chose SABR had previous knowledge or experience of this treatment. Professionals could influence decisions by using specific phrases such as "surgery is your golden ticket" or comparing the effectiveness of treatments using percentages e.g. "surgery is 100% and SABR is 99.9%". Patients said they were happy with the way the trial was presented to them. However, they asked for time to come to terms with their diagnosis and then to be offered the trial alongside treatment options as early as possible to allow informed decision making.

Conclusion:
Information from interviews to date suggests that patients with NSCLC may prefer to be informed about clinical trial options at an early stage in their care pathway. This not only enables them to take account of all the information but also encourages equipoise when considering different treatment options. Treatment preferences should be explored to assess the basis for making a decision about taking part in the trial or choosing a particular treatment and to identify potential factors that could influence these decisions.

Background:
Tumor Treating Fields (TTFields) is a novel, non-invasive, anti-mitotic treatment modality, based on low intensity alternating electric fields. TTFields predominantly affect two phases of mitosis: metaphase – by disrupting the mitotic spindle, and cytokinesis – by dielectrophoretic dislocation of organelles. TTFields were shown to extend the survival of newly diagnosed glioblastoma patients when combined with temozolomide. Efficacy of TTFields in non-small cell lung cancer (NSCLC) of all histologies has been demonstrated multiple preclinical models as well as in a phase I/II study in combination with pemetrexed, where overall survival was extended in more than five months compared to historical controls.

Methods:
The hypothesis of the study is that the addition of TTFields to standard of care second line therapies in advanced NSCLC will increase OS compared to treatment with standard second line alone. 512 patients with either squamous or non-squamous NSCLC will be enrolled in this prospective, randomized study. Patients will be stratified based on: 1) second line therapy (either PD-1 inhibitor or docetaxel), histology (squamous Vs. non-squamous) and geographical region. The main eligibility criteria are first disease progression (per RECIST Criteria 1.1), ECOG score of 0-1, no prior surgery or radiation therapy, no electronic medical devices in the upper torso and absence of brain metastasis. Docetaxel or PD-1 inhibitors (nivolumab or pembrolizumab) will be administered at the standard dose. TTFields will be applied to the upper torso using a small, portable medical device for at least 18 hours/day at home, allowing patients to maintain daily activities. TTFields will be continued until progression in the thorax and/or liver according to the immune-related response criteria (irRC). Follow up will be performed once q6 weeks, including a CT scan. Following progression in the upper torso, patients will be followed monthly for survival. The primary endpoint will be superiority in overall survival (OS) between patients treated with TTFields in combination with either docetaxel or PD-1 inhibitors, compared to docetaxel or PD-1 inhibitors alone. A co-primary endpoint will compare the OS in patients treated with TTFields and docetaxel to those treated with PD-1 inhibitors alone in a non-inferiority analysis. Secondary endpoints include progression-free survival, radiological response rate based on the irRC, quality of life based on the EORTC QLQ C30 questionnaire and severity & frequency of adverse events. The sample size is powered to detect a Hazard Ratio of 0.75 of TTFields-treated patients compare to the control group.

Results:
Trial Progress

Conclusion:
Trial Progress

Background:
The standard treatment for stage IIIA-N2 non-small cell lung cancer (NSCLC) is definitive chemoradiotherapy. However, the strategy for resectable IIIA-N2 disease remains controversial. This phase II multi-institutional trial (WJOG5308L) was designed to evaluate the feasibility for neoadjuvant chemoradiotherapy followed by surgery (tri-modality) in patients with pathologically-proven N2 NSCLC.

Methods:
Patients with resectable IIIA-N2 (pathologically proven N2) were eligible. Neoadjuvant chemotherapy consisted of weekly paclitaxel (40mg/m2) plus carboplatin (AUC 2) for 5 weeks. Concurrent radiotherapy (RT) was prescribed with 50 Gy in 25 fractions to the mediastinum and primary tumor. Patients underwent surgical resection, unless PD disease, followed by two courses of paclitaxel plus carboplatin consolidation chemotherapy. The primary endpoint was complete resection (R0) rate. Secondary endpoints were progression-free survival, overall survival, response rate, protocol completion rate and morbidity/mortality.

Results:
From December 2011 to November 2013, 40 patients were enrolled. The median follow-up time was 33.97 (7.2-46.3) months. The radiological responses to neoadjuvant chemoradiotherapy were as follows: no complete response, 23 (57.5%) partial response, 16 (40.0%) stable disease and one (2.5%) progression. 34 of 40 patients underwent surgery. Reasons for not receiving surgery were radiation pneumonitis (n=4), PD (n=1) and delay of protocol (n=1). Of 34 resections, twenty-eight were lobectomies, three were bilobectomies, two were pneumonectomies, and one was exploratory thoracotomy. Six patients underwent sleeve lobectomy, without any complication. Thirty-two patients achieved the primary endpoint, complete resection (R0) rate 80% (32/40). Pathological complete response (PCR) rate was 30.3%. Finally, 20 patients (50%) completed all planned tri-modality treatment. The 2-year progression-free and overall survival rates for all patients were 62.5% and 75.0%, respectively. The 2-year recurrence-free survival for patients who received R0 was 61.5%. Neutropenia was the main grade 3/4 morbidity and tolerable. 30-days mortality rate was 0 %. Two treat-related deaths (late bronchial fistula) occurred. Sites of first disease recurrences were mediastinal lymphnodes (n=9, 22.5%), lung (n=8, 20%), and brain (n=4, 10%).

Conclusion:
Tri-modality treatment, neoadjuvant chemoradiotherapy followed by surgery, for resectable IIIA-N2 NSCLC seems feasible and promising.

Background:
The majority (around 80%) of cases of lung cancer are detected at a late stage when prognosis is poor. The EarlyCDT®-Lung Test detects autoantibodies to abnormal cell surface proteins in the earliest stages of the disease with a specificity of 93% which may allow tumour detection at an earlier stage thus altering prognosis. The primary research question is: Does using the EarlyCDT®-Lung Test to identify those at high risk of lung cancer, followed by computed tomography (CT) scanning, reduce the incidence of patients with late-stage lung cancer (III & IV) or unclassified presentation (U) at diagnosis, compared to standard practice? We have completed recruitment with 12 208 study subjects randomised by June 2016.

Methods:
A randomised controlled trial in general practices serving areas of Scotland representing the most socially disadvantaged quintile based on Scottish Index of Multiple Deprivation. Adults aged 50 to 75 at high risk for lung cancer (>20 pack years) and healthy enough to undergo potentially curative therapy (Performance Status 0-2) are eligible to participate. The intervention is the EarlyCDT®-Lung Test, followed by X-ray and CT in those with a positive result. The comparator is standard clinical practice in the UK. The primary outcome is the difference, after 24 months, between the rates of patients with stage III, IV or unclassified lung cancer at diagnosis. The secondary outcomes include: all-cause mortality; disease specific mortality; a range of morbidity outcomes; cost-effectiveness and measures examining the psychological and behavioural consequences of screening. Participants with a positive test result but for whom the CT scan does not lead to a lung cancer diagnosis have been offered 6 monthly thoracic CTs for 24 months. An initial chest X-ray was used to determine the speed and the need for contrast in the first screening CT. Participants who were found to have lung cancer are being followed-up to assess both time to diagnosis and stage of disease at diagnosis.

Results:
575/ 6 120 (9.8%) of the test group had a positive test with 207 found to have lung nodules > 8mm. 16 lung cancers have been detected, 12(75%) of which are early stage and 11 abnormalities are undergoing further investigation. At this stage of the trial we have no outcome data for the comparison group.

Conclusion:
The study will determine the EarlyCDT-Lung test’s clinical and cost effectiveness. It will also assess potential morbidity arising from the test and potential harms and benefits of EarlyCDT-Lung test screening.

Background:
Circulating tumor cells (CTCs), which can be found in the peripheral blood of cancer patients, represent a simple and minimal-invasive source for monitoring neoplastic evolution or response to anti-cancer therapy. In recent years, numerous technology platforms for the enrichment and molecular characterization of CTCs have emerged, but comparative results and data demonstrating clinical utility are lacking for most of these platforms. To overcome this, the Innovative Medicines Initiative (IMI) consortium CANCER-ID (www.cancer-id.eu), which represents a joint undertaking of experts from academia and pharmaceutical industry, joined forces to define standards in blood-based biomarkers including the evaluation of different CTC enrichment technologies.

Methods:
CTC enrichment technologies including the CellSearch system, Parsortix PR1 and the Siemens filtration device were evaluated in a multicenter ring trial by using standardized spike-in samples of non-small cell lung cancer (NSCLC) cell lines, which were selected based on their different molecular/genetic features. NSCLC cells were spiked into blood of healthy volunteers with informed consent. To increase the comparability of results, spike-in samples were generated in a centralized way following well-defined protocols for pre-analytic sample handling including sample fixation, storage and shipment. Spike-in samples were subsequently analyzed using different CTC enrichment technologies by at least three CANCER-ID partners in a blinded way according to standard operating procedures (SOPs).

Results:
To reflect clinically relevant disease subtypes, NSCLC cell lines were extensively profiled for copy number aberrations, mutational status (e.g. KRAS, EGFR), expression of cell surface antigens (e.g. EPCAM) as well as cell size. Based on this, cells lines with different molecular/genetic profiles were used to generate complex spike-in samples modeling the heterogeneity of real-life patient material. Spike-in samples were subsequently analyzed by at least three different CANCER-ID partners to determine sensitivity and specificity of the different platforms. In addition, comparative data was generated using the FDA approved CellSearch system, which represents the gold-standard for CTC detection and enumeration.

Conclusion:
IMI CANCER-ID is a public-private partnership in the field of liquid biopsies with 37 partners from 13 countries providing access to a variety of CTC enrichment technologies and patient samples. Making use of this major advantage, we describe the first efforts to establish standards in CTC enrichment and molecular characterization by generating comparative data in a multicenter ring experiment. The results will be used to improve SOPs for the analysis of patient blood samples, which represents a promising tool to monitor disease progression and/or therapeutic response. Support: IMI JU & EFPIA (grand no. 115749)

Background:
Post-operative complications in the thoracic surgery patient population can be costly to healthcare systems and devastating to patients and their families. The most common complications are respiratory, cardiac and gastrointestinal in nature. It is estimated that these complications occur at a rate of 3-5%. In an effort to improve patient outcomes, a nurse led multidisciplinary team developed and implemented the WINNERS Study (Walking with INtegrated Nursing, Exercise, Respiratory/Rehab Services), designed to determine if a formal pre-operative/perioperative interactive patient education program would positively impact patient outcomes and improve satisfaction following thoracic surgery.

Methods:
Figure 1 All general thoracic surgery patients undergo informed consent and are randomized to current standard of care verbal pre-operative teaching vs pre-operative/perioperative interactive patient education program. The multidisciplinary team developed formal patient educational materials, written and audiovisual, used to educate and prepare patients for what they should expect post-operatively with respect to the importance of secretion management, ambulation, general aspects of what to expect after surgery and the importance of their active participation in their post-operative recovery. The study design is outlined in Figure 1. The endpoints include length of stay, reintubation rates, pneumonia incidence, quality of life measurements, physical function measurements (PFT / 6min walk / total steps). Patient satisfaction is measures with the Quality of Life Instrument, SF-36 at pre-determined time-points.



Results:
Patients are currently actively enrolling into the study without any recruitment issues or adverse events.The preliminary analysis demonstrates a favorable impact on patient outcomes and improved patient satisfaction.

Conclusion:
This study is ongoing.

Background:
In the USA there is a national initiative in healthcare to decrease hospital readmissions, decrease the cost of care while patients are hospitalized and to increase patient. A recent study evaluating mortality rates in the lung cancer resection patients reported a 30-day readmission was associated with a 6-fold increase in the 90-day mortality of this patient population (14.4% vs 2.5%). This report not only forces thoracic surgery teams to extend their operative mortality focus and reporting beyond the traditional 30-day time period but it also emphasizes the critical value and positive impact continued post-operative care for the first three months after discharge can have on patient outcomes. The expert care delivered by thoracic surgery nurses plays a critical role in decreasing post-operative complications and ensuring patients are safely discharged from the hospital. The valuable impact thoracic surgery nurses have on preventing hospital readmissions and improving patient satisfaction is the intended focus of this clinical trial. The positive impact telehealth interventions have on multiple different disease processes supports investigation of this care modality for the thoracic surgery patient population. We have designed a clinical trial focused on implementing a TeleNursing program with the specific aims of preventing hospital readmissions and improving patient satisfaction.

Methods:
Our thoracic surgery practice currently has a “day-after-discharge” follow-up phone call program that is directed by the thoracic surgery nurses in the practice. Pertinent clinical details of each patient’s post-operative course are relayed to the thoracic surgery nurses. The nurses call patients 2-3 days after discharge and asked questions related to medications, pain management, sign or symptoms of infection, activity level and expectations, sleep, appetite and general understanding of all discharge instructions. This interaction is documented in the electronic medical record. This program has been expanded to compare the efficacy of the phone calls vs scheduled video-calls between nurses and patients. Patients are randomized to standard of care day after discharge phone calls vs the TeleNursing follow-up video-call; discharge day 2, 1-month, 2-month and 3-month. All patients complete a patient satisfaction questionnaire at predetermined time points. The primary objective is to decrease hospital readmission rates and the secondary objective is to improve patient satisfaction.

Results:
Although the results of this clinical trial are pending, interim analysis indicates that patients are willing to participate in this program and are pleased with the nurse-patient interaction beyond their hospital stay.

Conclusion:
This clinical investigation is ongoing

Background:
Transcutaneous Computed Bioconductance (CB) has been shown to be different between malignant and benign lung lesions. We have launched a multicenter study to evaluate the utility of the Computed Bioconductance (CB) measurement following the CT scan in the diagnosis of lung cancer in Chinese population.

Methods:
In this multicenter study, we analyzed the result of a non-randomized prospective trail enrolling 123 patients with suspicious lung lesions studied by CT and CB. The pulmonary nodules or lesions confirmed by CT scan are greater than 4mm and smaller than 50mm. A CB test by BSP-E2-1000-A (Prolung Biotech Wuxi Co., Wuxi, China) was operated within these patients prior to an abnormal CT, then the tissue biopsy or surgical specimen would be conducted within 14 days. The detailed protocol could be found on ClinicalTrails.gov identifier NCT02726633.

Results:
Among the current 123 enrolling patients, 34（28%） cases were diagnosed of benign lesion, and 83 (67%) cases were diagnosed of malignant lesion depend on pathological diagnosis, 6 (5%) cases were eliminated due to patient refusal of biopsy. In malignant group, 32 (39%) cases were in stage I; 17 (20%) cased were in stage II and IIIA; 30 (36%) cases were in stage IIIB and IV. In addition, 10 (12%) cases were with EGFR mutation and all were adenocarcinoma. In benign group, 2 (6%) cases were diagnosed of tuberculosis and most other were inflammation and fibrosis lesion. The sex ratio was 45/78 (female vs. male). In addition, body mass index, lung functions test, serum tumor biomarker, nodule position and appearance, medical, treatment and smoking history were collected in the study. Among all cases, 31 had concomitant PET performed and standardized uptake value were collected.

Conclusion:
In this enrolling study, a pre-biopsy assessment of malignant probability with a CT-detected lung lesion, the method which combined CT and CB was evaluated at first time. This non-invasive risk-stratification technology could improve the diagnostic efficacy of lung cancer.

Background:
To investigate the clinical applicability of the high throughput screening (HTS) using patient-derived tumor cells (PDC) which were established from patients with non-small cell lung cancer undergoing surgery.

Methods:
PDCs were isolated and cultured from surgical specimen from NSCLC at Samsung Medical Center. We performed the HTS for 24 drugs (23 targeted agents and 1 positive control drug) with a micropillar/microwell chip platform using PDCs. Scanned images of the live cells were obtained using an optical fluorescence. With 6 dosages per drug in 7 replicates, the dose response curves and corresponding IC~50~ values were calculated from the scanned images.

Results:
From October 2015 to February 2016, 15 samples from patients with non-small cell lung cancer were collected. PDCs were successfully established in 12 (80%) patients, and nine of 12 cases were successfully cultured in 3-d suitable for 23-drug HTS platform. Three PDCs demonstrated a sensitivity to Neratinib (HER-2/EGFR inhibitor). These PDCs are currently being profiled to elucidate the underlying molecular mechanisms for neratinib sensitivity.

Conclusion:
Differential chemosensitivity were observed which suggests that this HTS platform based on 3D culture with micropillar/microwell chips and PDC model could potentially provide a preclinical tool for predicting the efficacy of targeted agents in lung cancer.

Background:
Epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 receptor tyrosine kinase (ROS1) gene mutations in lung adenocarcinoma (LA) cases give an opportunity to use some of targeted therapy agents. The aim of this study is to obtain EGFR, ALK and ROS1 gene mutation frequencies in Turkey and to examine the factors affecting these frequencies.

Methods:
EGFR, ALK, ROS1 mutation analyses were examined in a total of 971 LA cases; 745 men (76.7%), and 226 women (23.3%) diagnosed in 12 hospitals from different districts of Turkey were enrolled in the study. The demographic characteristics, smoking status, asbestos exposure history, radiological findings associated with asbestos exposure (AE) were investigated with relation to the frequencies of EGFR, ALK and ROS1 gene mutations. In the univariate analysis of the study data chi-square and t-tests were used. To determine the independent factors associated with gene mutations, multivariate logistic regression model was created with the variables that give p <0.10 level of significance in univariate analysis.

Results:
The mean age of 971 patients was 60.8±9.8 years (range:23-91). Smoking rate was 92.6% in men, 42.5% in women (p<0.001). The number of patients with AE history was 279 (28.7%) and the number of patients with radiologic findings associated with AE was 114 (11.7%). The frequencies of EGFR, ALK and ROS1 mutations were 15.9% (152/956), 3.3% (26/768) and 1.6% (6/379), respectively. Female patients were more likely to have EGFR mutations compared with male patients (37.8% versus 9.3%; p<0,001). Never-smokers had higher incidence of EGFR mutations than smokers (39.6% versus 10.3%; p<0.001). The patients with radiological findings of AE had a 24.6% rate of EGFR mutations compared with a 14.7% rate of patients with no radiological findings (p=0.007). ALK rearrengement was detected in patients with younger age, having history of AE or radiological findings associated with AE (11.1%; p<0.001, 5.9%; p=0.014, 6.7%; p=0.044, respectively). No associated factor was found with ROS1 fusion frequency.

Conclusion:
To have a relationship between radiographic findings associated with AE or AE history and EGFR and ALK mutation frequencies is an original finding. The obtained results will be useful in the discussion of standards of treatment with the new agents and pathogenesis. *This study was carried out through the project named as “Network cooperation for the management of environmental and occupational exposure to mineral fibers induced pulmonary pathologies” which was supported by General Directorate of Health Researches, Republic of Turkey, Ministry of Health.

Background:
Randomized controlled trial evidence to guide treatment of early stage lung cancer has been challenging for a variety of reasons. There is now increasing recognition of the power of large databases collected in the context of clinical care to provide important information and there are new statistical techniques for analysis to address unrecognized confounders. We have initiated a new multi-center, international collaborative network for this purpose.

Methods:
Based on an extensive literature review, scientific articles, and a series of focus sessions with a panel of expert surgeons, as well a panel of former patients, a series of critical questions regarding treatment of early lung cancer has been developed. Data forms of relevant data from both physicians and patients pre- and post-surgery to account for potential confounders have been developed, tested, and are being entered into a web-based data collection system that also includes relevant imaging data. Sites are being registered into this new network

Results:
The four primary questions we found needing additional evidence that would be of most concern in regard to treatment of early lung cancer were the following Under what circumstances should limited resection be performed? How large should resection margins be when performing limited resection? When should a watchful waiting approach be considered? When should radiotherapy be considered an option for primary treatment The entire Mount Sinai Health System network which includes 5 hospitals has started enrollment. Treatment is according to usual care but documented in the IELCART registry. Four additional health systems are in the process of joining which requires completing the enrollment application and obtaining IRB approval to submit data to the IELCART registry. Since starting in March 2015, we have enrolled over 30 participants. Actual time required by the surgeon to complete the surgical data prior to surgery is a few minutes. Time to the patient and coordinator to complete the data forms prior to surgery requires between 30 and 60 minutes.

Conclusion:
We anticipate that approximately 10 health care systems will ultimately enroll in the IELCART. Within 2 years, we anticipate starting to have statistically meaningful results in answering the relevant questions. Beyond these, the IELCART registry by continuing to collect data as part of routine clinical practice will provide an important resource to answer future questions in a timely manner as they arise, including performing studies in the neo-adjuvant setting and companion diagnostics.

Background:
Discovery of oncogenic genetic alterations in certain NSCLC subgroups, and their use as biomarkers and molecular targets for cancer therapy has been paradigm shifting. This has made early identification of these genetic (EGFR, KRAS, ALK, c-MET, ROS1,PI3K, HER2) mutations pivotal for achieving better clinical outcomes. Various testing guidelines which are reviewed periodically have been unable to keep pace with the rapid technological and scientific advances in the diagnostic field. Lack of awareness and in-depth understanding of the testing guidelines may result in patients potentially missing out on the eligible targeted therapies.

Methods:
A literature search was conducted for molecular testing guidelines in NSCLC, that may have been published in major peer reviewed journal, presented at a major conference or recommended by a local regulatory body. Comparisons were made to identify key commonalities and differences in terms of patient flow, tests recommended, timing of tests and type of tests. A local algorithm was derived to be pressure tested at key testing centres. Digital platforms such as ALK-Testing website (www.alktesting.asia) and virtual reality (VR) simulations were created and utilized to educate and increase awareness on molecular testing amongst all the stakeholders.

Results:
Review of the major NSCLC molecular testing guidelines and algorithms revealed several potential gaps. Consequently, an updated, a simpler and a potentially cost-efficient molecular testing algorithm for NSCLC patients has been formulated. The algorithm recommends single stage upfront reflex testing for major genetic aberrations (IHC or targeted sequencing) concurrent to histological diagnosis to facilitate tissue preservation and decrease turn-around-time (TAT). Further, to improve the efficiency and TATs for testing, and broaden awareness beyond centres of excellence, an ALK-testing website with information on the various testing facilities, current guidelines and testing protocols was created. Currently, use of liquid biopsies is advocated mainly in NSCLC patients who maybe too fragile, unable to provide a tumour specimen or an apt case for delineating resistant mechanisms. To quantify the impact of the new algorithm, an expansion study involving 4-5 key health centres is planned. Furthermore using VR platform, simulations on tumour heterogeneity and various ALK-testing scenarios have been created for educating the respective stakeholders and driving testing protocols.

Conclusion:
The modified diagnostic algorithm and education through digital and virtual media has the potential to bring consistency and uniformity in diagnosing patients with NSCLC, who are likely to benefit from targeted therapies. Finally, improvements in efficiency and TAT will inform physicians on management decisions without any unwarranted delays.

Background:
Doublecortin and CaM kinase-like-1 (DCLK1) is a kinase that regulates microtubule polymerization in migrating neurons. DCLK1 is also suggested to be a tumor stem cell marker in colon and pancreatic cancer. The expression status of DCLK1 and its role in lung cancer remain largely unknown. LRRK2-IN-1, a potent therapeutic agent for the treatment of Parkinson’s disease, has shown to inhibit DCLK1 kinase activity.

Methods:
DCLK1 expression status in human non-small cell lung cancer (NSCLC) cell lines was examined by quantitative real-time RT-PCR and western blotting. Cell proliferation assay was made after treatments with either si-DCLK1 or LRRK2-IN-1.

Results:
DCLK1 was expressed in most of the cell lines examined in various degrees. In DCLK1-expressing cell lines, si-DCLK1 treatment showed growth inhibition. LRRK2-IN-1 treatment also showed growth inhibition, in a dose-dependent manner.

Conclusion:
DCLK1 can be a target molecule for NSCLC treatment. LRRK2-IN-1 might be therapeutic for DCLK1-expressing lung cancer, through inhibition of its kinase activity.

Background:
Effective information exchange is an asset to effective cancer care (Thorne et al, 2005). Lung cancer is a disease with many biomedical, physical and psychological consequences. This underlines the need for patient-centred care, tailoring communication to the specific needs, values and information preferences of each individual (Kissane et al, 2010). In the context of patient-centred care, communication with healthcare professionals can impact the effectiveness of the clinical encounter and influence clinical outcomes for patients with cancer (Aiello et al, 2008). However, the way in which healthcare professionals exchange information with patients can be affected by wide-ranging, external factors. The presence and involvement of a companion can increase the challenge and complexity of information exchange during cancer consultations (Albrecht et al, 2010). Companions add extraordinary dynamics to the clinical interaction and their potential to influence the exchange, either in a mediating or moderating manner warrants further investigation. As patients with lung cancer are commonly accompanied to the consultation by companions and as national and international policies advocate accompaniment, research in this area is germane.

Methods:
Qualitative, multiple case study design. Each case centred on a patient with lung cancer. It included health professionals patients consulted with and any accompanying companion(s). Seven cases were recruited, including 12 companions, and six professionals. Participants were recruited in 2010-2011 at outpatient clinics. Data were: consultation recordings, debrief interviews immediately post-consultation and later in-depth patient (possibly with companion) interviews. Analysis followed case study pattern matching and coding traditions.

Results:
Each patient was accompanied by at least one companion. Three levels of negotiated companion accompaniment were identified: reciprocal/mutually agreed, partially negotiated/coerced and non-negotiated. Companions mediated and moderated information exchange across six major constructs. Mediating constructs were physical, emotional and informational, and moderating constructs were companion control, companion agenda and companion as expert. Companions with a non-negotiated presence were powerful and expert and moderated information exchange.

Conclusion:
Companion accompaniment to lung cancer clinics if often a negotiated process and one that patients may not have total autonomy over. Accompanying companions can influence the exchange of clinical information in both a mediating and moderating manner. The level of negotiated companion presence at lung cancer consultations has clinical implications that require policy, professional and patient attention. In order to facilitate the delivery of patient-centred care and communication healthcare professionals should be aware of and respect patient preference for companion accompaniment and involvement when policy initiatives often recommend companion presence during cancer consultations.

Background:
Providing healthcare information is very important for lung mass patients after lung surgery for achieving good post-operative rehabilitation, understanding their disease, taking medication, adjusting daily life activity such as stop smoking, and health promotion. The aim of this study is to evaluate the providing healthcare information (HI) from physicians or nurses to patients before discharged and to explore the adding discharge information needs of patients.

Methods:
Descriptive research with prospective data collection design was conducted. All lung mass patients undergoing lung surgery at General Thoracic Surgery Unit, Department of Surgery, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand during April 1[st], 2015 to July 1[st], 2016 were enrolled in this study. Lung Information Needs Questionnaire: Thai translation was provided to patients on the day before discharge date.

Results:
Figure 1There were 56 patients enrolled in this study including 18 women and 38 men. The mean age was 59.16 years (SD= 13.64). The percentage of the physicians or nurses who provided HI about; (1) disease knowledge was more than 80%, except disease recurrence, plan of follow-up and treatment; (2) a reason for taking inhalers or medications was 89.3%, however more than 30% of them were still not clear understand; (3) self-management was more than 75 %; (4) Giving up smoking, only 50 %; (5) promoting exercise was more than 90, but 17.3 % of these were not sure what to do.; (6) diet was only 62.5 %. For the open ended question, the percentage of patients who need more discharge information about disease, treatment, pain management, recurrent prevention and truth telling was 21.4 %. The percentage of patients who need more discharge information about food for post-operative lung surgery was 1.8%.



Conclusion:
The physicians and nurses should more provide clearly healthcare information to their patients before discharge.

Background:
The National Cancer Survivorship Initiative (NCSI) was set to improve the quality of care for people living with and beyond cancer. The NCSI publication, Living With and Beyond Cancer: Taking Action to Improve Outcomes (2013) outlines actions the NHS can take to improve the experience and care for cancer patients. A key outcome identified was the recovery package, which consists of: - an assessment of holistic needs and the development of a care plan to address these issues -a treatment summary that explains to the GP and individual what treatment has taken place and ongoing management - a cancer review by the GP within six months of diagnosis - a health and well being educational event. The generally poor prognosis for lung cancer patients is widely recognised, yet within clinical practice we are seeing more people living with lung cancer, receiving surgery and active treatments for lung cancer and many surviving over two years post diagnosis. The cancer survivorship initiative and the recovery package may be applicable to many site specific cancers and is part of the five year NHS plan but little evidence is available for people living with and survivng lung cancer. The aim of the study is to conduct an initial exploration to identify and understand what people who have had treatment for lung cancer and mesothelioma have experienced in terms of ongoing support to enhance their recovery.

Methods:
To generate an in-depth understanding of the patient experience through qualitative interviews with patients, carers and family members and identify a) what people received b) whether this met their recovery needs c) whether and how the four recovery package components need to be modified and delivered to meet the needs of lung cancer and mesothelioma patients d) whether other components need to be added A mixed method study using survey and qualitative research methods and including interviews of patients and relatives who have survived two years from a diagnosis of lung cancer or mesothelioma. Patients will be sent a postal questionnaire and an information sheet and those agreeing to be interviewed will be contacted, the interview will be guided by a topic guide developed in relation to the literature, the recovery package recommendations and survey responses. Interviews will be conducted, audio recorded and selectively transcribed removing any identifying data. All data will be entered onto qsr NVIVO for management. Framework Analysis methods will be used.

Results:
Section not applicable

Conclusion:
Section not applicable

Background:
Background: Surgical resection is considered the treatment of choice for patients with early stage, non-small cell lung cancer. It is shown that these patients experience many concurrent symptoms after surgery. Patients with good social support experiences less emotional distress and have an increased survival compared to those with poor social relationships. It is shown that lung cancer patients receives less social support than other cancer patients. However, the knowledge about surgically treated lung cancer patients’ social support is limited. There is also limited knowledge about social supports influence on patients’ symptom burden. The purpose of this study was to describe patients’ experience of social support 1 month after lung cancer surgery, and to evaluate the relationship between the level of social support and number of symptoms in these patients.

Methods:
Patients were recruited from three university hospitals in Norway. They completed different questionnaires 1 month following surgery including; demographic and clinical characteristics, symptoms and social support. Patients’ medical records were reviewed for disease and treatment information. The Social Provisions Scale (SPS) measured social support and symptoms was measured by a multidimensional symptom assessment scale (i.e., Memorial Symptom Assessment Scale (MSAS)). Descriptive statistics were used to present demographic and clinical characteristics. The relationship between social support and number of symptoms was analyzed by Pearson’s correlation coefficient.

Results:
The sample consisted of 129 (57%) men and 99 (43%) women with a mean age of 65.8 years (SD 8.5, range 30 to 87). The patients experienced a relatively high level of social support ( =84.93, SD=9.4); however it was lower than the social support experienced by Norwegian breast cancer patients ( =87.96, SD=7.55). The total number of symptoms 1 month after surgery was 13 (SD 6.8). When looking into the subscales and SPS patients had the lowest score on the subscale “Opportunity for nurturance” (the sense that others rely upon one for their well-being) ( =11,3, SD=2,8). Patients that experienced lower social support had a significant higher number of symptoms (r=0.168, p=0.017). There was a significant correlation between a higher number of symptoms and social support on five of six subscales of social support.

Conclusion:
Findings from this study show that patients have a high number of symptoms after surgery and that patient with poor social support experiences a higher symptom burden. Clinicians need to assess patients’ social support and plan the care and follow up for the patients with low social support.

Background:
Bronchoscopy is a standard procedure to investigate and treat respiratory pathology. When patients have high risk respiratory conditions e.g. chronic obstructive pulmonary disease, the administration of sedation and analgesia is often restricted to help prevent respiratory complications. In this study, limited sedation and analgesia was given up to maximum doses of midazolam 5mg and fentanyl 100mcg. Prior to this study, the patient experience of bronchoscopy with limited sedation and analgesia was relatively unexplored. The aim of this study was to explore the patient experience of bronchoscopy with limited sedation and analgesia.

Methods:
A qualitative, interpretive approach was used to collect data, analyse and write up the stories of the 13 participants in the study. Data were collected using unstructured interviews. These were transcribed then analysed phenomenologically (after Van Manen, 1990).

Results:
Bob was scared that he had lung cancer and required a bronchoscopy with biopsy to determine this. During the procedure Bob was aware and heard the doctors say they could not do a biopsy. This made Bob angry and frustrated. John was also aware during his bronchoscopy and remembered coughing and choking during the procedure. John described choking as the worst feeling. Rachel was fearful that the bronchoscopy procedure would be uncomfortable and anticipated throat discomfort with coughing. Rachel expressed feeling unprepared before the procedure resulting in heightened anxiety. She also said the humour of the hospital workers helped relieve her anxiety pre-procedure. Rachel was not aware during her procedure, but suffered a sore throat and aggravation of her asthma post procedure.

Conclusion:
Patients’ experiences of fear dominated the findings. For example, coughing and choking during the procedure may potentially lead to fears that they are impeding the diagnostic process. The fear that they may have lung cancer may elevate levels of anxiety and possibly impact other emotional responses, recollection of instructions and patient education. Fear of the procedure can be reduced with caring and supportive healthcare workers. It is proposed that effective communication may promote appropriate education, support and reduce unrealistic expectations, and ease patient fears. Helpful educational material could include patient experiences of the procedure plus their acceptance of negative experiences in order to obtain a medical diagnosis. Ultimately, improved pharmaceutical interventions and anaesthetic support to improve patient experiences and manage post-procedural problems may be beneficial.

Background:
The incidence of cancer increases along with the number of medicines used for the systemic healing of cancer. By using those medicines some side effects can occur. Trastuzumab could cause cardiovascular problems. The most common side effects of erlotinib are skin rash and diarrhea. The purpose of the study was to assess the difficulties and side effects for the patient receiving a combination of trastuzumab and erlotinib and the health educational role of a nurse in given situation.

Methods:
The case study included a female patient, diagnosed with cancer of the genitals, metastatic lung cancer and breast cancer, treated in the Unit for Medical Oncology clinic, Department of Oncology, University Clinical Centre Maribor. The patient was invited to an interview where the purpose of a case study was explained. The patient could easily refuse to participate in a case study. Data was collected retrograde from medical records and healthcare documentation and from the conversation with the patient for the time period of 18 years, from 1998 to June 2016.

Results:
The patient is receiving the medicine erlotinib in tablet form from 2012 and trastuzumab in the form of subcutaneous injections from 2015. Introducing erlotinib caused no side effects. In November 2014 extended lashes, I. stage skin rash, mild diarrhea and mild conjunctivitis have emerged. All symptoms were controlled by symptomatic therapy. Skin rash of II. - III. stage appeared in January 2015, mostly on the scalp, but the patient nevertheless continued taking biological medicine. In February 2016 the skin rash was reduced after the intensity of the therapy was modulated. After receiving trastuzumab the patient only noticed mild pain in bones and muscles.

Conclusion:
The patient is being monitored since her first diagnosis, through surgical procedures, radiations, chemotherapy and biological medicines treatments. Through conversation we found out that she is conscious, eager for all the available information and that she accepted cancer diagnosis and all the treatment as something she must overcome and talk about. The patient believes that biological medicine application, continuous medical education and healthcare help by overcoming the symptoms of the disease and its side effects. She lives normally, is capable of the efforts of everyday life and during the entire treatment works as a manager. She does not mind coming regularly to the medical oncology clinic.

Background:
The National Lung Cancer Forum for Nurses (NLCFN) is a UK professional organization of around 300 Lung Cancer Nurse Specialists (LCNSs). LCNSs are the multi-disciplinary team members who spend the most time with patients. They can make valuable contribution to research in lung cancer. In 2015 the Shape of Caring report highlighted the need to develop a research culture in nursing.[1] However, research career pathways and opportunities are not as well defined for nurses, as they are for doctors.[2] The NLCFN is committed to developing the research skills and capacity of its members and to facilitate research collaborations between academics and practitioners. They therefore developed research training for LCNSs called ‘TORCH for Nursing’. The BIL-TORCH Programme for LCNSs was a collaborative initiative by NLCFN and Boehringer-Ingelheim Limited (BIL).

Methods:
A two day residential BIL TORCH for Nursing Workshop was held in April 2016 and was funded by BIL. The Workshop aimed to: Develop the skills and confidence of LCNSs and Research Nurses in lung cancer research. Bridge gaps in lung cancer between nursing research and practice. Facilitate the relationships between LCNSs and Research Nurses to encourage better recruitment into lung cancer clinical trials. Address the barriers to UK lung cancer nurse-led research. Evaluation consisted of: Rapid appraisal at the end of day 2 An e-survey one week after TORCH An e-survey 6 months after TORCH

Results:
Response rates were: 100% for rapid appraisal. 78% (n=14) for the one week survey. 6 months follow-up will be in October 2016. Quantitative data indicated an increase in knowledge, understanding and confidence in research methods and skills. Participants reported an increased ability to develop networks to facilitate research and an ability to develop a research question or proposal. Qualitative data indicated how participants found the day inspiring and motivating. They reported benefit from the discussion and collaboration between LCNSs, academics and research nurses. All delegates would recommend TORCH for Nursing to their colleagues.

Conclusion:
The evaluation to date has demonstrated the positive impact of TORCH for Nursing. Two project groups have been established with Faculty and delegates to develop fundable proposals based on 2 research questions developed during the workshops. TORCH for Nursing Workshops will be repeated in 2017 with the aim of becoming an annual event.

Background:
Clinical audit may improve best practice within health. The UK National Lung Cancer Audit (NLCA) collects data from UK hospitals about care of patients with thoracic cancers. We aimed to replicate collection of the NLCA data elements from hospitals caring for patients with thoracic cancers within the Victorian Comprehensive Cancer Centre (VCCC) and associated Western and Central Melbourne Integrated Cancer Service (WCMICS).

Methods:
Retrospective audit of patients newly-diagnosed with lung cancer or mesothelioma in 2013 at 6 major VCCC or WCMICS hospitals. The objectives were: to adopt/adapt the NLCA dataset for use in the Australian context; and analyze the findings using descriptive statistics to identify variations in care. Individual data items from the NLCA were tailored to the Australian context in consultation with an expert steering committee. Data was collected from existing datasets including the Victorian Cancer Registry, Victorian Admitted Episodes Dataset and individual hospital databases. Individual medical records were audited to collect missing data.

Results:
845 patients were diagnosed during 2013. Most were aged 65-80 (55%) and 62% were male. Most had non-small cell lung cancer (81%) with 9% small cell and 2% mesothelioma. Data completeness varied greatly between fields. Headline indicators of clinical care in the table below are compared to NLCA data. A significant area of concern identified was lack of access of many patients to a specialist lung cancer nurse.

Conclusion:

Benchmark	VCCC/WCMICS (%)	NLCA-2013 (%)
Patients with histological diagnosis	810/845 (96%)	(75%)
Patients with CT before bronchoscopy	384/492 (78%)	(91%)
NSCLC patients receiving PET scan	544/748 (73%)	(35%)
Patients with stage documented	518/845 (61%)	(93%)
Patients discussed at multi-disciplinary meeting	585/845 (69%)	(96%)
Patients seen by lung cancer nurse specialist	110/845 (13%)	(84%)
Lung cancer nurse specialist present at diagnosis	0/845 (0%)	(65%)
Patients receiving active treatment	643/845 (76%)	(60%)
Patients treated with surgery	242/845 (29%)	(15%)
Patients treated with radiotherapy	370/669 (55%)	(29%)
Patients treated with chemotherapy	327/638 (51%)	(70%)
Patients seen by specialist palliative care	179/845 (21%)	(30%)

Lung cancer care at participating hospitals appeared to be comparable or better to many of the headline indicators of the NLCA. However, performing the audit retrospectively resulted in significant amounts of missing data for some fields. For future audits, prospective data collection should be harmonized across sites and correlated with survival outcomes. Initiatives to improve access to specialist lung cancer nurses are urgently needed.

Background:
Surgical resection for lung cancer reduces the pulmonary capacity relative to the extent of the resection. The forced expiratory volume in the first second (FEV1) correlates significant to the experience of dyspnoea and lung function by the patient. In this study we analysed changes in FEV1 over time after lung surgery to investigate if standard rehabilitation has an effect on lung function. Furthermore we analysed the effect of physical exercise using the 6 minute walk test (6MWT) before and after a standardized physical exercise program.

Methods:
FEV1 is measured in 225 pulmonary resections (175 lobectomies, 31 pneumonectomies, 17 resections and 2 explorative thoracotomies) performed in a single surgical unit. FEV1 is measured before surgery and after 1, 2, 6 and 12 months. All patients are alive after 1 year. Patients were treated in accordance with national guidelines and 131 patients received oncologic treatment during the first year after surgery. Patients were postoperatively offered to join a physical lung rehabilitation program starting 3 to 6 weeks after surgery twice a week for 4 – 10 weeks.

Results:
Figure 1. First year postoperative change in FEV1 Figure 1 Median distance traveled after 6 minutes was 484 meters before the exercise program and 557 meters after. Change is significant; P= 0,0001, paired T test). A significant reduction in FEV1 before and one month after surgery was observed, but between one month and one year after surgery no significant change was observed.



Conclusion:
As expected FEV1 declines after pulmonary resection for lung cancer. Physical exercise in a standardized rehabilitation program has a positive effect on the short term physical capability of the patient, but this effect is not reflected in the long term lung function test. Short intensive physical exercise after pulmonary resection in lung cancer will have an effect but sustained effects calls for fundamental and persistent efforts.

Background:
Readmission after thoracic surgery is not well documented. It impacts on patients’ physical and psychological wellbeing, whilst also increasing healthcare costs. The Thoracic Enhanced Recovery programme at Papworth Hospital (a regional cardio-thoracic centre) has reduced average length of stay from 12 days (2010) to 5 days (2014). The lung cancer nurse specialists (LCNS) were concerned that a shorter length of stay may increase the incidence of readmission. An audit was undertaken to determine the number of thoracic oncology surgical patients readmitted within 30-days of discharge.

Methods:
From 1[st] April 2015 to 31[st] July 2015 all surgical patients were contacted by a LCNS 30 days following discharge. A formic questionnaire including demographic, socioeconomic, surgical factors and readmission details (if appropriate) was completed.

Results:
74 patients underwent surgery, 68(92%) completed the questionnaire. Of these 11(16%) were never smokers, 45(66%) ex-smokers, 12(18%) current smokers. Lobectomy was the most common operation 45(66%). Video-Assisted Thoracoscopy (VATS) accounted for 72% of all operations. 60/66 (91%) felt ready for discharge, 9/68(13%) were discharged home with a pleural drainage system, 40/64 (63%) were aware to contact LCNS for advice. Average length of stay 6.6 days, thoracotomy 7.5 days, current smokers 9 days, patients readmitted 10 days. 30-day readmission rate was 13/68(19%) of these 9(69%) were readmitted within 7 days. Figure 1



Conclusion:
Initially our concern was that a shorter length of stay may increase the incidence of readmission. However our findings showed that a longer length of stay (and current smoking status) was associated with an increased risk of readmission. This audit therefore suggests that enhanced recovery at Papworth Hospital is a safe and effective practice. Recommendations Review patient education / encourage patient self-referral for advice. Improve discharge planning / communication with the community. Establish a smoking cessation clinic / telephone service. Implement a thoracoscore to accurately identify and target the highest risk patients. Repeat audit over a longer period.

Background:
Lung cancer (LC) is a major cause of cancer death, morbidity and loss of function. Caregivers of LC patients provide emotional, physical, and financial support, but their contribution is under-reported. The Lung Cancer Canada (LCC) Faces of Lung Cancer Survey aimed to study the impact of LC diagnosis and treatment on patients and caregivers.

Methods:
This 15-minute online survey for patients and caregivers was conducted in August 2015. Participants were recruited from a database of patients and caregivers, who previously consented to survey participation; targeted emails, social media postings and other patient groups were also utilized. The questionnaire covered demographics, emotional issues and stigma, symptom burden, quality of life, treatment experiences, and unmet needs. Anonymously collected results were collated by LCC.

Results:
Overall, 91 patients and 72 caregivers completed 163 interviews. Of surveyed patients, 57% had no active cancer. Fatigue, depression, and respiratory complaints were the most challenging symptoms for patients. Fear/uncertainty was reported as the hardest thing about LC by 40% of patients and 17% of caregivers. Most caregivers were partners (54%) or parents (38%). 60% were the primary caregiver, and 79% were former caregivers: 68% of their care receivers had died. Most caregivers coped well (79%), but stressors included care-receiver’s declining health, their own emotions, and balancing responsibilities. Caregivers reported more negative feelings than patients: anxious/stressed 61%v42%, depressed/hopeless 32%v11%, cared for 13%v38%, confident/encouraged 11%v25%. Caregivers felt less support than patients from their healthcare team (75%v92%) and family/friends (65%v87%). Treatment satisfaction was lower among caregivers: only 58% felt very/somewhat satisfied (v 82% patients). 60% of patients and 68% of caregivers reported a negative stigma attached to LC. 35% of respondents felt there was less empathy toward LC than other cancers, and 38% of caregivers felt they had to advocate harder for LC than other cancers. Notably, some caregivers (8%) and patients (5%) reported a lack of compassion from medical professionals after a LC diagnosis. 37% of patients and 50% of caregivers reported a negative household financial impact from LC diagnosis.

Conclusion:
This report on the experiences of lung cancer patients and their caregivers highlights their reactions to the illness, and the associated prejudice and stigma. Lung Cancer Canada is working to improve patient access to supportive services, to decrease caregiver burden through support initiatives such as peer-to-peer support programs, to educate patients and caregivers on LC and their treatment options, and to advocate for LC patients in the face of established stigma.

Background:
Recent studies have found that patients with lung cancer consistently report suboptimal communication with their physicians which, in turn, can limit shared decision making and impair clinical outcomes. To address this gap, a patient/caregiver-focused educational initiative was developed to determine if online education modules could improve knowledge about treatment decisions and side effect management in advanced non-small cell lung cancer (NSCLC).

Methods:
The initiative consisted of 4 educational activities available on WebMD Education, a website dedicated to patient/caregiver learning. Each activity included demographic questions and a pre-/post-activity question to measure impact on knowledge. The activities launched online in between August and October, 2015, and data were collected through April, 2016.

Results:
After 9 months, a total of 8933 persons had participated in the education. Of those, 43% had lung cancer or were caregivers of a person with the disease, and 65% were female. The average age of individuals who participated in any 1 of the 4 activities varied based on topic. Significant post-participation improvements in knowledge were observed including: ·8% increase in comprehending that treatment-related side effects should be reported to their cancer care team both while on therapy and after completion of treatment with a cancer immunotherapy ·16% increase in understanding the mechanism of action associated with use of cancer immunotherapies in the treatment of lung cancer (p < 0.001) ·26% increase in recognizing first response with cancer immunotherapies will take longer than chemotherapy (p < 0.001) ·28% increase in understanding that molecular testing is necessary in individuals with advanced NSCLC, adenocarcinoma, in order to select the most appropriate treatment

Conclusion:
This study demonstrates that well-designed online patient/caregiver-focused education can be successful in improving familiarity with essential elements involved in the management of advanced lung cancer. Targeted and focused digital education empowers, engages and equips patient/caregiver with information needed for self-care condition management.

Background:
Patients with lung cancer rank maintaining their independence and being able to care for themselves as being of greater importance than the symptoms of their disease. Quality of life (QOL) and patient reported outcomes (PRO) provide measures of patients’ physical, functional, and psychosocial wellbeing.

Methods:
In October 2015, advocacy organization executives met to review and evaluate the importance of QOL and PROs within the context of clinical trials and their usefulness during the care of patients with lung cancer by community oncologists. The discussion included the impact of QOL, cancer-related weight changes, diet, and exercise on patients’ overall health and advocating the importance of QOL and PRO assessments in patients with lung cancer through social media.

Results:
QOL and PRO measures are associated with treatment outcomes and may be useful in patient management to evaluate individual treatments and survival. Malnourishment, common in patients with lung cancer, reduces survival. Reduced appetite contributes to cancer cachexia and sarcopenia. Sarcopenia can lead to frailty, decreasing patients’ independence and tolerance and responsiveness to treatment. Early intervention to improve diet and prevent weight loss of greater than >10% greatly improves patients’ functional status and facilitates cancer treatment. Where possible, activity should be encouraged. Exercise throughout cancer treatment is safe for cancer patients and improves physical function and QOL. Information about the importance of enhanced diet and exercise and the usefulness of QOL and PROs in the management of patients with lung cancer could be shared via social media.

Conclusion:
Patients with lung cancer value QOL more than symptom management. Clinical trial data suggest that higher baseline QOL and PROs correlate with better disease outcome; these tools may be useful in the overall management of patients (Hollen 2014). Treatments should be evaluated based on their impact on QOL and PROs as well as survival. Weight maintenance and exercise are essential for patients overall health and QOL, and should be included in patients’ treatment planning. Social media may be effective in raising awareness among patients with lung cancer and their caregivers about the importance of enhanced diet and exercise. Further discussion and research about the usefulness of QOL and PRO measures in the management of patients with lung cancer is warranted. Reference: Hollen PJ, Gralla RJ, Kris MG, et al. Measurement of quality of life in patients with lung cancer in multicenter trials of new therapies. Psychometric assessment of the Lung Cancer Symptom Scale. Cancer. 1994;73(8)2087-98.

Background:
Despite widespread endorsement of survivorship cancer care plans, fewer than half of all National Cancer Institute Cancer Centers use them routinely. This may be due to inconsistent evidence linking survivorship care plans and improved cancer outcomes. We sought to examine the association between two specific survivorship care elements and patient reported quality of life and post-treatment cancer surveillance.

Methods:
We studied adults with Stage I or II non-small cell lung cancer having undergone surgical resection (2010-2013). The two survivorship care elements of interest were defined as cancer treatment summary and surveillance plan documentation assessed via chart abstraction. Patient recall of treatment summary was further assessed by patient interview. Patient reported quality of life was assessed via telephone interview using the Functional Assessment of Cancer Therapy-Lung (FACT-L) validated survey instrument. Surveillance imaging was defined as chest CT performed 6 months following resection per NCCN guidelines and was assessed via chart abstraction. Median scores from FACT-L and subscales were compared using non-parametric equality of medians test for univariate analysis and linear regression for multivariable analysis. Surveillance rates were compared using logistic regression. All data were analyzed in STATA 13.

Results:
A total of 24 patients were interviewed at a median of 9.4 months [Interquartile range 2.8 months] following treatment and 16 patients consented for chart abstraction. For survivorship care elements, 77% of patients had a documented treatment summary, however only 30% of patients recalled receiving a treatment summary when interviewed. A surveillance plan was documented for 50% of patients. For patient reported quality of life, FACT-L total and subscale scores did not differ based on chart documentation of surveillance plan, treatment summary or patient recall of treatment summary. A total of 37% of patients received a post-treatment surveillance CT by 6 months in accordance with guideline recommendations. Chart documentation of surveillance plan was not associated with a difference in receipt of surveillance imaging however, patient recall of treatment summary was associated with increased odds of receipt of surveillance CT (OR 21.25 [95%CI 2.36-191.59, p=0.006) which persisted following adjustment for covariates (OR 24.45 [1.10-543.27], p=0.043).

Conclusion:
There is a disconnect between documentation of survivorship care and patient recollection of receiving the intended information. This study suggests that efforts aimed at improving the transfer and retention of information might lead to greater adherence to guidelines and receipt of quality cancer care.

Background:
Cachexia-anorexia (CA) is a weight loss/appetite loss syndrome commonly affecting cancer patients. It is characterized by progressive sarcopenia (loss of muscle mass) accompanied by weight and appetite loss. These physiological changes lead to a decreased ability to perform daily activities, a reduction in the quality of life of the patient, and a decrease in the efficacy of chemotherapy and other treatments. Typically, oncologists focus on palliation of the symptoms of CA, and the reduction of distress of patients and families instead of on a cure. Recently, drugs that offer the possibility of treatment have shown promise in clinical trials.

Methods:
We conducted an online survey of lung cancer patients to understand: Prevalence of CA among lung cancer patients Extent of impairment of quality of life of lung cancer patients How patients are managing the symptoms of CA The study was approved by Schulman IRB, Inc (IRB#201600600). Three hundred and thirty-five lung cancer patients were surveyed through different online platforms (social media and LUNGevity homepage).

Results:
Of the lung cancer patients surveyed, Six in ten report experiencing one or more of the physical changes asked about (unintended weight loss, loss of appetite, loss of muscle mass, and malnutrition) Patients currently undergoing treatment and Stage IV patients are more likely to experience these changes and be concerned than those who are not currently undergoing treatment or have less advanced lung cancer Unintended weight loss and other physical changes are most likely to lead to a decline in patients’ strength, energy level, and ability to engage in physical activities. Among patients who experienced a decrease in quality of life, the most important aspects they would like to improve or maintain are their energy level and their ability to remain independent. Patients were measured in their willingness to try new treatment approaches, especially when presented with a description of the adverse events associated with treatment.

Conclusion:
Cachexia-anorexia is common in lung cancer patients, including early-stage patients. Patient attitudes towards CA differ among those whose quality of life has been impaired due to weight loss and those who are able to continue living a normal life. Maintaining a sense of independence was of primary importance to all patients. Their willingness to try new treatment options, however, is based on understanding both the benefits and risks of these treatments, suggesting that a well-informed patient is more effectively engaged in their treatment decisions.

Background:
It has made it possible to live with cancer and to work with cancer, because of lung cancer treatment progress nowadays. It is indispensable for lung cancer patient effort to improve the patient’s own literacy, in order to live with cancer and to work with cancer. Lung cancer patients own has been started an attempt to improve the patient force in Japan. I will report on the current situation about them.

Methods:
1)Effectiveness of advocate project about ‘Working with cancer’ by National Cancer Center Japan（NCCJ） In Japan, ’Working with cancer’ recently became an important issue in the national control plan in Japan. I have shown leadership as the secretary to support projects on ‘Working with cancer’ at the Center for Cancer Control and Information Services,NCCJ. This project is patient participatory. Participating patients have devised to improve patient literacy and have made it possible to work with cancer. I will clarify the difference of patient consciousness compared between this project survey and the survey by Japanese Cabinet Office this year. 2)Importance of patient initiative In Japan, for the first time, the lung cancer patients groups network have launched since November on 2015 named JLCA, Japan lung cancer alliance. One of the goals of JLCA is to improve the lung cancer patient literacy in Japan. I will report JLCA activities about attempts to improve patient literacy in 2016.

Results:
1)Multiple lung cancer patients have participated in the project on ‘Working with cancer’ by NCCJ. They had actually carried out to work together with lung cancer. Results of comparison of the two surveys between project survey by NCCJ and the survey by Japanese Cabinet Office comes out clearly the difference. More ambitious to work with cancer in National Cancer Center projects survey. 2)JLCA has been in cooperation with ‘The Japan Lung Cancer Society’, ‘The Japanese Society of Medical Oncology’, and enthusiastic lung cancer doctors to advocates activities especially Dr.Sawa. JLCA has been held five more seminars to improve lung cancer patient literacy at various places of Japan in 2016.

Conclusion:
One of the goals for Japanese lung cancer patients is to improve the patient literacy nowadays. They have ambitions to improve the patient literacy. They have participated in various activities to improve the patient literacy. It was found for them to want to be ‘Living with cancer’ and ‘Working with cancer’. The important points are two thing, effective advocates projects and trial of patient initiative.

Background:
In Asian countries, the concept of cancer advocacy has not been sufficiently recognized. In Japan, Lung Cancer Society (JLCS) has led the lung cancer advocacy with a part of the NPO, and adopted the 2014 Kyoto Declaration. To evaluate the awareness and attitude of lung cancer advocacy activity among patients, medical workers, and the general population in Japan, web survey was planned for the perceptions of Kyoto declaration and JLCA (Japanese alliance for lung cancer advocacy) events which were carried out by JLCS in these 2 years.

Methods:
An internet survey using survey monkey was conducted which contained 6 closed-ended (selection one or free answers) and open-ended questions, depending on the JLCA network population in June 2016.

Results:
109 people of responded involving 36% of patients and their family, 25% of MD and medical worker, 19% of pharmaceutical company officials and 16% of news media. Perception of Kyoto declaration was 21% of attendee, 27% of well-known, 13% of partial known and 39% of non-awareness. Also the number of participants to the events of JLCA is, 49% of 0 times, 17% 0f 1-2 times, 24% of 3-4 times and 11% of more than 5 times. The most sympathy events ware voted to 1) lecture by a physician 57%, 2) lecture by survivor and the participants WCLC of cancer patients 46%, 3) information in the facebook and the web site 46% 4) citizen open lecture of lung cancer 39%, 5) Performance by society ambassador 38%, 6) advocacy program in annual meetings 26% and 7) Medical seminars around the country 26%. The proportion of respondents who have a certain reputation in the activities of JLCA was 76%. The requests to JLCA is, 1) is the most participation opportunities for information of new treatment and participation opportunities to clinical trial, followed by 2) wish to participate to all the programs in the Society.

Conclusion:
In Japan, awareness about the advocacy is improved, and it was found that the expect to Society for the diverse needs through the Internet survey.

Background:
Although half of people in Japan live in rural districts, cancer centers locate in urban area. Cancer control act was intended to accomplish equal accessibility of cancer medical care across the whole extent of Japan in 2006. According to the act, regional clinical pathways have been started to use. The aim of this study was to evaluate the pathways.

Methods:
Patients with lung cancer who underwent surgery in Kumamoto University Hospital between April 2010 and March 2014 were included. Candidate for the pathway of lung cancer was selected by following criteria. 1) Patient who lives far from our hospital. 2) Patient who eagers to join the pathway. Data were examined retrospectively. Patients usually visit local clinic and undergo examination at our hospital every 6 month. The medical informations are shared with patients, their family and medical staffs with hand-held chart.

Results:
During the study 630 lung cancer patients underwent resection in our hospital. Pathological stages of these patients were, IA in 439, IB in 90, IIA in 37, IIB in 13, IIIA in 71, IIIB in 2, and IV in 15. Of these 681 patients, 67 (11%) entered the regional clinical pathway in our hospital with mean age of 70 ± 10 years old. Pathological stages of the patients who joined regional clinical pathway were, IA in 51 (12%), IB in 8 (9%), IIA in 3 (8%), IIB in 0 (0%), IIIA in 5 (7%), IIIB in 0 (0%), and IV in 0 (0%). Mean observation period was 1083 ± 496 days (62 – 2181). Seven patients died during the study. Ten patients cancelled the pathway. The reasons why the pathway discontinued were as follows: recurrence of lung cancer in 1, other cancer occurrence in 2, patients’ own decision in 4, clinic’s issue in 5. Forty eight patients continue to use the pathway at the end of the study (72%). Mean duration of the pathway the patients used was 993 ± 481 days (3 – 2181). Mean distance between patients’ home and our hospital was 43 ± 34 km (2.6 – 144.5). Because local clinics located closed to patients’ home (mean distance: 12 ± 13 km (0.1 – 55.3)), mean time they spend for attending hospital was reduced from 61 ± 41 minutes (8 – 210) to 19 ± 18 (1 – 83).

Conclusion:
The pathway was used in 72% patients at the end of study and reduced the time patients visiting hospital.

Background:
Lung cancer patients now have the option of targeted therapies or immunotherapies. However, not all eligible patients are benefiting from these treatment approaches, partly due to lack of tumor testing. To determine whether inconsistent communications could be a contributor to the suboptimal biomarker testing rates, we conducted a communications audit to determine what terminology is currently being used, to come to a consensus on consistent terminology to describe the testing used to help choose lung cancer treatments.

Methods:
In phase I, we surveyed 28 organizations (patient advocacy organizations, pharmaceutical/ testing companies, government and health sites) with the aim of identifying various terms being used to reference molecular tumor testing. In addition, in-depth interviews were conducted with 15 lung cancer patients to gain insights into their understanding of molecular testing. Results from Phase I were discussed during a stakeholder meeting (Phase II) with 21 representatives of 11 different advocacy and pharmaceutical companies to come to agreement on terminology.

Results:
In Phase I, 9,379 mentions of eight different terms to reference molecular testing and targeted therapy were inventoried (Table). Overall, there were too many terms, with inconsistent usage. Patient interviews revealed that there was disparity between the terms used to talk to health care practitioners and to patients, thereby setting up a communications gap. In the Phase II meeting, stakeholders agreed on the importance of a more unified message to achieve common understanding of molecular testing and targeted therapies. Biomarker testing was the strong favorite. It integrates the concept of “biology” of the tumor and is more inclusive than “molecular testing,” now that PD-L1 testing is also a consideration for the new class of immunotherapy.

Searched Terms	Pharma/BioTech	Testing	Gov’t/Private	Cancer Orgs	Lung Cancer Orgs
Genetic Testing	77	65	1082	295	395
Molecular Testing	173	270	742	124	331
Mutation Testing	21	111	485	143	274
Biomarker Testing	109	172	390	29	156
Genetic Diagnostic	26	66	770	111	109
Molecular Diagnostic	113	231	798	94	98
Mutation Profiling	22	78	254	2	88
Molecular Pathways	74	91	787	35	88

Conclusion:
Consistent use of the term “biomarker testing” to encompass both targetable molecular mutations and PD-L1 protein expression is recommended for all stakeholders, allowing for additional elaboration on specific tests.

Background:
The Mid-South region of the US is the center of lung cancer incidence, and has a high proportion of underserved persons. We developed a multidisciplinary (MD) program for lung cancer care, involving weekly physician conferences, and a clinic in which conference-recommended treatment plans are discussed and implemented with patients. This study evaluates the reach and adoption of this program within a community healthcare system.

Methods:
We evaluated the reach of MD care by comparing demographic characteristics of participating patients, to the larger metropolitan and regional population of patients in a community healthcare system. Patients were referred to the program through their treating physician. Adoption was evaluated by assessing the number of physicians within each specialty who have referred patients to the MD program.

Results:
550 patients were presented at MD conference. and 265 were seen at the MD clinic from 2014-2015. MD patients were younger, more likely to be female (p<0.01), and African-American (p<0.01). In patients <65 years old, the MD clinic had >twice the percentage of uninsured patients (p<0.01). In patients >65 years old the MD clinic had a higher percentage of commercially insured patients (p<0.01) (Table1). 71 physicians referred patients to the MD conference; the greatest concentration of specialties were hematology/oncology (31%) and internal medicine (21%). 39 physicians referred patients into the MD clinic, with the greatest frequency from internal (30%) and pulmonary medicine (25%). When comparing the number of active physicians by specialty, to those who referred patients into the MD conference, hematology/oncology had the greatest amount (40%), followed by pulmonary medicine (31%). For clinic referrals it was pulmonary medicine (24%), followed by hematology/oncology (13%). Figure 1



Conclusion:
A MD model has been implemented that can effectively reach underserved populations within the region. MD care was adopted primarily by oncologists, pulmonologists, and internists. Further efforts should be taken to expand physician adoption.

Background:
In Egypt, cancer remains a taboo subject. Misconceptions that cancer is unpreventable and always fatal persist. Often seen as punishment, it is common for those diagnosed to be ostracized and abandoned. Awareness-raising and survivor stories are crucial in eradicating cancer stigma. The finale of the Cancer from Patients’ Perspective (CPP) Summit used a revolutionary approach to confronting stigma: a fashion show with survivors modeling powerful creations by famous Egyptian designers to communicate their individual cancer journeys.

Methods:
In October 2015, an online campaign was launched via Facebook to engage survivors and fashion designers. All interested survivors were accepted, those not online were registered for the project by the organizers. Survivor profiles were added to a separate, password protected Facebook group open only to the fashion designers, who then selected a survivor to dress by commenting on her story. After being matched, survivors and designers met an average of four times over two months to discuss and interpret the journey, collaborate on sketches, agree upon designs and for fittings. At the event, each design was rated from 1-10 by a panel of local, regional and international judges with the winner being the creation with the most points.

Results:
A cancer survivor moderated the fashion show, which over 350 attended. Lung cancer survivors joined those diagnosed with five other cancers, 35 in all participated. One by one, each survivor, wearing her creation, took the stage with her designer and together they told their story. The survivor then took her dramatic turn on the “catwalk.” Designs ranged from elegant evening dresses to edgy, theatrical concepts that displayed resiliency and triumph. At the end, results were tallied and the winner took her final turn on the runway.

Conclusion:
Experts say cancer stigma in the Middle East can be eradicated through education, positive survivor stories and media coverage. The CCP Summit hit all these elements and gave survivors voice in a unique and powerful manner. While there were challenges, including survivors not being allowed to participate over objections of male relatives and designers being cautioned against participating by their studios, the catwalk proves a movement to confront cancer stigma in the Middle East is underway. Through their participation, these survivor “warriors” raised awareness, gave hope to others and, by telling their stories, challenged misconceptions with grace, strength and beauty.

Background:
In-person support group attendance can address the greater unmet physical and emotional needs and high rates of distress experienced by those diagnosed with lung cancer. However, survivors tend to prefer lung cancer-specific groups, which can be challenging to start and maintain. As a result, there are <100 groups currently active in the US, inadequate to serve the 224,000 people diagnosed annually. The National Lung Cancer Support Group Network was established in 2015 to strengthen existing groups and form seven new groups in areas of high need. This study evaluates the psychosocial impact and benefits of group participation of the new lung cancer support groups.

Methods:
Using a pre/post-test design, consenting participants completed a baseline questionnaire including the CSS-15 Distress screening tool, Positive Affect Scale and Loneliness Scale prior to joining the group. After six months of attendance, follow-up was completed. The follow-up questionnaire included the CSS-15 Distress screening tool, Positive Affect and Loneliness scales and additional self-efficacy measures and 14 questions about group helpfulness. These are preliminary results from the first group at Gilda’s Club Nashville.

Results:
Demographics: At baseline, the participants (N=20) were mostly patients or survivors (68%), white (80%), female (64%) with an average age of 54.8. More than half reported being diagnosed at Stage IV. All were at risk for depression upon enrollment. Ten participants remained and completed the 6 month follow-up survey. Psychosocial outcomes: There was a significant decrease in overall distress (p=0.0067) following group participation but no change in positive affect or loneliness. Fewer participants reported life disruptions and feeling nervous or afraid at post-test. Eight of the follow-up participants (80%) remained at risk for depression. Group helpfulness: Eighty percent strongly agreed that after attending the group, they were better able to ask questions of their healthcare team, make treatment decisions and access information and resources. Participants felt more interested and determined after attending the group. Feelings of being isolated remained unchanged. All participants indicated that they would recommend this group to others and agreed that participation resulted in having a sense of belonging, acceptance and development of new friendships.

Conclusion:
Preliminary results show potential psychosocial improvements related to decreased distress, increased self-efficacy and positive benefits from group participation. Further data from this and the additional six groups will add statistical power to the findings. Study findings may provide evidence that participating in lung-cancer specific groups can be helpful in improving psychosocial outcomes.

Background:
40,000 people were diagnosed with Lung cancer in the UK in 2012. Invasive procedures and repeated clinic visits compound the stress of diagnosis. This study reports a non pharmacological approach to improving patient experience. Energy therapies exist in many medical traditions healing through interaction with the patient’s biofield –the invisible psychophysical entity including the body but extending beyond it in the form of energy. In this case a technique where a trained therapist uses light touch or hands held a short distance from the subject to transfer energy to the recipient and bring a greater sense of well being.

Methods:
112 patients were invited to receive an ‘Energy therapy’ session alongside their clinic appointment or bronchoscopy. The primary endpoint was reduction in anxiety. Pre and post treatment data was collected from self completed anonamised questionnaires using a 0-10 scale for subjective variables and non-invasive blood pressure recordings. Data was analysed using a students t-test.

Results:
83 patients took part in the study. 60% female, mean age 62.69. Table 1 summarises the questionnaire scores. Patients reported statistically significant reduction in anxiety, tension, stress and pain following a session of energy therapy. There was also an improvement in mood and sense of calm.

Change in mood scores before and after Energy therapy

Variable ( 0= best 10= worst)	Pre-treatment mean score N = 80	Post-treatment mean score N= 80	Degree of change (p)
Anxiety ( Do you feel anxious)	5.45	2.3	3.15 (<0.001)
Calm (do you feel calm)	4.89	1.71	3.175 (<0.001)
Tension ( do you have tension in your body?)	5.23	2.16	3.062 (<0.001)
Stress (do you feel stressed)	5.46	2.09	3.375 (<0.001)
Mood ( do you feel low in mood)	4.68	2.35	2.35 (<0.001)
Pain ( are you in pain)	3.40	1.73	1.675 (<0.001)
Systolic BP (n=78)	135.28	131.15	4.12 (0.007

Conclusion:
The role of complementary therapy in cancer care has long been recognised internationally and there are reports of Energy therapy used synergistically in palliative care and management of chemotherapy side effects[i]. We believe this is the first study to look at the role of complementary Energy therapy in supporting patients undergoing a cancer diagnosis. Complementary ‘energy’ therapy is a powerful tool to significantly reduce anxiety, tension and boost mood for patients undergoing investigation and treatment for lung cancer [i] Jain S, Mills P: Biofield therapies: Helpful or full of hype? A best evidence synthesis. Int J Behav Med 17:1–16, 2010

Background:
Lung cancer is the leading cause of cancer death in both men and women in Ireland. * Previous research has shown awareness of lung cancer is high yet the majority of lung cancer patients continue to be diagnosed at an advanced stage.** In 2015 the Irish Cancer Society performed an online survey to examine the attitudes of the public in relation to the signs and symptoms of lung cancer and identify the perceived barriers for people accessing their GPs/pharmacists with symptoms. Objectives: Test awareness of prevalence, symptoms, causes and impact of lung cancer. Examine the incidence of recent interactions with health care professionals on the subject of lung health. Identify the barriers to accessing primary care for lung cancer symptoms. Examine the experiences of those who have had interactions.

Methods:
Online survey of 1000 adults and booster sample of 100 smokers 65+. Sample was quota controlled on gender, age, social class and region to ensure a representative sample.

Results:
47% identified lung cancer as the leading cause of cancer death in Ireland. Half of Irish adults and 31% of smokers claim to be unconcerned about being diagnosed with the disease. 79% of smokers claimed to have never spoken with a doctor/ pharmacist about lung health and 59% of smokers have never spoken with a doctor/ pharmacist about giving up smoking. 54% said they would not go to their doctor if they had one or more symptoms of lung cancer due to obstacles like fear (22%), expense of doctor’s visit (17%) , because it is not serious enough (19%). 37% of smokers would be discouraged from visiting a doctor with symptoms. Reasons included don’t think there is much a doctor can do for their lung health (11%), worried about what they would be told (32%), too expensive (20%) and don’t want a lecture on smoking (20%).

Conclusion:
This study reveals a number of barriers to early detection of lung cancer which in turn can lead to late diagnoses. These include a lack of awareness and underestimating the severity of the disease. The cost, anxiety, and fatalistic attitude are barriers which can influence the design of a lung cancer awareness campaign. Enabling health professionals and establishing accessible services to address lung health with high risk populations in a supportive manner will improve early detection of lung cancer.

Background:
Lung cancer is the leading cause of cancer death in Ireland, in both men and women*. Incidence of the disease continues to increase and the majority of Irish lung cancer patients are diagnosed at an advanced stage**. The Irish Cancer Society runs an annual lung cancer awareness campaign promoting awareness of the signs and symptoms and the importance of early detection. A variety of mediums are utilised including production of printed and online information, promotion via online and social media platforms and targeting the media through radio, TV, online advertorials and regional print advertising.

Methods:
In 2016, following previous success online, we replicated an interactive symptom checker developed by the Australian Lung Foundation. The purpose of this online tool was to promote lung cancer awareness and early detection, the public were encouraged to complete the checker and bring their results to their general practitioner (GP). The symptom checker was promoted through various media platforms and this ultimately lead to the success of the project.

Results:
The campaign goal was 1,720 online health checker completions (25% of benchmarked lung cancer section website visitors). Result: There were 12,185 views of the checker. 3,145 people completed the checker with 2,801 downloading the result for their GP.

Conclusion:
A strong call to action to the online checker was valuable as it gave a tangible action to the public. The media played a key role in promoting the campaign message to our targeted audience and contributed to the overall success of the campaign demonstrating the benefit of balancing traditional and digital platforms.

Abstract:
Introduction Ireland has a proud record of leadership in the field of tobacco control. It was the first country in the world to introduce a Workplace Smoking Ban in 2013 and the first country in Europe to announce its intention to introduce plain packaging for cigarettes. In 2013 Ireland set a target date to achieve a tobacco free society with a targeted adult tobacco use prevalence of under 5%. Other countries to formally adopt a target for tobacco free societies include Finland 2040, New Zealand 2025, and Scotland 2034. Tobacco Free Ireland[1] is a new tobacco policy for Ireland coming more than a decade after the publication of the previous national policy Towards a Tobacco Free Society[2]. It is a timely successor because of the emerging non-communicable disease burden which is caused by risk factors that can be prevented. Tobacco is well known as a major contributor to ill-health and premature mortality. It is responsible for more than a third of all cancers. For the first time, we have a target date for Ireland to be tobacco free of 2025. The question is whether this target is in any way realistic. Discussion Tobacco Free Ireland addresses a range of tobacco control issues and initiatives and contains over 60 recommendations. A high level action plan, was drawn up in consultation with those who will lead out on the recommendations which outlines the responsibilities, actions necessary and timelines for the implementation of the recommendations. The recommendations to support Ireland becoming a tobacco free Society are categorised under:- • Protection of children and denormalisation of tobacco use • Legislative compliance and regulating the retail environment • Protect people from tobacco use • Offer help to quit tobacco use • Warn about the dangers of tobacco • Enforcement of bans on tobacco advertising, promotion and sponsorship • Raising taxation on tobacco products • National and International Partnerships For the first time in policy we see a commitment to substantially address supply side issues through introduction of levies such as an environmental waste levy and an industry profitability levy ring fencing income to address health promotion, cessation supports and illegal trade initiatives. The document fails to substantially address the inequality inherent in smoking patterns. In Ireland the bottom decile, at 35% prevalence, is more than twice as likely to smoke as the top decile at 16%. Specific deprived population targeted programmes such as the Irish Cancer Societies ‘We Can Quit’ programme, which challenges intergenerational smoking, have been successful and need to be funded and enhanced if a Tobacco Free Society is to be achieved. Conclusion Current adult smoking rates of 19.5%[3] suggest Ireland has some significant way to go towards achieving its target. Recent youth smoking rates of 13%[4 ]for 15-17 year olds and 8%[5] for 10-17 year olds suggests significant progress in reducing the uptake of smoking. Major investment is required to support increased quit attempts and increased success from quit attempts if the target of a Tobacco Free Ireland by 2025 is to be achieved. References 1. http://health.gov.ie/wp-content/uploads/2014/03/TobaccoFreeIreland.pdf 2. http://health.gov.ie/blog/publications/towards-a-tobacco-free-society-report-of-the-tobacco-free-policy-review-group 3. http://health.gov.ie/wp-content/uploads/2015/10/Healthy-Ireland-Survey-2015-Summary-of-Findings.pdf 4. http://health.gov.ie/blog/publications/irelands-report-on-the-european-schools-project-on-alcohol-other-drugs-in-ireland-espad/ 5. http://health.gov.ie/wp-content/uploads/2016/01/HBSC2014web3.pdf

Abstract:
Background: The Global Lung Cancer Coalition (GLCC) is a unique partnership, dedicated to improving disease outcomes for all lung cancer patients worldwide. Research is essential to drive improvements in cancer prevention, screening, diagnosis and treatment.[i] However, it is clear that lung cancer research is not being prioritised to a level that reflects its significant impact, with 1.8 million new cases globally every year.[ii] Poor lung cancer survival demonstrates that more can and should be done. The GLCC is calling for every country across the globe to examine and increase its investment in lung cancer research. Evidence of variations between countries in their approach to lung cancer research can be a powerful tool to advocate for increased investment and national policy that encourages a flourishing lung cancer research community. The GLCC commissioned the Institute of Cancer Policy at King’s College London to undertake a comprehensive examination of the state of global lung cancer research. The findings, published in the Journal of Thoracic Oncology, are intended to guide public policy and highlight where improvements can and should be made.[iii ]They have also been made available on the GLCC website with a range of campaigning materials for advocates to use in sharing insights and recommendations. Methodology: The GLCC commissioned the Institute of Cancer Policy at King’s College London to undertake a bibliometric review of global lung cancer research efforts. The team developed a complex validated mathematical algorithm to search articles and reviews in the Web of Science database for lung cancer research during 2004-13, looking to: · Identify the total number of papers in cancer research for each year in 24 leading countries, compared to that of other common cancers (breast and colorectal) · Isolate the number of papers referencing lung cancer or other relevant key words in their title The study identified the 24 countries globally with the most extensive research programmes in lung cancer. The authors’ research institutes were used to identify which country or countries had contributed to that paper. The study also analysed whether research outputs had changed over time as well as the focus of the research and how close the research is to patients. The methodology allows total number of papers, type, and research collaborations to be analysed over time. Results: The bibliometric review is a comprehensive and powerful resource allowing lung cancer patients, clinicians and policymakers to examine their national lung cancer research output and compare it with that of other countries. The 24 countries responsible for the majority of lung cancer research activity are: Australia, Austria, Belgium, Brazil, Canada, China (People’s Republic of), Denmark, France, Germany, Greece, India, Italy, Japan, Netherlands, Norway, Poland, Taiwan, Turkey, South Korea, Spain, Sweden, Switzerland, United Kingdom, and the USA (figure 1). Figure 1 Worldwide, the number of papers published on lung cancer has more than doubled from 2,157 papers in 2004 to 4,845 in 2013. However, there has only been a small increase in the proportion of global cancer research that is dedicated to lung cancer – from 4.4% in 2004 to 5.6% in 2013. By comparison (figure 2), both breast and colorectal cancer account for greater proportion of research activity, despite having a similar burden of disease. Figure 2 Colorectal cancer accounted for 6.2% of research activity in 2013 whereas breast cancer, at 10%, had nearly double the percentage of research activity compared to lung cancer. The figures can be used to make a persuasive case for increased investment in lung cancer research. To support this, the project team produced a campaigning toolkit, giving headline figures and statistics, tips for engagement and template briefings and press releases. Global and national-level briefing documents and infographics are also available on the GLCC’s website at: http://www.lungcancercoalition.org/en/state-global-lung-cancer-research. The GLCC is calling for every country across the globe to increase its investment in lung cancer research, to increase research efforts in aspects of care that are currently under-researched, and to collaborate with international partners to share findings and improve patient care. Conclusions: Feedback from GLCC members confirms that the bibliometric review is a valuable campaigning resource. The GLCC is keen for the review’s findings to be shared and for policymakers – nationally, regionally and globally – to consider how lung cancer research can be further supported. [i ]Yarden Y, Carols C, on behalf of the European Association for Cancer Research, Basic cancer research: why it is essential for the future of cancer therapy. European Journal of Cancer 2013, 49 issue 12. Accessed June 2015 [ii ]GLOBOCAN 2012, Lung Cancer, available here: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed June 2015 [iii ]Aggarwal A, Lewison G, Idir S, et al. The State of Lung Cancer Research: A Global Analysis; J Thorac Oncol. 2016 Jul;11(7):1040-50

Abstract:
Helpline: Adapting to changing needs and evolving science The Lung Cancer Alliance HelpLine launched over 21 years ago and until recently was the only lung cancer-specific toll-free line in the United States. The reasons people call—for information, understanding, referral, compassion and most of all, hope—remain the same over time. But to keep pace with dramatic advances in the ways lung cancer is detected, diagnosed and treated, the LCA HelpLine has adapted quickly to meet the changing needs of our community. For many survivors and their loved ones, understanding lung cancer and its treatment is a challenge. Those impacted by the disease tend to be older, poorer and less educated, groups which also prefer to get their initial cancer information from their treatment teams. With competing time demands, treatment teams may not have enough time to ensure information is understood or to be sensitive to providing it when the survivor can absorb, process and remember. Some are hesitant to admit they don’t understand all they have been told and are uncomfortable asking questions. Over the past 3.5 years, there have been nearly equal numbers of patients and caregivers calling the HelpLine. Roughly three-quarters of callers were women. In 2016, LCA began tracking more call statistics. Of those who told us the type of lung cancer, we see 83% NSLCC and 17% SCLC – quite representative of the lung cancer population. More than half (53%) were already in treatment. As the science has evolved and practice-changing discoveries are made, professional HelpLine staff provide up-to-date information, support and referrals to those in our community, no matter their place in the journey. The HelpLine provides the opportunity for in-depth conversations, problem solving and the development of questions to ask the team—it serves not as a substitute for conversations with treatment team but as support and complement to them. The LCA HelpLine also has grown with the internet. For some, the internet is a wealth of knowledge, psychosocial support and information. But sometimes even savvy users need help interpreting the information they have found. For others, the internet is a scary and overwhelming place, full of difficult statistics, conflicting recommendations and hard to understand concepts. Additionally, many in our community do not have access to the internet at all or lack broadband speeds that make it an effective tool. While the internet can be helpful, it does not take the place of contact with another caring person who can help. The HelpLine also gives us daily contact with lung cancer community and allows us to keep abreast of what lung cancer patients, their loved ones and those at risk need most. And as we listen, we adapt our services and programs to their needs. For example, we have recently started offering a new webinar series on the top symptoms and side effects reported by those in treatment and long-term survivors. Recently, the pace of scientific discovery and drug development in lung cancer has been accelerating rapidly. With six new drugs approved by the Food and Drug Administration in 2015 and countless new clinical trials launching to test not only new drugs but novel combinations of different classes of agents, patients and caregivers can be even more confused about the best treatment options for them. To address this changing environment, we have recently launched the LungMatch program to help patients find and understand personalized treatment options that they can discuss with their treatment team. LungMatch includes referrals to a concierge service for molecular testing if patients have not had it, a new, user-friendly online matching platform, and in-house personalized clinical trial navigation for interested callers on the HelpLine. The program is still in its infancy, but in the first month of tracking, we determined that 85% of callers asked had never been on clinical trials and only 50% reported molecular testing of the lung cancer. These early statistics indicate the widespread need in the lung cancer community. Through adapting to the changing needs of our community and helping them understand the evolving science, the HelpLine has been a lifeline for the lung cancer community in the United States for over 21 years.

Abstract not provided

Abstract not provided

Abstract:
Despite the reduction in cigarette consumption in many parts of the world, the incidence and mortality rate of lung cancer will remain high in the year 2030[1]. Over the last 50 years major advances in the treatment of lung cancer have included early detection by screening CT, improved cure rates with neo-adjuvant and adjuvant chemotherapy, the successful integration of chemotherapy with radiation for locally advanced disease, and prolonged survival times with chemotherapy in the metastatic setting. More recently, the discovery of targetable mutations and development of a myriad of small molecule tyrosine kinase inhibitors have transformed the natural history of lung cancer in select subsets. Furthermore, immunotherapy is now a reality in the treatment of patients with stage IV non-small cell lung cancer (NSCLC). Today, the integration of targeted agents and immunotherapy are being investigated in earlier stages of disease. With these recent advances, what does the future of chemotherapy hold in the treatment of stage I-IV NSCLC? Is there a future at all? Can we eliminate the need for chemotherapy altogether for most patients at any point in their disease history? The dream of replacing chemotherapy with more active, less toxic, and more convenient therapy for patients with stage I-IV NSCLC is a laudatory goal. Is it realistic by the year 2030? Certainly not. Chemotherapy is currently the only systemic therapy that has ever been known to cure patients in the neo-adjuvant or adjuvant setting for stage I-III NSCLC[2]. While many targeted agents can prolong life in the metastatic setting, to date all of those tested in the adjuvant setting have failed to improve upon standard therapy[3-5]. The graveyard of negative trials in the adjuvant setting includes those evaluating angiogenesis inhibition, epidermal growth factor tyrosine kinase inhibition, and vaccine therapy. The same can be said for locally advanced, unresectable NSCLC. While the integration of chemotherapy with radiation improves survival rates compared with radiation alone[6], thus far no other agents have successfully done so, including tyrosine kinase inhibitors, angiogenesis inhibitors, or monoclonal antibodies[7-8]. In the metastatic setting, chemotherapy improves survival whether given as induction therapy or as maintenance therapy. Chemotherapy is also more active than targeted therapy in the vast majority of patients who do not harbor targetable mutations. Even with the stunning success of immunotherapy for some patients with advanced NSCLC, it appears this will not be curative in this setting and nearly all patients will still be getting chemotherapy at some point of their disease history. In other words, chemotherapy works for patients with stage I-IV NSCLC. Just as we will do with targeted therapy and immunotherapy, we will not abandon what works, but rather we will improve upon it. Chemotherapy works in a broad group of patients with lung cancer. It targets DNA, topoisomerase, and the mitotic spindle, which are the key targets in all cells. The majority of patients’ tumors do not have targetable mutations and most patients do not respond to immunotherapy. While gains are expected over the next 15 years in targeted therapy and immunotherapy, it is likely that we will discover the plateau in the benefit to these strategies and eventually nearly all patients will develop resistance. While predicting the future is usually only a fool’s errand, the past is prologue. So, what is the future of chemotherapy in NSCLC? Better drug delivery systems; developing combination therapy with DNA repair agents, cell cycle checkpoint modulators, and immunotherapy; and improved biomarkers for efficacy and toxicity are each on the horizon. Improved targeting of the cancer cell, increased cancer cell drug concentrations, and reduction of normal cell toxicity can be accomplished through nano-carriers[9]. Nano-carriers can deliver chemotherapy directly to cancer cells by protecting these agents from being degraded in the circulation and being excessively protein bound, limiting active drug exposure. Nano-carriers include liposomes, carbon nanotubes, dendrimers, and polymeric compounds (micelles, conjugates, nanoparticles). These carriers are typically 100-150 nm in size but have large surface-to-surface volume ratios, enabling them to encapsulate cytotoxic agents and enhancing drug deliver to tumors. Thus far 8 have been FDA approved, including 2 polymer-protein conjugates, 5 liposomal formulations, and 1 polymeric nanoparticle, in various cancers. Another strategy to enhance drug delivery to tumors is through antibody-drug conjugates (ADC). These agents link an antibody to a protein overexpressed on the surface of a cancer cell to a potent cytotoxic such as a microtubule inhibitor or an alkylating agent. The cytotoxic is released only in the cancer cell after the ADC complex is internalized. Examples include TDM-1 and Brentuximab. Over 30 ADC’s are under clinical investigation, including several against lung cancer including Rova-T and Sacituzumab. Another promising strategy for the future treatment of lung cancer involves combining chemotherapy with drugs that interfere with DNA repair, silence DNA repair genes, or inhibit cell cycle arrest [10]. Examples of this approach include PARP inhibitors, DNA methylation agents, and checkpoint modulators. Combination trials of chemotherapy and immunotherapy are also underway. In this regard, ADC technology may prove a more effective strategy when combining cytotoxic drugs with immunotherapy. By improving chemotherapy drug delivery to cancer cells and reducing off-target toxicities, nanotechnology has the potential to most effectively combine chemotherapy with immunotherapy. Lastly, despite decades of clinical investigation, most patients are empirically treated with chemotherapy, regardless of the molecular characteristics of the tumor and the pharmacogenomics of the patient. Refinements in these areas are expected in the upcoming years. In conclusion, for better or worse, in the year 2030 chemotherapy will remain standard of care for the majority of patients with stage I-IV NSCLC. But, the year 2040 or 2050 may be a different story. References 1. Rahib L, Smith B, Aizenberg R, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancer in the United States. Cancer Res 2014;74(11):2913-2921. 2. Burdett S, Pignon J, Tierney J, et al. Adjuvant chemotherapy for resected early-stage non-small cell lung cancer. Cochrane Database Syst Rev 2015;2(3):doi: 10.1002/14651858.CD011430 3. Wakelee H, Dahlberg S, Keller S, et al. E1505: Adjuvant chemotherapy +/- bevacizumab for early stage NSCLC—Outcomes based on chemotherapy subsets. J Clin Oncol 2006;34(abstract 8507). 4. Kelly K, Altorki N, Eberhardt W, et al. Adjuvant Erlotinib Versus Placebo in Patients With Stage IB-IIIA Non–Small-Cell Lung Cancer (RADIANT): A Randomized, Double-Blind, Phase III Trial. J Clin Oncol 2015;33:4007-4014. 5. Van Steenkiste J, Zielinski M, Linder A, et al. Adjuvant MAGE-A3 Immunotherapy in Resected Non–Small-Cell Lung Cancer: Phase II Randomized Study Results. J Clin Oncol 2013;31(19):2396-2403. 6. O’Rourke N, Roque i Figuls M, Farre Bernado N, et al. Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev 2010; DOI: 10.1002/14651858.CD002140. 7. Kelly K, Chansky K, Gaspar L, et al. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol 2008;26(15):2450-6. 8. Bradley J, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 2015;16(2):187-199. 9. Fanciullino R, Ciccolini J, Milano G. Challenges, expectations and limits for nanoparticles-based therapeutics in cancer: a focus on nano-albumin-bound drugs. Crit Rev Onc Hemat 2013;88:504-513. 10. Helleday T, Petermann E, Lundin C, et al. DNA repair pathways as targets for cancer therapy. Nature Rev 2008;8:193-204.

Abstract:
By 2030 Chemotherapy will Remain Standard of Care for the Majority of Patients with NSCLC Stages I-IV: Contra Chemotherapy Cytotoxic chemotherapy has undeniably provided benefit for our patients with non-small cell lung cancer (NSCLC). However its nondiscriminatory application based on general tumor biology principles and not on the underlying biology of lung cancer has hampered its ability to dramatically improve survival and cures for lung cancer. Over the last twenty years we have seen multiple examples of how molecular characterization of lung tumors coupled with advances in drug development, have led to astonishing improvements in cancer outcomes. Hence, it is time to set a course toward abandoning chemotherapy. In addition to their superior efficacy, targeted therapies and immunotherapy have milder toxicity profiles compared to chemotherapy that all patients appreciate. We have already made significant progress in this quest. Our journey began with the discovery of EGFR (epidermal growth factor receptor) mutations and their exquisite sensitivity to EGFR-TKI (tyrosine kinase inhibitors). This observation was confirmed in the landmark IPASS trial that demonstrated the superiority of EGFR-TKIs over platinum-based chemotherapy for the first line treatment of patients whose tumors harbor these mutations (1). On the heels of this therapeutic advancement came the discovery of ALK (anaplastic lymphoma kinase) gene rearrangements and the replacement of doublet chemotherapy with an ALK-TKI in patients with ALK positive tumors (2). To date actionable driver mutations are found in at least 50% of patients with adenocarcinoma (3) and inhibitors to all of these mutations are in clinical development with the hope that they will have similar success as their predecessors. Of particular interest is developing inhibitors to KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) because it is the most frequent driver mutation occurring in approximately 20-25% of tumors. Today there is optimism that we will achieve this goal given it is the focus of the Stand Up To Cancer (SU2C) lung cancer dream team initiative and several novel agents are in development including direct KRAS therapy. Driver mutations are typically identified in patients who are never smokers, light former smokers or have a lengthy quit time. The remaining groups of patients’ (i.e. current smoker or recent former smokers) have a different biology that has been successfully exploited with immunotherapy. Immune checkpoint inhibitors have replaced single agent docetaxel as the standard of care for second line treatment of lung cancer for all histological subtypes of NSCLC (4-6). Most recently the KEYNOTE-024 a randomized trial of pembrolizumab versus doublet chemotherapy for untreated patients with advanced NSCLC whose tumor have > 50% PD-L1 (programmed death-ligand 1) IHC (immunohistochemistry) expression met its primary progression-free survival (PFS) endpoint and also improved overall survival (7). This will represent a new standard of care for approximately 25% of patients and will serve as the backbone for immune combinations. We are anxiously awaiting the results of a randomized trial of a PD-1 (programmed cell death protein 1) inhibitor plus a CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor versus platinum-based chemotherapy that is expected to report out in mid 2017. A similar study is actively accruing patients. The preliminary results on this dual immune combination were very promising and if positive would increase the number of patients receiving upfront immune therapy over chemotherapy (8). Additionally, there are numerous immune combinations involving drugs that target immune evasion and even more drugs that stimulate the immune system including cellular therapies that are being evaluated. The success of targeted therapy and immunotherapy in the advanced setting has quickly led to their evaluation in earlier stages of disease. There is a lot of enthusiasm for combining immunotherapy with radiation for patients with locally advanced lung cancer given the well-known immune modulatory effects of radiation. Moreover the bar for replacing weekly low dose concurrent chemotherapy with immunotherapy is low. In the adjuvant setting our Asian colleagues designed and conducted two randomized phase III trials in patients whose tumors have an EGFR sensitizing mutation to replace chemotherapy with an EGFR-TKI. Accrual is completed and we are awaiting the results. In regard to immunotherapy, enrolling phase III trials are evaluating immune checkpoint inhibitors as maintenance therapy but the pursuit of immunotherapy as a replacement for chemotherapy will follow. Beyond treatment of lung cancer, on the horizon is the exploration of targeted agents and immunotherapy as preventive agents. It is important to emphasize that our current and future success is the consequence of many factors: 1) the exponential advances in technology that has driven the science and drug development 2) rapid trial accrual and 3) regulatory authorities’ responsiveness to bringing efficacious treatments to patients as quickly as possible. This momentum is what will lead us to replacing chemotherapy for lung cancer. With 20%+ of patients with driver mutations and 25% of all NSCLC with high PD-L1 already benefiting from non-chemotherapy treatment, we are well on our way to ousting chemotherapy in NSCLC by 2030. References Mok TS, Wu Y-L, Thongprasert S, et al. Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma. N Engl J Med 2009, 361:947-57. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013, 368:2385-94. Vigneswaran J, Tan YH, Murgu SD, et al. Comprehensive genetic testing identifies targetable genomic alterations in most patients with non-small cell lung cancer, specifically adenocarcinoma, single institute investigation. Oncotarget 2016, 7:18876-86. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015, 373:123-35. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015, 373: 1627-39. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomized controlled trial. Lancet 2016, 387:1540-50. MERCK press release, July 2016 Hellman MD, Gettinger SN, Goldman JW, et al. CheckMate 012: Safety and efficacy of first-line (1L) nivolumab (nivo; N) and ipilimumab (ipi; I) in advanced (adv) NSCLC. J Clin Oncol 34, 2016 (suppl; abstr 3001).

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Abstract:
Superior sulcus tumors (SST) are unique among lung cancer in that they have a tendency for the invasion into the chest wall and a spread superiorly outside the lungs, namely into the brachial plexus and the sympathetic chain, therefore causing a well-defined constellation of symptoms and signs, such as chest wall/arm/shoulder pain, Horner’s syndrome, spinal cord compression, upper extremity edema etc. A primary surgical resection is rarely performed, and bi- or trimodality therapies are most often implemented, depending on tumor stage. A comprehensive evaluation of the tumor extent is mandatory before any intervention is undertaken. Following tumor biopsy to establish a diagnosis of non-small cell lung cancer, standard lung cancer staging studies need to be obtained, such as the chest and upper abdomen computerized tomography (CT) scan with intravenous contrast, a PET CT scan and contrast-enhanced brain imaging (CT or MRI). Routine blood work and pulmonary function testing are standard as well. However, there are two additional radiographic studies which are necessary for each superior sulcus tumors: (1) MRI scan of the brachial plexus; (2) MRI scan of the cervical and thoracic spine. The rationale for imaging of the brachial plexus is not to confirm that the plexus is invaded (which is evident based on the presenting symptoms and a physical examination), but rather to assess the degree of its vertical involvement, since only the lowest trunks of the brachial plexus can be safely resected without fear of causing paralysis of the upper extremity. The MRI of the vertebral column serves a double purpose: (1) to assess the degree (if any) of vertebral involvement and resulting resectability; (2) to image the proximity of the tumor to the spinal cord, which is crucial for radiation planning. SSTs can cause thecal sac or spinal cord compression by extending into the spinal canal through neural foramina, without apparent spine invasion, hence the need for the MRI, which provides a superior image quality than a chest CT scan. The overall treatment strategy depends on the nodal status (“N” stage). For those patients without nodal involvement (“N0”) or with involvement only of the ipsilateral hilar lymph nodes (“N1”), a common approach is to use concurrent induction chemo-radiotherapy, followed by the surgical resection. If obvious mediastinal nodal involvement is seen (“N2 or N3”), the recommendation is for definitive concurrent chemo-radiotherapy without subsequent surgery. Therefore, invasive staging of the mediastinum, either with mediastinoscopy or with EBUS, is mandatory, since it may result in avoiding surgery as part of management. General thoracic radiation therapy (RT) principles apply to the SSTs, such as: (1) use of the CT simulation for tumor and normal tissue imaging; (2) use of 6-10 MV photon energies (unless protons are applied); (3) careful definition of the GTV, Gross Tumor Volume, to include the visible tumor on lung windows and the abnormal lymph nodes on soft tissue windows; (4) adequate margins for the CTV, Clinical Target Volume, and the PTV, Planning Target Volume. In particular, a tendency to have very tight margins around the tumor which is in close proximity to the spinal cord should be avoided at all cost, since this may result in a marginal tumor failure. In comparison to lung cancers in other locations, local tumor progression of a SST can have devastating clinical consequences, resulting in unmanageable pain, limb paralysis and a low quality of life. The commonly used total RT doses are: 45-60 Gy in trimodality therapy (chemo-RT, then surgery) or 60-70 Gy in bimodality therapy (chemo-RT) in 2 Gy daily fractions. The dose-limiting normal structures are usually the spinal cord and brachial plexus. The maximum allowed dose to the spinal cord may need to be higher (54-55 Gy) in SSTs than in other lung cancers (50 Gy) in order not to compromise the minimum dose prescribed to the PTV by attempting to “spare” spinal cord. In patients presenting with severe pain, a simple field arrangement (such as anterior and posterior opposed fields) treating the tumor with wide margins is a good initial option allowing for a quick start, followed by a more advanced planning technique, such as 3-dimensional RT, intensity modulated RT (IMRT) or VMAT. The tolerance of brachial plexus was classically described as a maximum dose of 65 Gy, with recent publications suggesting that higher doses, up to 78 Gy result in 12% risk of Grade>3 radiation-related brachial plexopathy, and that brachial plexopathy is more common as a result of tumor progression than radiation damage. The most quoted prospective clinical trial reporting on treatment outcomes of SSTs is a landmark Phase II SWOG 9416 study, in which 95/110 enrolled patients without disease progression (86%) received thoracic RT to 45 Gy in 1.8 Gy fractions with concurrent cisplatin and etoposide chemotherapy, followed by surgery and further adjuvant chemotherapy. Eligible patients were those with T3-T4 primary tumors and N0 or N1 nodal status. The resection rate was 80% and 75% achieved a complete (R0) resection. The pathologic response rate (no tumor in the specimen or microscopic residual) was 56%; the overall 5 yr survival rate was 44% for all patients and 54% for those with a complete tumor resection. Since then, recognition in the surgical community that operating after RT doses higher than 45 Gy is safe, led to a more common use of the full RT dose, i.e. 60 Gy. If the patient initially planned for trimodality therapy is no longer a surgical candidate or refuses surgery, thoracic RT should continue to definitive dose without interruption. Therefore, it is crucial to perform re-imaging for response assessment in the last week of chemo-RT (if doses of <60 Gy are used) rather than schedule those several weeks later. References: Rusch, V.W., Giroux, D.J., Kraut et al. Induction chemoradiation and surgical resection for non-small cell lung carcinomas of the superior sulcus (initial results of Southwest Oncology Group trial 9416 (Intergroup trial 0160)) . J Thorac Cardiovasc Surg 121: 472–483, 2001. Kwong KF, Edelman MJ, Suntharalingam M et al. High-dose radiotherapy in trimodality treatment of Pancoast tumors results in high pathologic complete response rates and excellent long-term survival. J Thoracic Cardiovasc Surg, 129:1250-57, 2005. Eblan MJ, Corradetti MN, Lukens JN et al. Brachial plexopathy in apical non-small cell lung cancer treated with definitive radiation: dosimetric analysis and clinical implications. Int J Radiat Oncol Biol Phys.85:175-81, 2013.

Abstract:
Backgroud: Lung cancer is the leading cause of cancer deaths in the world. For patients with advanced non-small cell lung cancer (NSCLC), survival prognosis is very poor with chemotherapy and radiotherapy. However, the possibility of occult metastases may lead to discrepancy between clinical and pathologic staging and underestimation of the disease severity, and how to individualized choose the appropriate patients with locally advanced non-small cell lung cancer for surgery is controversies. In this study, we presented here the Chinese experience: individual precision surgery for locally advanced non-small cell lung cancer based on molecular staging.Methods: We developed several molecular biomarkers and molecular models from Circulation Tumor Cell (CTC ) detection, mi-RNA chip, Gene Chip from 1990. We used these Molecular biomarkers and molecular models for molecular staging, molecular typing, choosing indication of operation and neoadjuvant chemotherapy, predicting postoperative recurrence and prognosis of locally advanced non-small cell lung cancer.Results: We developed two molecular staging model for individualized surgical treatment for locally advanced non-small cell lung cancer involving heart, great vessels or both. 3308 patients with locally advanced non-small cell lung cancer were underwent completely resection of the cancer in the three medical center. The 1-, 3-, 5- and 10 year survival rate were 74.5%,62.3%,31.5% and 22.9%, respectively. We used our molecular staging model for neoadjuvant chemotherapy for 665 patients with locally advanced lung cancer. The 1-, 3-, 5- and 10-year survival rate were 79.35%, 51.46%, 27.39% and 20.34% of the patients, respectively. We used our molecular model to divide N2 lung cancer into invasive N2 and Non-invasive N2 group. We used our molecular models adenocarcinoma and squamous carcinoma to divide T4 lung cancer into high recurrence and low recurrence groups, and help postoperative adjuvant therapy.Conclusion: Our molecular staging and typing models can help us carry out individual precision surgery, predicting prognosis and cancer recurrence of the cancer for locally advancer no-small cell lung cancer.

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Abstract:
Stage III non-small cell lung cancer (NSCLC) is a heterogeneous disease characterized by either locally advanced tumor infiltration and/or mediastinal lymph node involvement. Due to improvements in chemo (CT)- and combined chemoradiation (CRT) therapy protocols, patients with locally advanced stage III NSCLC become potential candidates for curative resection more frequently. According to the TNM-7 classification, stage III NSCLC can be defined by the following T and N subsets: stage IIIA: T3 N1-2, T4 N0-1, T1-2 N2; stage IIIB: T4 N2, T1-4 N3. Five-year survival of stage III is generally around 25% taken all different therapy strategies together. Several studies have shown that induction treatment before surgery is beneficial in resectable cases and selected patients undergoing radical resection may have encouraging 5-year survival rates up to 60%. However, to date, no worldwide consent exists on the general role of surgery in curative attempt. Furthermore, it is still unclear if resectable patients might have greater benefit from induction CT compared to combined induction CRT and if concomitant CRT should be preferred over a sequential treatment. Only a small number of prospective phase II/III trials are available addressing these issues. A phase III trial comparing induction CRT plus surgery (S) with definitive CRT in patients with stage IIIA/N2 published in 2009 has questioned the role of surgery since there was no difference in overall survival (OS) between the two groups [1]. However, the 30-day mortality was unacceptably high (26%) in the subgroup of patients undergoing pneumonectomy and thus patients with CRT and lobectomy had significantly improved OS compared to those with CRT alone. Moreover, several other retrospective series have reported encouraging long-term survival in selected patients undergoing induction treatment followed by radical surgery. The benefit of adding sequential RT to CT prior to surgery (S) in stage IIIA/N2 has been investigated in a recent phase III trial [2]. Patients undergoing CRT/S had a non-significant superior median OS of 37 months compared to 26 months with CT/S. Both groups had similar disease free survival (DFS) and it was concluded that RT did not add any benefit to induction CT prior to surgery. However, those with CRT/S had an objective response, pathological complete response, a R0 resection rate and a mediastinal downstaging more frequently and less local progression compared to CT/S. The question whether to apply RT concomitantly or sequentially to CT has been investigated in a recent meta-analysis [3]. Pooled data from six prospective trials suggested that concomitant CRT, as compared with sequential CRT, improved survival of patients with locally advanced NSCLC, primarily because of a better locoregional control. However, these patients were treated without surgery and caution should be taken when transferring these conclusions to the neoadjuvant setting before surgery. From the surgical point of view, patients with local tumor invasion (T3-4 N0-1 including Pancoast tumors) have to be treated by different oncological principles than those with mediastinal lymph node (LN) involvement (N2). In patients with T3 tumors invading the chest wall, diaphragm, mediastinal pleura, phrenic nerve or parietal pericardium and N1 involvement, primary resection can be undertaken. Induction therapy may improve local control rates in larger tumors but it remains unclear if systemic treatment is beneficial prior to or after local resection. Intraoperative frozen section of resection margins should be mandatory and reconstruction of resected structures with synthetic material may be necessary. T4 tumors with invasion to the mediastinal structures or vertebral bodies are a unique subset of locally advanced NSCLC and multidisciplinary treatment can be challenging. Well selected patients may benefit from multimodality therapy including surgery and should be treated in well experienced centers [4, 5]. In patients with suspected N2 disease, invasive staging for histological confirmation has been widely accepted as a standard procedure [6]. In case of multilevel and/or bulky N2 disease, surgery should be avoided due to the expected poor outcome. However, it has been well shown that patients in good performance status with single or two level N2 disease with good response after induction therapy may have improved OS when undergoing curative resection [7, 8]. On the other hand, patients with persistent N2 disease after induction treatment tend to have worse OS and high recurrence rates and thus should not undergo surgery. This finding strengthens the impact of invasive re-staging after induction treatment as proposed by recent staging guidelines. In conclusion, selected patients with stage III NSCLC may have beneficial outcome after surgery combined with CT or CRT. However, this holds truth only for cases with response to induction treatment, nodal downstaging and when R0 resection is deemed achievable. Surgery should be avoided in patients with multilevel/bulky N2 disease or persistent mediastinal LN after induction treatment due to the expected poor outcome. The optimal sequence and modality of induction treatment has yet to be defined in larger prospective trails. References [1] Albain KS, Swann RS, Rusch VW, Turrisi AT, Shepherd FA, Smith C, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet. 2009;374:379-86. [2] Pless M, Stupp R, Ris HB, Stahel RA, Weder W, Thierstein S, et al. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet. 2015;386:1049-56. [3] Aupérin A, Le Péchoux C, Rolland E, Curran WJ, Furuse K, Fournel P, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol. 2010;28:2181-90. [4] Collaud S, Fadel E, Schirren J, Yokomise H, Bolukbas S, Dartevelle P, et al. En Bloc Resection of Pulmonary Sulcus Non-small Cell Lung Cancer Invading the Spine: A Systematic Literature Review and Pooled Data Analysis. Ann Surg. 2015;262:184-8. [5] Rusch VW. Management of Pancoast tumours. Lancet Oncol. 2006;7:997-1005. [6] De Leyn P, Dooms C, Kuzdzal J, Lardinois D, Passlick B, Rami-Porta R, et al. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. Eur J Cardiothorac Surg. 2014;45:787-98. [7] Friedel G, Budach W, Dippon J, Spengler W, Eschmann SM, Pfannenberg C, et al. Phase II trial of a trimodality regimen for stage III non-small-cell lung cancer using chemotherapy as induction treatment with concurrent hyperfractionated chemoradiation with carboplatin and paclitaxel followed by subsequent resection: a single-center study. J Clin Oncol. 2010;28:942-8. [8] Hancock J, Rosen J, Moreno A, Kim AW, Detterbeck FC, Boffa DJ. Management of clinical stage IIIA primary lung cancers in the National Cancer Database. Ann Thorac Surg. 2014;98:424-32; discussion 32.