bluuebunny/crossref_metadata_2025_split huggingface dataset:
Definitive thoracic radiotherapy in oligometastatic stage IV non-small cell lung cancer (NSCLC).
Authors: Fernandes Annemarie Therese , Xanthopoulos Eric , Handorf Elizabeth , Grover Surbhi , Sharma Sonam , Eaby-Sandy Beth , Evans Tracey L. , Stevenson James , Langer Corey J. , Mitra Nandita , Apisarnthanarax Smith , Lin Lilie , Rengan Ramesh 
Published: March 2020

e18032 Background: Intrathoracic tumor control in patients (pts) with metastatic NSCLC is controversial as most die of distant disease. But a subset of good performance status pts with minimal burden of extrathoracic disease may benefit aggressive treatment. We report outcomes in a subset of pts with oligometastatic NSCLC treated with definitive radiotherapy (RT) to the primary tumor. Methods: We identified29 stage IV pts from 01/04 - 08/10 who had ECOG ≤2 and ≤4 metastases who received ≥50 Gy thoracic RT with chemotherapy. Pts were assessed for local control, overall survival and toxicity. An exploratory analysis was performed matching these pts to pts receiving chemotherapy (CT) alone. Results: In the 29 chemoradiotherapy (CRT) pts, median age was 57 yrs, 72% had ECOG 1 and 91% were staged with PET. Median survival was 22 months. Eight patients had grade 2+ pneumonitis. Nineteen patients had grade 2+ esophagitis. Next, 2 CT pts were matched with each CRT pt on 4 factors: age, ECOG, and presence of multi-organ or contralateral lung disease. We excluded 4 CRT pts who did not match 2 CT controls. Median survival was 22 vs 9 months (p <0.01) for patients given CRT vs CT. Median time to local failure was 18 vs 6 months (p = 0.01). Median survival in locally controlled pts was 39 vs 19 months in pts with local failure (p = 0.02). On multivariable analysis, radiation (p <0.01, OR = 0.33), multiple metastatic organs at diagnosis (p <0.01, OR = 2.14), and gender (p <0.01, OR = 0.41) were associated with overall survival. Conclusions: Treatment ofNSCLC patients with oligometastatic disease with definitive dose radiation therapy may provide a local control and overall survival benefit in a subset of patients with minimal extrathoracic burden of disease.
A study of EGFR mutation in nonsmoker NSCLC: Striking disparity between north and south India patients.
Authors: Aggarwal Shyam , Patil Shekhar , Minhans Sachin , Pungliya Manish , N Soumitra 
Published: March 2020

e18041 Background: There is a high incidence of EGFR mutation in non-smokers with adenocarcinoma of lung- 70% the south-east Asia and 15% in Caucasians. There is no study in an Indian population yet. Methods: 55 cases of non smoker advanced adenocarcinoma of lung were enrolled in this study after June, 2008 in a retrospective fashion. 26 patients were enrolled from Sir Ganga Ram Hospital, Delhi in North India and 29 from HCG, Bangalore in South India. Assessment of mutation status was possible in 49 cases. ARMS technique was used to study the EGFR mutation. Results: A total 27 out of 49 cases were positive for EGFR mutation – 7/21 (33%) from North India and 20/28 (65%) from South India. The commonest mutation was del exon 19 (62%), followed by L858R exon 21 (25%), G719X exon 18 (7%) and insertion exon 20 (3%). Patients were treated either with gefitinib or chemotherapy. 8/12 (83%) patients treated with gefitinib upfront responded. Overall survival (OS) was not reached at a follow up of 11 months in EGFR mutation carriers. Only 2/27 patients died. Of the 22 cases with no EGFR mutation, 6 were treated with gefitinib in frontline and the rest with chemotherapy. OS was reached at 10 months in patients with no EGFR mutation. 10/22 of these patients died. Conclusions: The study brings about striking differences in the incidence of EGFR mutation in non-smoker NSCLC cases between North and South India. This could be due to ethnic issues. There is a need to continue to this study in these patient populations.
Outcome of non-small cell lung cancer in females with gefitinib therapy: An experience from eastern India.
Authors: Shahid Tanweer , Mukhopadhyay Soma , Basak Jayasri , Gangopadhyay Sudeshna , Dasgupta Swati , Mukhopadhyay Ashis 
Published: March 2020

e18043 Background: Non-small cell lung carcinoma is usually an incurable disease with average overall survival of 7-9 months. But studies in recent years have shown that adenocarcinoma in nonsmokers with epidermal growth factor receptor (EGFR) positivity has shown disease control for longer duration. Female patients with adenocarcinoma where EGFR is positive show higher response rate with EGFR blocker. In eastern India, lung cancer contributes 21.3% of all cancers and female lung cancer contributes about 20% of them. The aim of our study was to see the age at diagnosis, histological type, EGFR status, smoking status and the response rate with Gefitinib, an EGFR tyrosine kinase inhibitor, for the female patients with carcinoma of lung. Methods: We randomly selected 50 female lung cancer patients, who had not previously received chemotherapy, during the period from November, 2006 to November, 2011. The mean age group at diagnosis was 55 years (range 26-85 years). 48 patients (96%) never had smoking habit, 2 (4%) were active smokers and the rest were passive smokers. Results: Twenty six (52%) patients had histological type of adenocarcinoma, 18 (36%) had squamas cell carcinoma, 4 were poorly differentiated and 2 (4%) had large cell carcinoma. Trucut biopsy showed EGFR positivity in 22 patients. All patients were started with single agent Gefitinib therapy at least for 6 months; after that according to response rate, same dose was continued. If there were progression of the disease, they were switched over to other chemotherapeutic agents. The median follow up was 1.5 years; the progression free survival (PFS) was seen in 19 (38%) patients. Adenocarcinoma patients with EGFR positivity had significantly higher PFS than those with non-adenocarcinoma and EGFR negative status. There was no difference of response rate between smokers and nonsmokers (never-smokers). Older patients showed higher response rates. Conclusions: Our data suggested that older patients with adenocarcinoma and EGFR positivity had long term progression free survival. So in developing countries like ours, where molecular diagnosis is not feasible many a times, this result might help clinicians to select a beneficial subgroup in female lung cancer patients.
Phase I dose-escalation study of oral vinorelbine (VRLO) plus pemetrexed (PEM) in patients (pts) with advanced or metastatic non-squamous non-small-cell lung cancer (NSCLC).
Authors: Sierra Marta Isabel , Losa Raquel , Tresguerres Maria , Gutierrez Restrepo Eduardo , Perez Quionia , Alvarez Carlos , Berros Jose Pablo , Villanueva Noemi , Gracia Jose Manuel , Esteban Emilio 
Published: March 2020

e18044 Background: PEM and VRLO have shown high activity and good safety profile when given as single agent chemotherapy for NSCLC. Platinum combinations are considered the standard of care of first-line advanced NSCLC treatment. However, some patients cannot receive platinum salts, being treated with non-platinum combinations as an alternative treatment option. PEM is indicated for the 1st-line treatment of patients with locally advanced or metastatic NSCLC other than predominantly squamous cell histology. VRLO is indicated for stage III-IV NSCLC and has shown efficacy in all histology subgroups. Their combination could offer a treatment option in non-squamous 1st-line NSCLC. Methods: A phase I study is being conducted to determine the maximal tolerated dose (MTD) of PEM on day 1 plus VRLO given on days 1 and 8, with 3-weeks cycles as 1st-line treatment in locally advanced or metastatic non-squamous NSCLC pts. Results: As of Jan-2012, 18 pts (M/F: 13/5, median age 61, all PS 0-1) had received 104 cycles in 4 dose levels (DL): VRLO (mg/m2)/PEM (mg/m2): 60/500 (5 pts, DL1), 70/500 (7 pts, DL2), 60-80/500 (3 pts, DL3), 80/500 (3 pt-DL4). Safety: dose limiting toxicity as defined per protocol was neutropenia gr 4 with febrile neutropenia at DL2. Other toxicities were: neutropenia gr 3 (3 pts), gr 2 (2 pts); leukopenia gr 2 (3 pts). Other adverse events included: vomiting (gr 3 / 1 pt) (gr 2 / 5 pts); gr 2 asthenia (5 pts); constipation (gr 2 / 1 pt) (gr 1 / 2 pts); diarrhea (gr 1 /3 pts); fever (gr 1/1 pt); alopecia (gr 1/ 1 pt). Efficacy in 15 evaluable pts: CR, 0 pts; PR, 9 pts; NC, 3 pts; PD, 2 pts. Overall response rate, 60% (73% clinical benefit). Conclusions: The administration of PEM plus VRLO is feasible, the MTD being reached at 80/500 mg/m2. Further exploration of the combination will be planned after final analysis.
Final report of an open-label phase II trial of bevacizumab plus docetaxel and gemcitabine in metastatic, previously untreated nonsquamous non-small cell lung cancer (NSCLC).
Authors: Pennell Nathan A. , Kalmadi Sujith R. , Shapiro Marc A. , Daw Hamed , Rodriguez Cristina P. , Haddad Abdo S. , Rich Tara , Samsa Julia , Elson Paul , Ma Patrick C. , Dowlati Afshin 
Published: March 2020

e18046 Background: Platinum and non-platinum doublet chemotherapy has similar efficacy in advanced NSCLC patients (pts). Bevacizumab (B) improves outcomes when added to platinum doublets, but its safety and efficacy in combination with non-platinum doublets is unknown. This study was designed to test the combination of B, docetaxel (D), and gemcitabine (G) in first-line treatment of advanced NSCLC. Methods: Pts with metastatic, non-squamous NSCLC, PS 0-1, and measurable disease by RECIST were enrolled in this open-label, single arm phase II trial. Pts received D (75 mg/m2) on d1, G (900 mg/m2) on d1 & 8, and B (15 mg/kg) on d1 every 21d for up to 6 cycles, followed by B maintenance until progression or 12 mos total. Pts received growth factor d9. CT scans were performed every 6 wks. The primary endpoint was 1-yr progression-free survival (PFS), with secondary endpoints of safety, objective response rate (ORR), overall PFS, and overall survival (OS). Pts with tumor cavitation, untreated brain metastases, and hemoptysis were excluded. Planned enrollment was 46. Results: 13 pts were enrolled from 12/2009 to 4/2011. Pt characteristics: Median age 63 (35-69), 85% male, PS 0 (38%), PS 1 (62%). The median # of cycles of chemotherapy was 6 (1-6), median # cycles of B was 4 (1-15), with 2 pts coming off study prior to the first evaluation (1 grade 5 encephalopathy, 1 grade 4 febrile neutropenia). 5 pts (38%) had chemo dose reduction and 4 (31%) discontinued treatment for toxicity. 3 pts (23%) discontinued B prior to progression, 2 for tumor cavitation and 1 for grade 1 hemoptysis. The grade 3-5 non-hematologic toxicity rate was 69%, with 6 pts (46%) hospitalized with pneumonitis/pneumonia felt possibly related to study drugs. At this point enrollment was halted for safety concerns. The 1-yr PFS was 8%, and the median PFS was 6.9 mos (95% CI 2.0-NYR). 11 pts were evaluable for response, and 6 pts had partial responses for an ORR of 55%. The median OS was NYR with median follow up of 10.9 mos. Conclusions: The combination of B, D, and G was not tolerable at the doses and schedule used in this study. A formal phase I trial is needed if this combination is to be investigated further.
Effect of metformin on the effects of TKI on human lung carcinoma cells harboring KRAS or EGFR-T790M mutation.
Authors: Wang Yongsheng , Ma Yu , Li Dan , Guo Fuchun 
Published: March 2020

e18051 Background: K-ras and egfr-T790M mutation show primary and acquired resistance to EGFR-TKI in non-small cell lung cancer, respectively. The antidiabetic drug metformin has been associated with a decreased incidence and a better prognosis of lung cancer. The affects of metformin on the EGFR-TKI resistance in non-small cell lung cancer remain unknown. Methods: The effects of metformin on EGFR-TKI were investigated in k-ras mutant A549 cells, and egfr-T790M mutant H1975 cells both in virto and in vivo. The proliferation and apoptosis were tested. The underlying mechanisms were also analyzed. Results: Our data showed metformin significantly enhanced the inhibition activity of gefitinib both in A549 and H1975 cells in vitro. At the molecular level, metformin inhibited multiple signaling including LKB1-AMPK-S6K, PI3K-AKT and Raf-MEK-MAPK in a dose-dependent manner. Furthermore, the increased tumor inhibitions were observed in nude mice models of A549 (P<0.05)and H1975 (P<0.01). Conclusions: Metformin can increase the effects of EGFR-TKI in lung adenocarcinoma harboring K-ras and egfr-T790M mutation. Our study may provide a new strategy to overcome the EGFR-TKI resistance in NSCLC.
Weekly paclitaxel and bevacizumab as fourth-line treatment or beyond for metastatic nonsquamous non-small cell lung cancer.
Authors: Habib Stefanie , Delourme Julie , Dhalluin Xavier , Scherpereel Arnaud , Lafitte Jean-Jacques , Cortot Alexis B. 
Published: March 2020

e18066 Background: Paclitaxel (P) and bevacizumab (B) showed synergistic antitumor efficacy in preclinical models. In combination with carboplatin, PB prolonged progression-free survival (PFS) and overall survival (OS) in selected metastatic non-squamous Non Small Cell Lung Cancer (NSCLC) patients compared to carboplatin and paclitaxel. Currently, there are no standard treatments beyond third-line therapy in NSCLC. We sought to determine the efficacy of weekly paclitaxel and bevacizumab (wPB) in non-squamous NSCLC as fourth-line therapy or beyond. Methods: we retrospectively reviewed patients with metastatic non-squamous NSCLC who have been treated with wPB in our institution. Patients were identified from a prospective database. Treatment consisted in P 80mg/m² on days 1, 8, 15 and B 15mg/kg on day 1, every 3 weeks until progression or unacceptable toxicity. Patients were evaluated every 3 cycles. PFS and OS were calculated from the date of initiation of wPB and analyzed using the Kaplan-Meier method. Results: Twenty patients received at least one cycle of wPB between 2008 and 2011. All patients received wPB as fourth-line treatment or beyond. Eight patients (40%) had a partial response, 7 patients (35%) had stable disease and 5 patients (25%) had progressive disease. Grade 3-4 adverse events included neutropenia (20%), onycholysis (10%), infection (10%), pulmonary haemorrhage (5%), neuropathy (5%) and hypertension (5%). One patient died from a bowel perforation following second cycle of wPB. The median PFS was 6.4 months (CI95% 4.1-9) and the median OS was 9.6 months (CI95% 7-19.7). One patient who previously received bevacizumab as part of first-line chemotherapy and another patient harbouring an ALK rearrangement benefited from wPB during more than 8 months and 18 months, respectively. Conclusions: In our experience, wPB exhibited acceptable toxicity and had encouraging anti-tumor efficacy as fourth-line treatment or beyond in non-squamous NSCLC patients, supporting further evaluation in larger prospective studies.
Phase II study of pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab for Japanese nonsquamous non-small cell lung cancer.
Authors: Yokoi Takashi , Torii Yoshitaro , Katashiba Yuichi , Sugimoto Hiroyuki , Hayashi Mina , Shimizu Toshiki , Nomura Shosaku 
Published: March 2020

e18081 Background: Until recently non–small-cell lung cancer was treated as a single disease with “platinum-based doublet chemotherapy” comprising first-line treatment for advanced disease. However, survival outcome of advanced non-squamous non–small-cell lung cancer are improving since the appearance of pemetrexed and bevacizumab. These drugs show a high effect especially to Adenocarcinoma, but there are few reports of the regimen which combined these both agents. Then, we designed this study to evaluate the efficacy and safety of pemetrexed, carboplatin, and bevacizumab followed by maintenance pemetrexed and bevacizumab in patients with chemotherapy-naïve Japanese stage IIIB or stage IV non-squamous non–small-cell lung cancer. Methods: Patients received pemetrexed 500 mg/m2, carboplatin area under the concentration-time curve of 6, and bevacizumab 15 mg/kg every 3 weeks for up to six cycles. For patients who is not progressed after pemetrexed, carboplatin and bevacizumab therapy, pemetrexed and bevacizumab were continued until disease progression or unacceptable toxicity. Primarity endpoint is response rate. Results: 23 patients were enrolled between March 2010 and April 2011 and treated. Median age was 64 (40-74), 15 patients were male, 6 patients were PS 0, 20 patients were Stage IV. Response rate was 69.5% and disease control rate was 100%. Median PFS was 8.5 months and median OS was not reached. Median time to response was 1.2 months. There were no grade 3 or worse hemorrhagic events. The feasibility was modest. Conclusions: Pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab was efficacy and tolerable regimen in Japanese patients with non-squamous non-small-cell lung cancer. This regimen also has a trend of shorter period for response. It may contribute to the better QoL.
Clinical characteristics of NSCLC harboring ALK 2p23 translocation at Cleveland Clinic.
Authors: Feng Yan , Pennell Nathan A. , Samsa Julia , Lanigan Christopher , Arrossi A. Valeria , Farver Carol , Tubbs Raymond R. , Ma Patrick C. 
Published: March 2020

e18085 Background: The ALK 2p23 translocation, ALK(+), is an important druggable target in 5-7% of non-small cell lung cancer (NSCLC). However, the break-part FISH assay is labor-intensive. Better understanding of the target population’s clinical features and alternative screening tests are desirable to enable cost-effective patient selection for molecular therapy. Methods: NSCLC patients (N=120) seen at the Cleveland Clinic (CC) who had clinical screening ALK 2p23 FISH (Abbott Molecular) were included in this retrospective analysis. Biopsy specimens were also tested using immunohistochemistry (IHC) for ALK overexpression via clone D5F3 (Cell Signaling Tech.) with OptiView ultrasensitive detection (Ventana Medical Sys.). Clinical data were extracted from electronic medical records. Comparison was performed using Fisher’s exact test, Wilcoxon rank sum test or log-rank test. Results: Of the 120 tumors tested, 34 (28.3%) were ALK(+) by FISH, predominantly adenocarcinomas (33/34). 97% of the samples were also tested by ALK-IHC, with a concordance rate of 99%. Comparing to ALK (-) group, ALK(+) patients were younger (median 53 vs 65, p<0.01) and mostly never/light smokers (91% vs 43%, p<0.01). ALK(+) tumors tended to have higher number of metastatic sites at diagnosis, especially for liver metastasis (26.5% vs 10.5%, p=0.04). Interestingly, venous thrombosis (DVT/PE) was also significantly more common in ALK(+) patients (35.3% vs 16.3%, p=0.03). 17 (50%) patients were treated with crizotinib in the ALK(+) group. Two cases with positive screening ALK-IHC helped to identify FISH(+) tumor areas. Of those tumors with EGFR status available (n=103), 6 were EGFR mutation-positive, all being ALK(-). No significant OS difference was seen in ALK(+)/EGFR(-) patients (n=28) compared to ALK(-)/EGFR(-) patients (n=69). Conclusions: ALK 2p23 (+) NSCLC at CC was more commonly seen in younger patients and never/light smokers. They tended to have greater number of metastases, especially in the liver, and significantly higher risk of venous thrombosis. ALK-ultrasensitive IHC using the D5F4 clone helped to identify FISH(+) tumor areas and may be considered a cost-effective screening test demonstrating high concordance with ALK FISH.
Effect of loss of a chromosome 7 containing multiple copies of EGFR gene on acquired resistance to EGFR-TKIs in EGFR mutated NSCLC.
Authors: Furugaki Koh , Iwai Toshiki , Moriya Yoichiro , Fujimoto-Ouchi Kaori 
Published: March 2020

e18091 Background: The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) show notable effects for non-small cell lung cancers (NSCLC) harboring EGFR activating mutations. However, almost all patients eventually acquire resistance to EGFR-TKIs within several years. The major mechanisms of acquired resistance are acquisition of a secondary EGFR mutation T790M and amplification of MET. However, the mechanisms of other resistance remain unclear. In this study, we established novel erlotinib-resistant NSCLC cells and examined their resistant mechanism. Methods: Resistant cells were established by continuously exposing EGFR mutated NSCLC cells HCC827 to 0.1, 1 or 10 μM of erlotinib in 96 well plates for three months. The resistant mechanisms were determined by direct sequence analysis and EGFR FISH analysis. Results: Resistant cells were emerged from 14/96 and 3/96 wells by 0.1 μM and 1 μM of erlotinib exposure, respectively. No resistant cells appeared in the wells of 10 μM of erlotinib. The IC50 values of these resistant cells were more than 100-fold higher than that of parental cells. No secondary mutation of T790M was detected in any of the resistant cells. Instead, we found that 13/17 resistant cells were dominated by EGFR not amplified cells and one of resistant cells B10 consisted of more than 99.9% of them, while the parental cells consisted of 2.5% of EGFR not amplified cells. Then, we isolated EGFR not amplified clone 4D8 from parental cells and found that this clone also had a resistance to erlotinib comparable to the resistant cells B10. Metaphase FISH analysis showed that EGFR amplified cells in parental cells had a chromosome 7 containing multiple copies of EGFR, while EGFR not amplified cells in B10 did not have it. Furthermore, we found that EGFR not amplified cells were constantly emerged from EGFR amplified clone isolated from parental cells under normal cell culture condition. Conclusions: Loss of a chromosome 7 containing multiple copies of EGFR causes acquired resistance in HCC827 cells when exposed to relatively low concentration of erlotinib, while high concentration of erlotinib deprives HCC827 cells of the chance of emergence of resistant cells.
EGFR mutation analysis and treatment outcomes with tyrosine kinase inhibitors in EGFR mutants: The Manchester Lung Cancer Group Experience.
Authors: Peck Rahul , Connolly Elizabeth , Taylor Paul , Faivre-Finn Corinne , Blackhall Fiona Hellen , Wallace Andrew , Lee Lip , Bayman Neil , Burt Paul , Summers Yvonne J. 
Published: March 2020

e18095 Background: The presence of Epidermal Growth Factor Receptor (EGFR) activating mutations in patients with NSCLC was first described in 2005. Tumours exhibiting these mutations show sensitivity to treatment with an oral Tyrosine Kinase Inhibitor. Testing for EGFR mutations in patients with non-squamous NSCLC began in the Greater Manchester and Cheshire network in the last quarter of 2009. Methods: We audited the notes of consecutive patients who were identified with an activating EGFR mutation by the Central Manchester Genetics Laboratory between November 2009 and October 2011. Results: A total of 110 mutations were identified in tumour tissue from 98 patients. 13.6% were in exon 18, 38.2% in exon 19, 15.4% in exon 20 and 32.8% in exon 21. 65% of patients were female. The median age was 69 years (36-89). Notes were available for 85 patients, 59 of whom received treatment with an EGFR TKi. 7 had previously received radical treatment and 19 never received treatment. 7% were current smokers, 40% were ex-smokers, 30.6% had never smoked and smoking history was not documented in 22.4%. An initial response to treatment was seen in 55%, with stable disease in 15%.The mean duration of treatment was 7.6 months (2 weeks – 23 months), with 24 patients still receiving a TKi at the time of data analysis. The most commonly seen toxicities were diarrhoea and rash. Only 1 patient had no documented toxicity from their TKi. 17 patients (29%) had treatment discontinued or interrupted because of toxicity. In 8 of these, treatment was re-introduced at a reduced dose, and 3 patients went back to full dose. Conclusions: Our results confirm that treatment with a TKi is effective for those patients whose tumours harbour EGFR mutations, with a side effect profile consistent with published data.