bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study of lapatinib, a dual-tyrosine kinase inhibitor, and pemetrexed in the second-line treatment of advanced or metastatic non-small cell lung cancer
Authors: Ramlau R. , Thomas M. , Plummer R. , Reck M. , Heussel C. P. , Lau M. , Parikh R. , Kaneko T. , Oliva C. , Novello S. 
Published: August 2020

e19027 Background: Lapatinib is an oral, reversible small-molecule inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). EGFR overexpression is very common in non-small-cell lung cancer (NSCLC), ranging from 30% to 83%, whereas HER2 overexpression occurs in about 20%. Pemetrexed is currently given as second-line therapy and achieves a 9% response rate. The rationale for EGFR/HER2 inhibition in combination with pemetrexed is to demonstrate clinical synergy as previously shown with gemcitabine, another fluoropyrimidine pathway inhibitor. Methods: Eligible patients included those with stage IIIB or IV NSCLC and European Cooperative Oncology Group performance status of 0–2 following 1 previous chemotherapy treatment. Patients were treated in 3 escalating dose levels (DLs) of pemetrexed (given intravenously every 21 days) and daily lapatinib (DL 0: 400 mg/1,250 mg; DL 1: 500 mg/1,250 mg; DL 2: 500 mg/1,500 mg, respectively). A standard phase 1, 3+3 trial design was used. The primary objective was to determine the optimal treatment regimen. Results: Eighteen patients were treated (DL 0: n=4, DL 1: n=8; DL 2: n=6). The most common adverse events (any grade) were diarrhea (61%), rash (44%), fatigue (28%), nausea (28%), anemia (28%), anorexia (22%), vomiting (22%), dyspnea (17%), and neutropenia (17%). Grade 3/4 adverse events were lymphocytopenia (n=5) and neutropenia (n=5). Other related grade 3 events were diarrhea (n=2), nausea (n=1), decreased ejection fraction (n=1), and increased alkaline phosphatase (n=1). The optimal treatment regimen was determined as lapatinib 1250 mg given with 500 mg pemetrexed after occurrence of 3 dose-limiting toxicities during the first cycle in DL 2 (grade 3 diarrhea, grade 4 lymphocytopenia, and grade 3 mucositis). No further dose-limiting toxicities were observed in DL 0 or DL 1. Preliminary evidence of clinical activity was encouraging, with 3 patients showing partial response. Conclusions: The combination of lapatinib with pemetrexed is well tolerated; encouraging activity has been demonstrated in pretreated NSCLC patients and warrants further studies. [Table: see text]
Multidisciplinary management of brain metastases from non-small cell lung cancer: A retrospective study of 251 patients
Authors: Shenglin M. , Yaping X. , Xinmin Y. , Yang Y. 
Published: August 2020

e19030 Background: The detection of brain metastasis(BM) is becoming increasingly common in patients with non-small cell lung cancer (NSCLC). The aim of this study was to evaluate clinical course, prognostic significance, and treatment efficacy in patients with brain metastasis. Methods: The records of all patients with BM from December 2003 to January 2007 were reviewed, and a retrospective study of 251 patients with cytologically and histologically diagnosed NSCLC and brain metastasis detected by cranial computed tomography or magnetic resonance imaging was performed. Variables analyzed included the recursive partitioning analysis (RPA) grouping, weight loss, LDH in blood serum, sex, age, time of brain metastasis (synchronous vs. metachronous), number of brain metastases, maximum diameter of largest brain lesion, Karnofsky performance status, histologic type (adenocarcinoma vs. other types of NSCLC), TNM stage (without consideration of brain involvement), and the treatment modality used for both the primary NSCLC tumor and brain metastasis. Results: The overall 1-, 2- and 3-year survival rates were 34.1%, 13.7% and 8.7% with a median survival time of 9.0 months (95% CI 8.04–9.97 months). On multivariate analysis, RPA grouping, weight loss, LDH in blood serum and treatment were independent prognostic factors. The median overall survival (OS) time of chemotherapy alone, whole brain radiotherapy (WBRT) alone, surgery alone, WBRT with chemotherapy, surgery with chemoradiation, WBRT with Gefitinib and others management was 6.0, 9.0, 12.0, 9.0, 22.0, 13.0 and 4.0 months, respectively, which were significantly different (X2=43.104, P=0.000). The stratify analysis indicated the median OS of patients received concurrent WBRT/chemotherapy (13.0 months) was longer than it of patients received sequential WBRT/chemotherapy (9.0 months) (X2=3.89,P=0.049). Conclusions: The main prognostic factors of BM from NSCLC of pretreatment are RAP grouping, weight loss and LDH in blood serum. The effect of combined treatment of surgery with chemoradiation is favorable and the choice of the patient is important. The survival are prolonged by active multidisciplinary management of brain metastases. [Table: see text]
Hepatocyte growth factor as inducer of gefitinib resistance in non-small cell lung cancer harboring EGFR activating mutations
Authors: Yano S. , Wang W. , Li Q. , Yamada T. , Matsumoto K. , Mitsudomi T. , Yatabe Y. , Hanibuchi M. , Nishioka Y. , Sone S. 
Published: August 2020

e19034 Background: Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-activating mutations (EGFRmu) responds favorably to the EGFR tyrosine kinase inhibitors (EGFR-TKIs), gefitinib or erlotinib. However, 25–30% of patients with EGFRmu show intrinsic resistance, and the responders invariably acquire resistance to EGFR-TKIs. Here, we examined the role of hepatocyte growth factor (HGF), a specific ligand of MET, in gefitinib resistance of NSCLC with EGFRmu. Methods: NSCLC cells, PC-9 and HCC827, with EGFRmu, but not T790M second mutation in EGFR or MET amplification, were used in this study. Sensitivity to gefitinib was determined by MTT assay. Phosphorylation of MET, EGFR, ERBB3, and the PI3K/Akt pathway were examined by Western blotting. HGF expression in 20 tumors from 16 NSCLC patients with EGFRmu who were treated with gefitinib was determined by immunohistochemistry. Results: HGF induced resistance to gefitinib by restoring Akt phosphorylation independently of ErbB3. Specific down-regulation of MET, but not ErbB3, reversed gefitinib resistance and Akt phosphorylation induced by HGF. Importantly, high levels of immunoreactivity for HGF were detected in cancer cells of 3 of 3 intrinsic resistant tumors and in one of 2 tumors with acquired resistance without T790M second mutation or MET amplification. Conclusions: The findings indicate that HGF-mediated MET activation is a novel mechanism of intrinsic and acquired gefitinib-resistance in NSCLC with EGFRmu. Therefore, inhibition of HGF-MET signaling may be considerable strategy for more successful treatment with EGFR-TKIs. [Table: see text]
A phase II study of gemcitabine and vinorelbine combination followed by sequential gefitinib monotherapy in elderly patients with non-small cell lung cancer
Authors: Kasahara K. , Kita T. , Shibata K. , Nishi K. , Ishiura Y. , Araya T. , Tambo Y. , Sakai A. , Kimura H. , Fujimura M. ,   Kanazawa Lung Cancer Study Group
Published: August 2020

e19040 Background: Gemcitabine (GEM) and vinorelbine (VNR) combination have demonstrated activity as a 1st-line treatment in elderly patients with advanced non-small-cell lung cancer (NSCLC). Gefitinib (GEF) is effective as a 2nd-line treatment for NSCLC. We conducted a multicenter phase II trial to evaluate the efficacy and toxicity for treatment of GEM+VNR followed by sequential GEF in elderly patients (pts) with advanced or metastatic NSCLC. Primary endpoint is response rate, secondary endpoints were safety, progression-free survival (PFS), and overall survival (OS). Methods: Eligibility required hitologically or cytologically comfirmed NSCLC, no prior therapy, measurable lesion(s), ECOG PS 0–2, age equal to or over 70 years, and adequate organ functions. Patients were received 3 cycles, each at 4-week intervals, of GEM (1000 mg/m2, d 1, 15) and VNR (25mg/m2 d 1, 15), followed by 250 mg of GEF daily until disease progression or unacceptable toxicity. Results: Between June 2004 and November 2007, 60 pts were enrolled and 2 pts withdrew consent. Fifty-eight pts (35 male and 23 female, median age 77 years) were evaluated. Median number of GEM+VNR administrations was 3 (range 1–3). Median duration of GEF was 101 days (range 9–652 days). Grade 3/4 toxicities included leucopenia (29%), neutoropenia (40%), anemia (12%), febrile neutropenia (9%), and anorexia (9%) during GEM+VNR, anorexia (2%), and constipation (2%) during GEF. Best response rate of GEM+VNR was 17% and that after sequential GEF was 31%. Median PFS and median OS were 4.2 months and 12.6 months, respectively. Response rate, PFS, and OS were significantly favorable in female and never-smoker. Conclusions: Sequential treatment consisted with GEM+VNR and GEF was feasible with acceptable toxicities in elderly patients with NSCLC. [Table: see text]
Treatment and outcomes of elderly versus younger patients with advanced NSCLC at Mayo Clinic Arizona (MCA)
Authors: Paripati H. , Tong W. , Karlin N. J. , Dueck A. C. , Ross H. J. 
Published: August 2020

e19047 Background: Non-small cell lung cancer (NSCLC) is predominantly a disease of the elderly. Most patients (pts) present with incurable advanced disease, but chemotherapy for good performance status (PS) pts improves quality and quantity of life. Despite good PS, many elderly pts with metastatic NSCLC do not receive chemotherapy. This study compared treatment, outcomes, and survival in elderly vs younger pts with stage IV NSCLC. Methods: All analytic MCA Cancer Registry pts with stage IV NSCLC from 1998–2007 were retrospectively reviewed for type of therapy and outcome. Pts were analyzed by age: <75 vs ≥75 years old. Categorical variables were compared using chi-squared tests and survival was compared by Cox regression. Results: 344 pts with stage IV NSCLC were identified. 234 (68%) pts were <75 years old, and 110 pts (32%) were ≥75 years old. Median survival for all pts was 7 months. Among 302 pts with treatment data available, 60.8% of pts <75 years old received some form of systemic therapy (chemotherapy/targeted therapy) compared to only 32% of pts ≥ 75 years old (p <0.0001). Among pts with PS 0–1, pts <75 years old more frequently received systemic therapy than elderly patients (88.5% vs 32.1%, p<0.0001); whereas a difference was not evident in pts with PS 2–4 (34.1% vs 41.7%, p=0.49). Median survival in the <75 age group was 7 months vs. 3.4 months in the ≥75 age group (p=0.048). In the <75 age group, median survival was 12 months in pts who received chemotherapy vs. 2 months in the other or no treatment group (p<0.0001). In the elderly group, median survival was 10 months in the chemotherapy group vs. 2 months in the pts who received other or no treatment (p=0.0003). Thus, the median survival was significantly improved among the pts who received systemic therapy independent of age. Statistical significance persisted when stratifying by PS. Conclusions: Pts with stage IV NSCLC have improved survival with systemic therapy independent of age. Our results confirm that despite an improvement in survival similar to younger pts, elderly patients with metastatic NSCLC are often undertreated. Prospective trials should be designed to include metastatic NSCLC patients without age discrimination No significant financial relationships to disclose.
Frequency of carcinoma not otherwise specified (NOS) as a histologic diagnosis among non-small cell lung cancer (NSCLC) cases between 1989 to 2006: An epidemiologic study from the California Cancer Registry
Authors: Ou S. I. , Zell J. A. 
Published: August 2020

e19049 Background: Recent clinical trials demonstrated differential survival benefit from different chemotherapy regimens according to NSCLC histologies. We investigated the distribution of carcinoma NOS (not otherwise specified) among NSCLC cases in California. Methods: Retrospective population-based analysis of 175,298 NSCLC patients diagnosed histologically or cytologically from the statewide California Cancer Registry from 1989 to 2006. Results: Carcinoma NOS accounted for 22.2% of all NSCLC patients, was most commonly diagnosed cytologically (36.7%) and had the worst 5-year survival estimates (5.8%) and median OS (5 months) compared to other major histologies. The proportion of carcinoma NOS was highest among stage 4 disease and increased significantly from 1989 to 2006 among all patients, both males and females, all 4 major ethnicities (Caucasian, African-American, Hispanic, and Asian), all age- categories, and all AJCC stages. The percentage of the very elderly (80+) increased from 10.8% to 17.1% among all NSCLC patients and they had the highest percentages of carcinoma NOS and cytologically-diagnosed NSCLC among all age categories. Among stage 4 patients, carcinoma NOS patients derived less survival benefit from chemotherapy than adenocarcinoma patients during the most recent period of diagnosis and Cox proportional hazards analysis indicated carcinoma NOS (vs. adenocarcinoma; HR = 1.061, 95% CI: 1.040- 1.083) and cytologically-diagnosed NSCLC (vs. histologically-diagnosed NSCLC, HR = 1.043, 95% CI: 1.024–1.062) were independent unfavorable prognostic factors for OS. Conclusions: Carcinoma NOS was a common histologic diagnosis and was increasing in proportion among NSCLC in California from 1989 to 2006. This may be partially attributed to the increasing number of the very elderly patients and stage 4 patients. No significant financial relationships to disclose.
Evaluation of the accuracy of FDG-/FLT-PET for early prediction of non-progression in patients with advanced non-small cell lung cancer (NSCLC) treated with erlotinib
Authors: Zander T. , Scheffler M. , Nogova L. , Hellmich M. , Stoelben E. , Engel-Riedel W. , Krug B. , Dietlein M. , Neumaier B. , Wolf J. 
Published: August 2020

e19054 Background: EGFR mutations predict response to erlotinib treatment in advanced NSCLC. However, also a subgroup of patients with wildtype EGFR benefits from erlotinib treatment. This subgroup could not yet be defined by molecular means. In this trial we set out to prospectively evaluate the accuracy of [18F]FDG-/[18F]FLT-PET analyses for early prediction of non-progression in chemo-naive patients with advanced NSCLC treated with erlotinib. Methods: Patients with NSCLC stage IIIB/IV without prior systemic treatment for NSCLC were eligible and treated for 6 weeks with erlotinib in this single centre diagnostic pilot trial. Primary endpoint was the accuracy of [18F]FDG/18F[FLT] PET after 1 week of treatment to predict non-progression as defined by RECIST criteria in CT scans after 6 weeks of treatment. Here we present the evaluation of 20 patients of this ongoing trial in accordance with the data monitoring board (EudraCT number 2005–005393–73; NCT00568841 ). Results: Twenty patients were recruited from 9/07 to 9/08. Seventeen patients were eligible for final analysis. The AUC for [18F]FDG PET at week 1 to predict non-progression was 0.857 ±0.105 (p=0.013) and 0.643±0.137 (p=0.32) for [18F]FLT PET. Using [18F]FDG PET specificity was 1 and sensitivity 0.71 for prediction of non- progression after six weeks (p=0.006 Fishers exact). In addition, [18F]FDG PET after 1 week of treatment clearly predicted tumor non- progression after 18 weeks of treatment with a predefined cut-off of -20% change in sSUVmax. (p=0.0004, Fisher´s exact). Finally, using this cut-off value [18F]FDG-PET after one week of treatment, predicted progression free survival (p=0.001, log rank test), with differences in median PFS of 45 days vs 320 days. Using univariable Cox regression, both [18F]FDG and [18F]FLT PET predicted PFS [hazard ratio 2.1 (p=0.006, Wald test) and 2.3 (p=0.011), respectively, per standard deviation]. Conclusions: Our observations indicate that early [18F]FDG but not [18F]FLT PET analysis predicts non-progression after 6 weeks of first-line erlotinib treatment in patients with advanced NSCLC. In addition, early [18F]FDG PET predicts non-progression after 18 weeks of treatment and progression free survival. [Table: see text]
Treatment and outcome of patients with brain metastases from non-small cell lung cancer (NSCLC)
Authors: Ali A. , Goffin J. R. , Arnold A. , Ellis P. M. 
Published: August 2020

e19058 Background: The prognosis of patients with brain metastases from NSCLC is generally poor. However, some reports suggest that the outlook of patients with brain metastases at the time of diagnosis may be similar to that of patients with advanced NSCLC without brain metastases. We undertook a retrospective review of NSCLC patients with brain metastases to examine the outcomes of care for patients with brain metastases from NSCLC. Methods: All new lung cancer patients seen in our institution between July 2005 and June 2007 were assessed for the development of brain metastases. Baseline characteristics, treatment and outcome data were extracted from the chart. The primary outcome of interest was a comparison of survival of patients with brain metastases at diagnosis compared with patients who developed brain metastases later. Results: 91 of 878 (10.4%) new patients seen over the 2 years developed brain metastases. There were 43 men and 48 women. The median age was 64 yrs (sd 10.6yrs). 45 patients had brain metastases at presentation while 46 developed brain metastases later. 34 (37%) had a solitary brain metastasis. 18 (20%) underwent surgical resection. The median overall survival for all patients was 7.8m. Patients with brain metastases at diagnosis had a significantly shorter overall survival than patients who developed brain metastases later (9.8m v 4.3m, p=0.001). Survival following diagnosis of brain metastases was similar for both groups (3.7m v 4.8m, p=0.53). Patients presenting with brain metastases were less likely to be referred to a medical oncologist (51% v 74%, p=0.02) and less likely to receive chemotherapy (18% v 41%, p=0.01). Conclusions: These data suggest that NSCLC patients with brain metastases at diagnosis have a significantly worse outcome than patients who develop brain metastases at a subsequent time point in their illness. Few patients received systemic therapy following diagnosis of brain metastases and further research is needed to determine the utility of chemotherapy in this patient group. No significant financial relationships to disclose.
Cross-talking between bone marrow-derived cells and lung cancer cells
Authors: Zhang J. , Liao M. , Niu X. , Xiang J. , Zhao Y. , Chen H. , Lu S. 
Published: August 2020

e19068 Background: Disseminated cancer cells may initially require local nutrients and growth factors to thrive and survive in bone marrow. However, data on the influence of bone marrow derived cells(BMDC, also called bone stromal cells in some publication) on lung cancer cells is largely unexplored. This study is to explore the effect from bone marrow derived cells on biological behavior of lung cancer cells. Methods: The difference among lung cancer cell lines in their abilities to bone metastasis was tested using SCID animal model. Supernatant of bone marrow aspiration(BM) and condition medium from human bone stromal cells(BSC) were used to study the activity of bone stromal factors. Affymetrix gene chip U133A 2.0 was used to study the gene expression profile of H460 cells, after exposure to secreted proteins from bone stromal cells. Results: In accordance with other literature repors, H460 was found with high bone metastasis potential, while SPC-A1 and A549 cells were low bone metastasis lung cancer cells. We found bone stromal factors significantly increased the proliferation, invasion, adhesion and expression of angiogenosis-related factors, and inhibited the apoptosis for high bone metastasis H460 lung cancer cells. These biologic effects were not seen in SPC-A1 or A549 cells, which are low bone metastasis lung cancer cells. Adhesion of H460 cells to bone stromal cells consistently up-regulated 31 genes. Ontoexpress software showed main function of 31 genes were associated with signal transduction pathways(5 genes), and adhesion molecule(5 genes), including integrin b3 and ADAMTS-1, two potential targets related with bone metastasis. Conclusions: We concluded bone marrow derived cells had a profound effect on biological behavior of lung cancers, therefore favoring the growth of lung cancer cells in bone. No significant financial relationships to disclose.
Gefitinib versus platinum contained doublet chemotherapy in chemotherapy-naive patients with stage IIIb or IV non-small cell lung cancer of adenocarcinoma histology: A retrospective case control study
Authors: Xu Y. , Zhou Y. , Huang M. , Zou B. , Zhang X. , Zhang X. , Zhou L. , Zhu J. , Gong Y. , Hou M. , Lu Y. 
Published: August 2020

e19070 Background: The results of the ISEL study in non-small cell lung cancer (NSCLC) suggest greater benefit of gefitinib among Asian patients and non-smokers compared with the overall trial population. Methods: We conducted a retrospective case-control study to compare outcomes for gefitinib versus platinum doublet chemotherapy as first line treatment in selected NSCLC patients (stage IIIB/IV adenocarcinoma, PS 0–2). Patient receiving platinum chemotherapy were selected on the basis of disease stage (IIIB or IV), gender, smoking history, WHO performance status (PS) (0–1, or 2) and age (< 60ys or ≥ 60ys) being matched to patients receiving gefitinib. Gefitinib and chemotherapy arm patients were selected by 1:2 ratio in order to increase statistical power. The study was approved by local institute review board. Results: 99 chemo-naïve adenocarcinoma patients treated in our institute from January 2006 to December 2007 were collected: 33 received gefitinib and 66 received chemotherapy. The baseline characteristics are listed in table 1 . The median duration of follow-up was 10 months. Patients receiving gefitinib experienced significantly higher ORR and DCR, and prolonged PFS ( table 1 ). Patients receiving chemotherapy experienced more frequent grade 3–4 neutropenia (42.4% vs 0%), thrombocytopenia (21.2% Vs 0%), febrile neutropenia (7.5% vs 0%) and nausea (24.2% vs 3.0%). The most commonly recorded adverse events in the gefitinib arm were rash/acne (9.1%), diarrhea (3.0%), nausea (3.0%) and anemia (3.0%). Conclusions: The limitations of case-control studies are acknowledged, yet these results were supported by IPASS. Gefitinib as first-line treatment confers clinically relevant benefit in Asian NSCLC patients with adenocarcinoma histology versus platinum based chemotherapy. [Table: see text] [Table: see text]