bluuebunny/crossref_metadata_2025_split huggingface dataset:
A randomized phase II trial comparing pulsed erlotinib before or after carboplatin and paclitaxel in patients with stage IIIB or IV non-small cell lung cancer
Authors: Riely G. J. , Rudin C. M. , Kris M. G. , Senturk E. , Azzoli C. G. , Brahmer J. , Fogle M. , Ginsberg M. , Miller V. A. , Rizvi N. A. 
Published: March 2020

7619 Background: A randomized phase 3 trial failed to show any improvement in response rate (RR) or overall survival (OS) when erlotinib was added to carboplatin and paclitaxel (TRIBUTE). However, preclinical data suggested that administration of erlotinib before or after chemotherapy may improve efficacy of chemotherapy [Gumerlock et al ASCO 2003, Solit et al Clin Can Res 2005]. We designed this trial to test the hypothesis that administration of pulsed erlotinib prior to or following chemotherapy would improve the response rate in patients with advanced NSCLC. Methods: All patients had chemotherapy naive, stage IIIB or IV NSCLC and were former or current smokers. All patients received carboplatin (AUC 6) and paclitaxel (200 mg/m2). Patients were randomly assigned to one of three arms: erlotinib 150 mg days 1,2, and chemotherapy on day 3; erlotinib 1500 mg days 1, 2 and chemotherapy on day 3; or chemotherapy on day 1 and erlotinib 1500 mg on days 2,3. Patients received up to six 21-day cycles of treatment. The primary endpoint was overall RR (CR+PR) using RECIST. We planned to enroll 29 patients to each arm in a “pick the winner” design comparing arms to the chemotherapy alone arm of TRIBUTE (RR 19%) with a desirable RR of 50%. Results: Eighty-seven patients were randomized to 3 arms. Accrual is complete. The most common grade 3/4 toxicities were neutropenia (39%), fatigue (15%), and anemia (12%). Grade 3/4 rash or diarrhea were uncommon. Conclusions: Treatment with erlotinib before (150 mg on days 1 and 2 or 1500 mg on days 1 and 2) or after (1500 mg on days 2 and 3) administration of carboplatin and paclitaxel failed to improve response rates compared to TRIBUTE. The benefit of pulsatile administration of erlotinib predicted by preclinical models was not evident in this clinical trial. Supported by Genentech, Inc. [Table: see text] [Table: see text]
Distinctive characteristics of non-small cell lung cancer in the young: A SEER analysis of patients under 40 years old
Authors: Goodgame B. , Vlahiotis A. , Piccirillo J. , Baggstrom M. , Govindan R. 
Published: March 2020

7621 Background: Non-small cell lung cancer (NSCLC) is diagnosed at a median age of 65 and is rare in younger people. The presentation and natural history of the disease in younger patients (age < 40) may not be the same as in typical, or older patients (age > 40). Methods: We identified in the SEER (Suveillance Epidemiology and End Results) registry, all patients diagnosed with NSCLC from 1990 to 2005. Patients were grouped by age at diagnosis, < 40 or = 40. Data on gender, cell type, extent of disease, overall survival, and cause of death were obtained from the SEER database. Cancer-specific survival was defined as time to death from cancer, in which case deaths from other causes are counted as censoring events. Results: In the SEER registry, 3,421 patients with NSCLC diagnosed at an age < 40 were identified, along with 323,566 patients age > 40. Younger patients were more likely to be women, 48% vs 43% (p < 0.0001), and more likely to present with distant disease 53% vs 49% (p < 0.0001). Adenocarcinoma and other, or non-specified types of NSCLC were more common in younger patients, 38% and 44% respectively, vs. 35% and 32% in the older patients. Squamous cell carcinoma was far less common in younger patients, 8.5% vs 23.5% in older patients (p<0.0001 for all comparisons). Overall and cancer specific survivals were higher for the younger cohort within each stage group. For example, 3 year overall survival for patients with distant (metastatic) disease was 8.8% in the younger patients and 4.7% in the older patients. For local disease, 5 year cancer specific suvivals were 92% in the younger patients and 62% in the older patients. Conclusions: Patients with NSCLC who are < 40 years old at diagnosis are more likely to be women and have adenocarcinoma and far less likely to have squamous cell carcinoma. Overall and cancer-specific survivals are better in these younger patients. No significant financial relationships to disclose.
Gene predictors for extrathoracic metastases (EM) in advanced bronchioloalveolar carcinoma (BAC) of the lung obtained from formalin-fixed, paraffin-embedded tissue (FFPE)
Authors: Weiss G. J. , Franklin W. A. , Zeng C. , Tran Z. V. , Coldren C. D. , Magree L. , Sugita M. , Bunn P. A. , Kelly K. 
Published: March 2020

7622 Background: Advanced BAC is typically a more indolent tumor confined to the lungs, thus raising the question of the role for bilateral lung transplantation (BLT). In a small series, BLT produced a 5-year survival rate of 50%. Determining biological predictors of EM could identify the most ideal candidates for curative BLT. Methods: We retrospectively reviewed patient records from 1/1/98–10/1/06. RNA was extracted from FFPE tissue. RNA was amplified using Arcturus kits and profiled by Affymetrix X3P chips, which contain 47,000 transcripts and 61,000 probe sets. Chi-square and t-tests were used to compare clinical characteristics. Log-rank and Cox hazards modeling were used to determine clinical factors that predict either overall survival or time to EM. Logistic regression modeling was used to examine clinical factors predicting rate of EM. Hybridization signals and detection calls were generated in BioConductor, using gcrma and affy tools, and normalized to benign tissue. Univariate analysis was performed to identify genes of interest. Results: Patients with advanced BAC/adenocarcinoma with BAC features at diagnosis, (TanyNanyM1 [lung only]; n=20), and matched cohort of locally-advanced adenocarcinoma (TanyN2–3M0) and pure adenocarinoma with pulmonary metastases only, (TanyNanyM1 [lung only]), were identified (n=45). There was no significant difference for age, gender, smoking history, survival, or EM between the 2 groups. Arrays have been performed on 12 samples (4 BAC, 5 lung adenocarcinoma, 2 benign lung, and 1 benign lymph node). Preliminary analysis shows 27 genes were significantly up- and down-regulated vs. benign tissue (p<0.01). Seven of these genes were highly altered and may differentiate risk for EM. Conclusions: Gene expression profiling may discern risk for EM not readily apparent from clinical characteristics and could serve to identify advanced BAC patients with low risk for EM that may benefit from BLT. Gene profiling of 12 additional tumor samples is ongoing and results will be updated. We plan future validation of candidate genes in collaboration with cooperative groups or other multi-center sites. Supported by a grant from Cancer League of Colorado. No significant financial relationships to disclose.
New perspectives on metastatic patterns in lung cancer: The M. D. Anderson thoracic medical oncology database
Authors: Oh Y. , Lee J. J. , Hanneken J. M. , Liu S. , Camarillo M. C. , Taylor S. H. , Lippman S. M. , Hong W. K. , Stewart D. J. , Karp D. D. 
Published: March 2020

7630 Background: We previously reported a retrospective study suggesting that sites of metastatic disease characterize distinct prognostic groups with non-small cell lung cancer (NSCLC) (ASCO 2005 Abstract No: 7197). To confirm these observations, we prospectively evaluated pts with newly diagnosed NSCLC to correlate extent of disease with survival. Methods: We developed a prospective comprehensive database of 2,487 pts registered in the Thoracic Medical Oncology Department from 9/1/2004 - 8/31/2006, with up to 845 days follow-up. 694 were untreated stage IV NSCLC pts with data for ECOG performance status (PS), TNM staging, histology, identification of all metastatic sites, and survival. Results: Bone was the most common metastatic site, affecting 280 pts, 114 having bone only metastases (280/114). Similarly, the following results were found for lung (261/137), brain (143/46), adrenal (112/36), and liver (98/31). PS = 0 (101), PS = 1 (329), PS = 2 (103), PS = 3 (74), PS = 4 (10), PS = unknown (77). As of January 2007, median survival for the group was 8 months. By the Cox regression model, statistically significant effects on overall survival were seen for gender, smoking status, age, performance status, and number of metastases. The following hazard ratios [with 95% CI] of death were seen for males vs. females 1.41 ([1.13, 1.75], p = 0.0025), former smokers vs. non-smokers 1.66 ([1.18, 2.31], p = 0.0032), active smokers vs. non-smokers 1.79 ([1.21, 2.64], p = 0.0036), for one year increase in age 1.02 ([1.00, 1.03], p = 0.0046), for one unit increase in performance status 1.63 ([1.45, 1.82], p < 0.0001) and for one unit increase in number of metastases 1.48 ([1.32, 1.66], p < 0.0001). Pts with one metastatic site had superior survival over pts with more sites. Six of 10 metastatic sites were found to have significant independent effects on overall survival, based on log-rank test. Conclusions: Number and sites of metastases were strong independent determinants of survival in NSCLC. Furthermore, our work suggests marked heterogeneity of metastatic patterns at presentation. Pts with fewer metastatic sites demonstrate better survival. Future targeted therapy protocols should stratify according to metastatic sites to better analyze patterns of failure and outcomes. No significant financial relationships to disclose.
A double blind phase II study of BIBF 1,120 in patients suffering from relapsed advanced non-small cell lung cancer (NSCLC)
Authors: Von Pawel J. , Kaiser R. , Eschbach C. , Stefanic M. , Love J. , Gatzemeier U. , Reck M. 
Published: March 2020

7635 Background: Vascular endothelial-(VEGF), platelet derived- (PDGF), and fibroblast growth factor (FGF) with their receptors compose critical cellular pathways controlling angiogenesis. BIBF 1120 is an oral potent triple angiokinase inhibitor targeting VEGFR, PDGFR, FGFR kinases. Methods: In this double blind multi-center trial, patients with an ECOG score of 0–2 with locally advanced or metastatic (stage IIIB/IV) relapsed NSCLC after failure of first or second line chemotherapy were randomly assigned to daily treatment with 2x250 mg or 2x150 mg of BIBF 1,120 until progression. In the event of dose limiting toxicity, a single dose reduction to open label treatment with 2x150 or 2x100 mg of BIBF 1,120 was allowed. Patients with stable brain metastases or squamous cell carcinoma were not excluded. Primary endpoints were progression free survival (PFS) and objective tumor response (RECIST, determined every 6 weeks). Results: Seventy three of 74 patients enrolled received BIBF 1120 (61% males, median age: 64 years, range 36–80). The most common histology was adenocarcinoma (55%), followed by squamous cell carcinoma (23%). The median PFS of all patients (n= 73) was 1.6 months without significant difference between both treatment arms. The stable disease rate was 48% without objective tumour responses. However, patients with an ECOG performance status of 0 or 1 (n= 57) had a median PFS of 2.9 months and a three- and 5 months PFS rate of 46% and 31%, without any difference between both treatment arms. The stable disease rate was 59%. Patients treated with 2x250 mg per day had more dose limiting CTCAE Grade 3 and 4 toxicities compared with patients treated with 2x150 mg (27% versus 2.8%, p=0.006, two-sided Fisher-test). The most frequent adverse events irrespective of relatedness observed in 73 patients were of CTCAE Grade 1 or 2 and included nausea (41%), diarrhoea (41%), vomiting (33%), fatigue (29%) and abdominal pain (22%). Grade 3 and 4 toxicities included nausea (8%), diarrhoea (7%), vomiting (4%), abdominal pain (4%) and AST and/or ALT elevations (5.4%). Conclusions: BIBF 1120 is safe and well tolerated and showed promising efficacy data in ECOG 0–1 patients. A high disease control rate of 59% could be observed. [Table: see text]
Single-agent compared to combination first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) and a performance status (PS) of 2
Authors: Bonomi P. , Villaflor V. M. , Oldham F. B. , Sandilac L. , Singer J. W. 
Published: March 2020

7637 Background: Impaired performance status in NSCLC is associated with poor prognosis and reduced tolerance for treatment- related toxicities. Current treatment guidelines agree that PS 2 patients with advanced NSCLC benefit from systemic chemotherapy; however, no consensus exists on specific treatment recommendations; i.e., single-agent vs. combination chemotherapy. Methods: Two recent phase III randomized trials in advanced NSCLC (STELLAR 3 and 4) enrolled exclusively PS 2 patients and compared experimental treatment to either standard combination chemotherapy (paclitaxel/carboplatin; P/C), or single agent chemotherapy (vinorelbine or gemcitabine; V or G). An exploratory comparison of the control arms was performed to determine the degree of benefit and amount of added toxicity associated with standard combination vs. single agent chemotherapy. Results: Combination chemotherapy resulted in improved time to progression compared to single agent ( Table ). However, no statistical difference between treatment arms was noted for overall survival and 1-yr survival. Adverse events are listed in the table . Overall, the frequency of serious adverse events was 40% in the combination-arm and 35% in the single agent-arm. When only considering drug-related toxicities, the frequency of serious adverse events was 21% in the combination-arm and 5% in the single agent-arm. Conclusions: PS 2 patients receiving single agent chemotherapy have a similar outcome compared to those receiving combination chemotherapy; serious treatment related toxicities are less frequent with single agent therapy. Based on the currently available evidence, the use of single-agent therapy seems reasonable in PS 2 patients. [Table: see text] [Table: see text]
Phase II study of cetuximab in combination with carboplatin and docetaxel for patients with advanced/metastatic non-small cell lung cancer (NSCLC)
Authors: Belani C. P. , Ramalingam S. , Schreeder M. , Steis R. , Guidice R. , Marshland T. , Butler B. 
Published: March 2020

7643 Background: Cetuximab, a chimeric IgG1 monoclonal antibody against the external domain of the epidermal growth factor receptor (EGFR), has demonstrated single-agent activity against NSCLC. When administered in combination with carboplatin and docetaxel, a commonly used regimen for advanced NSCLC, cetuximab exhibits synergistic interaction in preclinical studies. Therefore, we conducted a phase II study to evaluate the efficacy of the combination of cetuximab, carboplatin, and docetaxel for the treatment of advanced NSCLC. Methods: Chemotherapy-naive patients = 18 years with histologically/cytologically confirmed stage IIIB (w/ effusion) or stage IV NSCLC received cetuximab (400 mg/m2 on day 1 and 250 mg/m2 on days 8 and 15) plus docetaxel (75 mg/m2 on day 1) and carboplatin (AUC=6 on day 1) every 21 days for up to 6 cycles. Thereafter, patients without evidence of disease progression (CR/PR/SD) were continued on single-agent cetuximab (250 mg/m2/week) for a maximum of 1 year or until disease progression. The primary endpoint was response rate. Results: 81 patients were enrolled and 76 are evaluable for response. Patient characteristics included: gender male/female, 43/38; median age 63 years (range 42–83); ECOG performance status 0/1/, 31/50; and stage IIIB/IV- 5/76. The median number of cycles administered was 4 (range 1–6). The response rate (CR/PR) was 14.5% (95% CI, 7.5 to 24.4), with a median progression-free survival of 4.7 months and a median overall survival of 11 months. With combination therapy, the salient grade 3/4 events were neutropenia (28%), febrile neutropenia (3.8%), hypotension (4%), hypokalemia and hypomagnesemia (5%), hypersensitivity (1%), acne-like rash (3%), peripheral neuropathy (1%), and myalgia (1%). Twenty-five patients received maintenance therapy with single-agent cetuximab (median duration of treatment was 12 weeks) and this was well tolerated. Conclusions: This large multicenter phase II study of the novel combination of cetuximab with docetaxel and carboplatin shows promising efficacy for patients with advanced and metastatic NSCLC and has an acceptable toxicity profile. No significant financial relationships to disclose.
Population characteristics and prognostic factors in metastatic non-small cell lung cancer (NSCLC): The Fox Chase Cancer Center (FCCC) experience
Authors: Paralkar V. , Li T. , Langer C. J. 
Published: March 2020

7644 Background: With increasing use of MRI and PET to stage NSCLC, the demographics, performance status and distribution of metastases at diagnosis in this patient (pt) population are changing; it is important to reassess the prognostic roles played by baseline clinical variables in the modern therapeutic era. Methods: We retrospectively evaluated the charts of 189 consecutive, unselected pts with stage IV NSCLC seen and followed at the Fox Chase Cancer Center between Oct 2000 and Aug 2003. Data on a variety of pt variables including demographics, histology, metastases, key laboratory tests and treatment were compiled. We intended to identify those that played statistically significant prognostic roles. Results: Median age at diagnosis was 62 years; 77% of pts had PS 0–1 at first presentation. 58% had single organ metastasis; 35% had metastases to the brain (half of these had brain only and a third had solitary brain metastasis). 51% of all pts received palliative radiation to the brain at some point after dx. Overall median survival was 10.8 months. The 1-yr, 2-yr, 3-yr and 4-yr overall survival rates were 44.2%, 21.9%, 11.6% and 7.8% respectively. On multivariate analysis, statistically significant negative prognostic factors included PS ≥ 2 (HR: 1.9, 95% CI: 1.1–3.3), serum albumin ≤ 3 (HR: 1.7, 95% CI: 1.1–2.8) and metastases to > 1 organ (HR: 1.6, 95% CI: 1.03–2.3). Bone and liver metastases, though associated with worse survival in univariate analysis, were not found to be independent predictors of survival. Gender had no bearing on outcome. Conclusions: Survival rates in this advanced NSCLC cohort equal or exceed contemporaneous ECOG figures. PS, serum albumin and number of organs with metastases are independent prognostic factors in NSCLC. The increasing detection of brain metastases at 1st presentation of metastatic NSCLC suggests that the role of prophylactic cranial irradiation in the management of early NSCLC should be explored. No significant financial relationships to disclose. [Table: see text]
Global histone modifications predict prognosis of resected non-small cell lung cancer patients
Authors: Barlesi F. , Giaccone G. , Gallegos-Ruiz M. I. , Loundou A. , Span S. W. , Lefesvre P. , Kruyt F. A. , Rodriguez J. 
Published: March 2020

7662 Background: Epigenetic modifications, such as methylation and/or acetylation of histones, may contribute to the development and progression of cancer. We investigated whether histone modifications influence prognosis of non-small cell lung cancer (NSCLC). Methods: We used immunohistochemistry to assess histone 3 lysine 4 dimethylation (H3K4diMe), and acetylation of histone 2A lysine 5 (H2AK5Ac), histone 2B lysine 12 (H2BK12Ac), histone 3 lysine 9 (H3K9Ac), and histone 4 lysine 8 (H4K8Ac), in resected tumor samples of 138 NSCLC patients. In addition, the genotype of a tandem repeat polymorphism in the histone 3 methyltransferase SMYD3 gene was determined using PCR and capillary electrophoresis. Data were analyzed using a recursive partitioning analysis (RPA). Results: The overall median expression of H3K4diMe, H2AK5Ac, H2BK12Ac, H3K9Ac, and H4K8Ac were 75, 10, 0, 25, and 80%, respectively. The RPA classified the patients into seven distinct prognostic groups based on TNM stage (first node), histology (second node) and histone modifications (third node). H3K4diMe (< or =85% tumor cells), H3K9Ac (< or =68% tumor cells) and H2AKAc (< or =5% tumor cells) were retained by RPA. The SMYD3 genotype was not retained by RPA. The seven groups were associated with significantly different disease- free (p<0.0001) and overall survival (p<0.0001). Interestingly, the four groups determined by stage I patients (below the first node) displayed dramatic differences in survival (median from 10 months in adenocarcinoma, H3K9Ac=68%, to 147 months in non-adenocarcinoma, H3K4diMe=85%). Conclusions: The prognostic influence of global histone modifications is greater in early stage NSCLC and it may help in the selection of early stage NSCLC patients for adjuvant treatment and provides a rationale for the use of combination of standard chemotherapy with drugs interacting with histone modifications such as histone deacetylases (HDAC) inhibitors. No significant financial relationships to disclose.
Novel mutations and mutation pattern of epidermal growth factor receptor (EGFR) gene in Chinese patients with primary lung adenocarcinoma
Authors: Mok T. , Lui P. , Lam K. C. , Yim A. , Wan I. , Lee S. , Hsin M. , Leung L. , To K. 
Published: March 2020

7667 Background: EGFR mutation is a diverse and complex phenomenon. Shigematsu et al (JNCI 97:339,2005), analyzing NSCLC samples from multiple ethnicities and histologic cell types, reported 11 types of in-frame deletions in exon 19 (46%), 9 missense mutation in exons 18, 20, 21 (45%) and 8 in-frame insertion in exons 20 (9%). 3/130 tumors (2.3%) had multiple mutations. Here we report the incidence, mutation pattern and novel finding of EGFR mutation in a homogenous ethnic group with adenocarcinoma of lung. Methods: Between 2004 and 2006 we isolated genomic DNA from 194 (archival 53, prospective 141) primary lung adenocarinoma for PCR amplification of EGFR exon 18–21. We isolated tumor cell by micro-dissection. PCR products were purified and sequenced using the BigDye Terminator Cycly Sequencing Ready Reaction Kit (Applied Biosystem) and run on Applied Biosystem 3100 Genetic Analyzer. Results: We found 79 EGFR mutations in 73 tumors (37.6%). Six (8.2%) had double mutations. IN-FRAME DEL: 10 types in exon 19 (39 cases, 49.4%); 1 type in exon 18 (1 case). MISSENSE MUTATION: 2 types in exon 18 (2 cases); 4 types in exon 20 (5 cases) and 2 types in exon 21 (29 cases, 36.7%) IN-FRAME INSERTION: 3 types in exon 20 (3 cases). Typical exon 19 E746-A750del and exon 21 L858R mutations accounted for 31% and 34%, respectively. We found 11 types of mutations not previously described.( Table ) Four pts with novel mutations received EGFR TKI and 3 attained PR (all with exon 19 del). Two pts have T790M mutations without prior exposure to EGFR TKI and both with double mutations. Conclusion: Mutation pattern of EGFR gene in Chinese pts with adenocarcinoma is similar to the Shigematsu report. The overall incidence of EGFR mutation and multiple mutations are higher but in-frame insertion in exon 20 is less common. Majority of the novel mutations are rare mutations involving exon 18 and 20. No significant financial relationships to disclose. [Table: see text]