bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of publicly-sponsored lung cancer trials in US: Are experimental treatments better than the control ones?
Authors: Soares H. P. , Djulbegovic B. , Kumar A. , Tanvetyanon T. , Bepler G. 
Published: March 2020

7157 Background: Lung cancer is one of the leading causes of cancer deaths in the US. A considerable number of these patients are treated in randomized clinical trials (RCTs). However, how often experimental lung treatments are superior to control treatments is not known. To accurately assess this, three factors have to be taken into consideration: publication rate, methodological quality of trials and the choice of the comparator intervention. Methods: All phase 3 RCTs that were completed to date by 3 National Cancer Institute cooperative groups (ECOG, NCCTG and RTOG) were eligible for the analysis. We identified 50 RCTs enrolling 11,631 lung cancer patients. The methodological quality of the trials was assessed for possible effects of bias and random error on the outcomes of the trials. The possible impact of the choice of a comparator intervention was also assessed. To evaluate the outcomes, we extracted data on survival (OS), disease free survival (DFS), response rate (RR) and treatment-related mortality (TRM). In addition, the final investigators’ preference about experimental or control interventions was used to assess whether experimental treatments were better than controls. Results: In terms of OS, DFS and RR experimental treatments were as likely as control treatments to be successful—Hazard ratio [HR]= 0.96 (99%CI 0.92–1.01)], [HR = 0.98 (99%CI 0.98–1.17)] and [RR = 1.11 (99%CI 0.84–1.46)], respectively. TRM was worse with experimental treatments [HR = 1.61 (99% CI 1.10–2.36)]. Investigators’ preferences for experimental vs. control treatments were 30% and 70%, respectively (p < 0.001). The quality of trials was high. We did not find any evidence that the methodological quality of trials/choice of comparator influenced the results. Conclusions: We found that there is no clear pattern that predicts which treatment will be better. In aggregate, there is about an equal chance for experimental and standard treatments to result in successful outcomes or that the outcomes may not differ between two types of the treatments, although TRM is slightly higher with experimental arms. This is a welcome finding because if one intervention (experimental or control) was consistently better, maintaining randomization will be difficult. No significant financial relationships to disclose.
Clinical benefit of erlotinib in male smokers with squamous-cell NSCLC
Authors: Clark G. M. , Cameron T. , Das Gupta A. 
Published: March 2020

7166 Background: Previous NSCLC trials have suggested female non-smokers with adenocarcinoma are most likely to benefit from treatment with EGFR inhibitors such as erlotinib. Thus, male smokers with squamous-cell carcinoma might be expected to fail treatment with erlotinib monotherapy. Methods: In a double-blind, placebo-controlled study of 731 patients with incurable stage IIIB/IV NSCLC who had failed 1 or 2 prior chemotherapy regimens, patients were randomized in a 2:1 ratio to receive either erlotinib 150 mg or placebo (Shepherd et al NEJM 2005; 353(2):123–132). For a subset of male patients with squamous-cell carcinoma and a history of smoking, median survival was estimated from Kaplan-Meier survival curves. The hazard ratio (HR) for death and corresponding 95% confidence interval (CI) were calculated from a univariate Cox model and statistical significance was described by a log-rank statistic. Results: In the ITT population the adjusted HR for death between the erlotinib and placebo arms was 0.73 (P < 0.001). Among male smokers with squamous-cell carcinoma, overall survival was significantly improved among patients receiving erlotinib (N = 100) compared with patients with similar attributes in the placebo arm (N = 57): HR = 0.66, 95% CI 0.47 to 0.92, P = 0.016. This difference resulted in median survival time of 5.5 months in the erlotinib arm compared with 3.4 months in the placebo arm. Conclusions: Although male smokers with squamous-cell carcinoma have not been considered ideal candidates for treatment with erlotinib, survival benefits were observed in this subset of patients. [Table: see text]
Targeted COX-2 and EGFR TK inhibition in advanced non-small cell lung cancer
Authors: Reckamp K. L. , Czernin J. , Weber W. A. , Dubinett S. M. , Figlin R. A. 
Published: March 2020

7179 Background: Prostaglandin E2 (PGE2) activates Erk/MAPK signaling pathway in an epidermal growth factor receptor (EGFR) tyrosine kinase (TK)-resistant manner as a result of cyclooxygenase-2 (COX-2) overexpressed in lung cancer. Because 10% of patients respond to this class of drugs, evaluating agents that may overcome resistance and determining the population of patients most likely to respond is crucial. Imaging tumor metabolism by positron emission tomography with the glucose analog fluorodeoxyglucose (FDG-PET) is an innovative approach for assessing the efficacy of targeted agents. We studied the combination of COX-2 inhibition (celecoxib) and EGFR inhibition (erlotinib) in a phase I trial in advanced non-small cell lung cancer (NSCLC) and added FDG-PET imaging as a potential method for evaluation of early response. Methods: A phase I, dose escalation trial to investigate the optimal biologic dose (OBD) of the combination of celecoxib and erlotinib in pts with refractory stage IIIB/IV NSCLC. FDG-PET was evaluated in selected patients at baseline, week 2 and week 8 of study treatment. Tumor metabolic activity was quantitatively assessed by standardized uptake values (SUV). Changes in SUV were compared to CT imaging at week 8 with response defined by RECIST criteria. Results: Twenty-two subjects were enrolled and 21 were evaluable for the determination of the OBD, toxicity assessment and response. Rash and skin-related effects were the most commonly reported toxicities. Seven patients demonstrated partial responses and five patients developed stable disease. Responses were seen in patients both with and without EGFR activating mutations. The duration of partial response was 24–93 wks. TTP was 83 weeks in one patient with stable disease. A patient evaluated by FDG-PET had a significant decrease in SUV (-45%) at week 2 which corresponded to partial responses by RECIST at week 8. Conclusions: FDG-PET as a measure of tumor glucose utilization appears to be a promising tool for assessing early response to targeted therapies. A randomized Phase II trial is planned comparing erlotinib and celecoxib with erlotinib plus placebo in advanced NSCLC, and evaluating FDG-PET response as a marker of early efficacy. Supported by UCLA Lung Cancer SPORE NCI P50 CA 90388, GLAVAHS CDA and STOP Cancer Award. [Table: see text]
Routine detection of EGFR mutations in patients with NSCLC: A comparative study of three alternative methods in 105 patients
Authors: Zalcman G. , Richard N. , Hardouin A. , Gervais R. , Antoine M. , Mittre H. , Baumann J. J. , Galateau-Salle F. , Cadranel J. , Kottler M. 
Published: March 2020

7184 Background: The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) has been reported in lung adenocarcinoma patients with tumoral EGFR mutations. Those mutations were found mainly by direct genomic sequencing on snap-frozen surgical specimens. Conversely, TKIs are used in metastatic patients who do not undergo tumor resection. In these patients, there is a need for routine sensitive molecular procedures, to overcome the small size of non-surgical bronchoscopy paraffin-embedded biopsy samples. Methods: Patients were selected on clinical and pathological characteristics: never (n = 43) or former smokers, patients with non-squamous NSCLC (n = 105) or patients with bronchioloalveolar adenocarcinoma (n = 34). Direct genomic sequencing assay was performed as reported elsewhere. Denaturing, high-performance, liquid chromatography (DHPLC) assay was performed with EGFR-specific primers that amplify exons 18, 19, and 21. A multiplex, allele-specific, oligonucleotide PCR (MASO-PCR) assay was carried out with a set of primers that identify the 14 most frequent molecular events described for the EGFR gene, which covers 90% of EGFR gain-of-function mutations described to date. Results: 123 samples were screened from 105 non-squamous NSCLC patients (female/male ratio = 0.84). Non-surgical biopsy specimens were available in 38 patients. EGFR mutations were detected by at least two of three procedures in 18/105 patients (17%). In paraffin-embedded specimens with low tumor content, EGFR heterozygous mutations were found either by MASO-PCR alone (n = 2, confirmed in the matched surgical sample by another procedure), or both by MASO-PCR and DHPLC (n = 16); they were missed by nucleotidic sequencing in 6 samples. 18 patients received TKI. 6 dramatic responses were achieved in patients with EGFR mutation, while no mutation could be found in non-responsive patients. Overall disease control was obtained in 8/18 patients (44%). Conclusions: MASO-PCR and DHPLC appear more sensitive than direct sequencing in non-surgical paraffin-embedded biopsies, which represent the bulk of samples in lung cancer patients. We propose that the cost-effective MASO-PCR be used for routine screening of EGFR mutations in NSCLC patients. No significant financial relationships to disclose.
Phase II open-label study to investigate efficacy and safety of PTK787/ZK 222584 orally administered once daily at 1,250 mg as second-line monotherapy in patients (pts) with stage IIIB or stage IV non-small cell lung cancer (NSCLC)
Authors: Gauler T. C. , Fischer B. , Soria J. , Gounant V. , Griesinger F. , Krissel H. , Laurent D. , Eberhardt W. E. 
Published: March 2020

7195 Background: Overexpression of vascular endothelial growth factor receptor (VEGF-R 1–3) in NSCLC is associated with poor prognosis and shorter overall survival. PTK787/ZK 222584 (PTK/ZK), a novel, oral, anti-angiogenic compound blocks tyrosine kinase signaling from all VEGF receptors. Methods: A prospective, single-arm, multi-center, proof-of-principle phase-II study to investigate both efficacy and safety of PTK/ ZK in patients with stage IIIB/IV NSCLC who received prior first line treatment with a platinum based chemotherapy regimen. All pts were relapsed/refractory as determined by available imaging. All pts were planned to receive 1,250 mg of PTK/ZK once daily (qd) for continuous treatment until disease progression or unacceptable toxicities. Response evaluation is based on RECIST criteria. Disease stabilization of at least 12 weeks based on CT/MRI-imaging was defined as clinically relevant drug activity. All pts had dynamic contrast enhanced MRI investigations for additional efficacy analysis and serum asservations for serum proteomic analysis. Results: To date, 56 pts have been enrolled. PTK/ZK is generally well tolerated. Most frequent adverse events (AEs) are nausea and vomiting. One pt developed interstitial lung disease (ILD) and in one pt with tracheal stent a fatal lung bleeding occurred. No other unexpected serious AEs have been reported. Maximum response for 48 evaluated pts include one pt with a partial response (PR) (2%), 27 pts with stable disease (SD) (56%), (disease control rate 58%), and 20 pts with progressive disease (PD) (42%). The pt with PR has responded for over 20 weeks. 15 pts have SD for at least 12 weeks; 5 pts of these had SD for at least 28 weeks. Conclusions: These preliminary results suggest that second-line treatment with single-agent PTK/ZK is generally safe and well tolerated. In pts with refractory disease in stage IIIB/IV NSCLC, a considerably high rate of disease control could be achieved in this study. The study is currently recruiting for twice daily (bid) treatment. [Table: see text]
C/EBPα expression by immunohistochemistry lacks prognostic or predictive significance in primary resected non-small cell lung cancer
Authors: Costa D. B. , Stephenson P. , Kocher O. , Tenen D. G. , Feins R. H. , Keller S. M. , Schiller J. H. , Johnson D. H. , Halmos B. 
Published: March 2020

7202 Background: The transcription factor CCAAT/enhancer binding protein alpha (C/EBPα) is down-regulated in a majority of lung cancers. We sought to determine if C/EBPα could be a prognostic or predictive factor in non-small-cell lung cancer (NSCLC). Methods: Our cohort originated from ECOG 3590/4592 (randomized trial of postoperative adjuvant therapy with thoracic radiation or cisplatin and etoposide plus thoracic radiation in patients with completely resected stages II and IIIA NSCLC; and its laboratorial study). 166 tumor samples contained material for immunohistochemical (IHC) analysis of C/EBPα expression. We used a scoring system comparing tumor staining to that of basal bronchial cells (3+). 0 or 1+ (weak) staining suggested lack of, while 2 or 3+ (strong) suggested C/EBPα expression. Our primary outcomes were differences in progression-free and overall survival between the groups with weak or strong staining. Results: Among the 166 patients analyzed for C/EBPα IHC, the median progression free and overall survival were 30.7 and 40.3 months, respectively; which do not differ from the complete E4592 cohort. 92 patient samples (55%) had 0 or 1+ staining, and the remaining 74 (45%) 2 or 3+. The median progression free survival for patients with weak and strong C/EBPα IHC expression was 31.5 and 30.2 months, respectively (p = 0.84). The median overall survival between the weak and strong groups was 47.5 and 38.3 months, respectively (p = 0.54). 10 years after enrollment, 27% (25/92) of patients were alive in the weak, and 24% (18/74) in the strong C/EBPα IHC group. No difference between our primary outcomes by C/EBPα expression was identified. There was no difference in outcome by treatment arm, tumor histology, stage, or patient’s characteristics. There was a trend towards loss of C/EBPα and less differentiated tumor samples (p = 0.07). Conclusions: C/EBPα is a novel tumor suppressor gene in lung cancer with loss of expression in over 50% of NSCLC. However, our data demonstrate that in a subset of patients with resected NSCLC, C/EBPα IHC status is neither a prognostic nor a predictive marker. Further studies are needed to establish the molecular mechanisms of C/EBPα inactivation in lung cancer and its possible role as a new therapeutic target. No significant financial relationships to disclose.
Long-term survival differences for bronchioloalveolar carcinoma (BAC) patients with ipsilateral intrapulmonary metastasis at diagnosis
Authors: Zell J. A. , Ou S. I. , Ziogas A. , Anton-Culver H. 
Published: March 2020

7207 Background: It has been suggested that survival for BAC patients with stage IIIB disease due to multiple lesions in the same lobe is improved over other stage IIIB patients, and that patients with multicentric BAC have improved survival over BAC patients with distant metastasis. To determine the prognostic implications of these various subsets of advanced stage BAC patients, we compared survival rates using a large population-based cohort. Methods: A case-only analysis of data from the U.S. SEER database during 1998–2002 was conducted. The primary outcome measured was overall survival (OS). OS and lung cancer-specific survival (LCSS) univariate analyses were conducted using the Kaplan-Meier method; multivariate survival analyses were performed using Cox proportional hazards ratios. Results: 2653 incident cases of BAC were analyzed with a 5-year follow-up duration, including 831 patients with advanced (i.e. stage IIIB or IV) BAC. Patients with stage IIIB BAC due to multiple lesions in the same lobe (n = 96) had significantly improved median OS (46 months) and LCSS (not reached at >58 months) compared to other stage IIIB BAC patients on univariate analysis (n = 133; OS = 8 months, LCSS = 9 months) (P < 0.0001). Stage IV BAC patients with intrapulmonary metastasis (n = 320) had significantly improved median OS (13 months) and LCSS (15 months) compared to those with stage IV BAC due to distant spread on univariate analysis (n = 282; OS = 7 months, LCSS = 7 months) (P < 0.0001). These observed survival differences remained after adjustment for age, gender, ethnicity, and surgical treatment status (Table). Conclusions: Patients with stage IIIB BAC due to tumors in the same lobe have significantly better outcomes than other stage IIIB BAC patients. Stage IV BAC patients due to intrapulmonary spread have significantly improved outcomes over stage IV BAC patients with distant metastasis. These results add further support for modification to the current NSCLC staging system. [Table: see text] No significant financial relationships to disclose.
Predicting gene promoter methylation in lung tumors through examination of sputum and serum
Authors: Belinsky S. A. , Grimes M. , Johnson D. , Levy D. , Schiller J. 
Published: March 2020

7208 Background: Personalized medicine may be a key approach in improving survival for advanced lung cancer. Success for this approach is seen with the response of cancer patients with an activating mutation within the epidermal growth factor receptor to the growth fact inhibitor, gefitinib. Genes involved in all types of normal cell function are targeted for inactivation by promoter hypermethylation during lung cancer development. This makes gene-specific promoter hypermethylation an attractive target for novel treatment strategies. One obstacle to targeted therapy is accessibility of tissue from peripheral tumors for methylation analysis. The purpose of this study was to determine the predictive power of sputum and serum to detect NSCLC through analysis for methylation of genes in these fluids. Methods: Tissue, serum, and sputum were obtained from 72 stage III NSCLC patients participating in a Phase III trial of Carboplatin, Paclitaxel and Radiotherapy, With or Without Thalidomide (ECOG 3598). Methylation specific PCR assessed methylation of the p16, MGMT, DAPK, RASSF1A, PAX5-α, PAX5-β, H-cadherin, and GATA5 genes. Results: At least one gene was methylated in 89% of tumors. Prevalence for methylation ranged from 15–47% and did not differ between gender. Methylation of ≥ 3 genes was seen in ∼50% of tumors. The agreement between sputum or serum in classifying methylation status of any gene in the tumor ranged from 54– 69%. The reduced sensitivity was presumably due in part to absence of tumor DNA in the biological fluids of methylation positive tumors. Logistic regression models revealed 3.1 (CI, 1.2, 8.2) and 4.2 (1.1, 16.1) increased odds for methylation of the p16 and MGMT gene, respectively in tumors if the serum or sputum was positive for methylation. The effect of tumor histology for predicting methylation using sputum and serum is being examined. Conclusion: These studies demonstrate for genes such as p16 and MGMT the possibility of interrogating biological fluids to predict for methylation in the primary tumor. (Supported by CA-89551). No significant financial relationships to disclose.
Rituximab maintenance improves progression-free and overall survival rates after combined immuno-chemotherapy (R-FCM) in patients with relapsed follicular and mantle cell lymphoma: Final results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG)
Authors: Dreyling M. , Forstpointner R. , Gramatzki M. , Böck H. , Hänel M. , Seymour J. , Planker M. , Dührsen U. , Wilms K. , Unterhalt M. , Hiddemann W. 
Published: March 2020

7502 Background: Rituximab (R) prolongs the progression-free survival (PFS) in patients with follicular lymphoma (FL) when given either simultaneously with or as maintenance after chemotherapy only. Methods: In the current study the impact of R maintenance after remission induction with an R-containing combined immuno-chemotherapy (R-FCM) was evaluated. Patients with advanced stage relapsed or refractory FL and mantle cell lymphoma (MCL) were eligible. The study design comprized 4 courses of chemotherapy with Fludarabine (25 mg/m2/d days 1–3), Cyclophosphamide (200 mg/m2/d days 1–3) and Mitoxantrone (8 mg/m2/d day 1) (FCM) ± Rituximab (375 mg/m2/d day 0). Patients entering a complete (CR) or partial remission (PR) underwent a second randomization for R maintenance (4 weekly doses (375 mg/m2/d) at three and nine months after end of induction) or observation only. Randomization was stratified for histology, prior therapies (up to 2 lines vs. >2), induction (±R), and response (CR vs. PR). After improved outcome of the R-FCM arm had been observed in the initial 147 randomized patients, all subsequent patients received a combined immuno-chemotherapy induction. Results: 176 of 195 randomized cases are evaluable, 138 of whom had received an R-containing induction. In these patients (as well as the total group) the median PFS after end of induction has not been reached in the R-maintenance arm in contrast to 17 months in patients with no further treatment (p = 0.001). This improvement was seen both in FL (n = 81; p = 0,035) and MCL (n = 47; p = 0,049). More importantly, overall survival rate was also improved after R maintenance with borderline significance (3 y rate 82% vs. 55%; p = 0,056). No major sided effects of R maintenance have been observed and the rate of serious infections was similar in both study arms (p = 0.72). Conclusions: The final analysis of this study confirms that R maintenance after combined immuno-chemotherapy (R-FCM) is highly effective and improves the progression-free survival—with a strong trend towards improved overall survival—of patients with relapsed FL and MCL. [Table: see text]
Survival in patients with multiple myeloma receiving zoledronic acid: Stratification by baseline bone alkaline phosphatase levels
Authors: Berenson J. , Shirina N. , Chen Y. M. , Dimopoulos M. 
Published: March 2020

7505 Background: Zoledronic acid is indicated for the treatment of bone metastases in patients with multiple myeloma and has been demonstrated to reduce the risk of skeletal morbidity. However, it is unknown whether there is a survival benefit secondary to the reduction in skeletal complications. To assess the effect of zoledronic acid on survival in patients with multiple myeloma, we conducted a retrospective analysis of a subset of patients in a large, randomized, controlled trial. Methods: Survival data were analyzed for multiple myeloma patients (n = 209) treated with zoledronic acid 4 mg (n = 107) or pamidronate 90 mg (n = 102) who had at least 1 post-baseline safety evaluation and information on baseline bone alkaline phosphatase (BALP) levels (a marker of bone metabolism). Patients were retrospectively stratified by baseline BALP levels according to the following criteria: low BALP (< 146 U/L) and high BALP (≥ 146 U/L). Survival data were analyzed over 25 months on study. Results: The overall survival rate at 25 months was significantly higher in patients treated with zoledronic acid compared with pamidronate (76% versus 63%; P = .038, Cox regression). Among patients who had a low baseline BALP level, the survival rates were similar for both treatment groups. However, among patients with a high baseline BALP level, zoledronic acid treatment significantly improved survival at study end compared with pamidronate (82% versus 55%; P = .048, log-rank test). Conclusions: This exploratory analysis suggests that zoledronic acid treatment may improve survival compared with pamidronate, and this effect was observed primarily in patients who had a high baseline BALP level, indicating more aggressive osteolytic disease. [Table: see text]