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Effect of Thoracic Radiotherapy Timing and Fractionation on Survival in Nonmetastatic Small Cell Lung Carcinoma

Wong, Andrew T; Rineer, Justin; Schwartz, David; Becker, Daniel; Safdieh, Joseph; Osborn, Virginia; Schreiber, David
BACKGROUND: The optimal timing of thoracic radiation therapy (RT) in relation to chemotherapy is unknown in the treatment of nonmetastatic small cell lung cancer (SCLC). We analyzed the National Cancer Data Base (NCDB) to assess the effect on overall survival (OS) of RT timing with chemotherapy for patients with SCLC. MATERIALS AND METHODS: The NCDB was queried for patients diagnosed with nonmetastatic SCLC from 1998 to 2011 who had undergone definitive chemoradiation. The patients were stratified into quartiles according to the interval between the start of chemotherapy and the start of RT. The first and second quartiles (RT started 0-20 days after chemotherapy) were classified as "early" RT and the third and fourth quartiles (RT started 21-126 days after chemotherapy) as "late" RT. Patients were included if they had received hyperfractionated 45 Gy in 30 fractions or standard fractionation of >/= 60 Gy in 1.8- to 2-Gy fractions. Kaplan-Meier analyses of OS were performed, and multivariable Cox regression analysis was conducted to assess the effect of the covariates on OS. RESULTS: A total of 8391 patients were included (50.5% had received early RT). Early RT was associated with significant improvement in survival (5-year OS, 21.9% vs. 19.1%; P = .01). On subgroup analysis, the survival advantage for early RT was significant for patients receiving hyperfractionated RT (5-year OS, 28.2% vs. 21.2%; P = .004) but not for those receiving standard fractionation (19.8% vs. 18.4%; P = .29). On multivariable Cox regression analysis, hyperfractionated RT was associated with reduced mortality (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.85-0.96; P = .001), but early RT was not (HR, 0.98; 95% CI, 0.94-1.04; P = .53). CONCLUSION: These data support the early initiation of hyperfractionated thoracic RT for nonmetastatic SCLC.
PMID: 27686970
ISSN: 1938-0690
CID: 2262702

Patterns of care and survival outcomes of palliative radiation for prostate cancer with bone metastases: comparison of /=10 fractions

Schreiber, David; Safdieh, Joseph; Becker, Daniel J; Schwartz, David
BACKGROUND: To review the palliative radiation fractionation regimens, trends and survival of men within the National Cancer Database (NCDB) diagnosed with prostate cancer and bony metastases. METHODS: A total of 3,871 patients from the NCDB were included in the analysis (patients treated from 2004-2012). The following fractionation regimens were analyzed [8 Gy x 1, 4 Gy x 5 (short course radiation therapy)], were compared to 3 Gy x 10, 2.50 Gy x 14-15 and 2 Gy x 20-30 (long course radiation therapy). Descriptive statistics, multivariable logistic regression and multivariable cox regression analysis were utilized to assess the data. RESULTS: Longer fractionation schemes were used for 91.7% of patients. Treatment at an academic center (OR, 2.93), increasing distance from treatment center (OR, 1.48-1.59), treatment to the ribs (OR, 2.47), and year of diagnosis 2009 or later (OR, 2.31-3.26) were associated with an increased likelihood of receiving short course radiation, while treatment to the spine (OR, 0.34) was associated with a decreased likelihood of short course radiation. On multivariable analysis, longer course of radiation was associated with increased overall survival (HR =0.66; 95% CI: 0.56-0.78, P<0.001.). However, on landmark analysis this difference disappeared once limiting the survival analysis to men who survived >/=18 months [HR =0.83; 95% CI: 0.62-1.11, P=0.21]. CONCLUSIONS: Fractionation schemes of >/=10 treatments remain the dominant palliative course of radiation therapy offered for metastatic prostate cancer. However, utilization of
PMID: 28209069
ISSN: 2224-5839
CID: 2459712

Survival of Asian Females With Advanced Lung Cancer in the Era of Tyrosine Kinase Inhibitor Therapy

Becker, Daniel J; Wisnivesky, Juan P; Grossbard, Michael L; Chachoua, Abraham; Camidge, D Ross; Levy, Benjamin P
INTRODUCTION: We examined the effect of access to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy on survival for Asian female (AF) EGFR mutation-enriched patients with advanced lung adenocarcinoma. MATERIALS AND METHODS: We used the Surveillance Epidemiology and End Results database to study patients with stage IV lung adenocarcinoma diagnosed from 1998 to 2012. We compared survival (lung cancer-specific survival [LCSS] and overall survival) between AFs and non-Asian males (NAMs), an EGFR mutation-enriched and EGFR mutation-unenriched population, respectively, with a diagnosis in the pre-EGFR TKI (1998-2004) and EGFR TKI (2005-2012) eras. We used Cox proportional hazards models to examine the interaction of access to TKI treatment and EGFR enrichment status. RESULTS: Among 3029 AF and 35,352 NAM patients, we found that LCSS was best for AFs with a diagnosis in the TKI era (median, 14 months), followed by AFs with a diagnosis in the pre-TKI era (median, 8 months), NAMs with a diagnosis in the TKI era (median, 5 months), and NAMs with a diagnosis in the pre-TKI era (median, 4 months; log-rank P < .0001). In a multivariable model, the effect of a diagnosis in the TKI era on survival was greater for AFs than for NAMs (LCSS, P = .0020; overall survival, P = .0007). A lung cancer diagnosis in the TKI era was associated with an overall mortality decrease of 26% for AFs (hazard ratio, 0.740; 95% confidence interval, 0.682-0.80) and 15.9% for NAMs (hazard ratio, 0.841; 95% confidence interval, 0.822-0.860). CONCLUSIONS: We found increased survival for lung adenocarcinoma diagnoses made after widespread access to EGFR TKIs, with the greatest increase among AF patients enriched for EGFR mutations. The present analysis eliminated the effect of crossover, which has complicated assessments of the survival advantage in EGFR TKI randomized trials.
PMID: 28029530
ISSN: 1938-0690
CID: 2383632

Clinical Utility of Liquid Diagnostic Platforms in Non-Small Cell Lung Cancer

Levy, Benjamin; Hu, Zishuo I; Cordova, Kristen N; Close, Sandra; Lee, Karen; Becker, Daniel
: A firmer understanding of the genomic landscape of lung cancer has recently led to targeted, therapeutic advances in non-small cell lung cancer. Historically, the reference standard for the diagnosis and genetic interrogation for advanced-stage patients has been tissue acquisition via computed tomography-guided core or fine needle aspiration biopsy. However, this process can frequently put the patient at risk and remains complicated by sample availability and tumor heterogeneity. In addition, the time required to complete the diagnostic assays can negatively affect clinical care. Technological advances in recent years have led to the development of blood-based diagnostics or "liquid biopsies" with great potential to quickly diagnose and genotype lung cancer using a minimally invasive technique. Recent studies have suggested that molecular alterations identified in cell-free DNA (cfDNA) or circulating tumor DNA can serve as an accurate molecular proxy of tumor biology and reliably predict the response to tyrosine kinase therapy. In addition, several trials have demonstrated the high accuracy of microRNA (miRNA) platforms in discerning cancerous versus benign nodules in high-risk, screened patients. Despite the promise of these platforms, issues remain, including varying sensitivities and specificities between competing platforms and a lack of standardization of techniques and downstream processing. In the present report, the clinical applications of liquid biopsy technologies, including circulating tumor cells, proteomics, miRNA, and cfDNA for NSCLC, are reviewed and insight is provided into the diagnostic and therapeutic implications and challenges of these platforms. IMPLICATIONS FOR PRACTICE: Although tumor biopsies remain the reference standard for the diagnosis and genotyping of non-small cell lung cancer, they remain fraught with logistical complexities that can delay treatment decisions and affect clinical care. Liquid diagnostic platforms, including cell-free DNA, proteomic signatures, RNA (mRNA and microRNA), and circulating tumor cells, have the potential to overcome many of these barriers, including rapid and accurate identification of de novo and resistant genetic alterations, real-time monitoring of treatment responses, prognosis of outcomes, and identification of minimal residual disease. The present report provides insights into new liquid diagnostic platforms in non-small cell lung cancer and discusses the promise and challenges of their current and future clinical use.
PMCID:5016074
PMID: 27388233
ISSN: 1549-490x
CID: 2246392

Attacking a Moving Target: Understanding Resistance and Managing Progression in EGFR-Positive Lung Cancer Patients Treated With Tyrosine Kinase Inhibitors

Levy, Benjamin P; Rao, Parth; Becker, Daniel J; Becker, Kevin
Multiple randomized studies have demonstrated improved response rates, progression-free survival, and quality of life for treatment-naive, advanced-stage adenocarcinoma patients harboring sensitizing EGFR mutations when they are treated with tyrosine kinase inhibitor therapy, as compared with chemotherapy. Despite improved outcomes with these agents, the majority of patients will eventually develop resistance and subsequent clinical progression. Recently, there has been a firmer understanding of the molecular mechanisms of the resistance that develops as a consequence of treatment, most notably the identification of a second-site EGFR mutation, T790M. While this understanding can inform subsequent treatment decisions, disease progression can be heterogeneous, and there are several competing therapeutic options. Treatment decisions must consider this clinical heterogeneity, factoring in the pace of disease growth, lung cancer-related symptoms, and the potential presence of T790M mutations. Herein, we review the available literature addressing these competing strategies and attempt to clarify best treatment practices, including the emerging role of T790M-directed therapies.
PMID: 27432364
ISSN: 0890-9091
CID: 2242952

Therapeutic Effects of Repurposed Therapies in Non-Small Cell Lung Cancer: What Is Old Is New Again

Saxena, Ashish; Becker, Daniel; Preeshagul, Isabel; Lee, Karen; Katz, Elena; Levy, Benjamin
: The recent emergence of targeted and immunotherapeutic agents has dramatically changed the management for patients with non-small cell lung cancer (NSCLC). Despite these advances, lung cancer is not exempt from the challenges facing oncology drug development, including the huge financial cost and the time required for drug implementation. Repositioning noncancer therapies with potential antineoplastic properties into new therapeutic niches is an alternative treatment strategy offering the possibility of saving money and time and improving outcomes. The goal of such a strategy is to deliver an effective drug with a favorable toxicity profile at a reduced cost. Preclinical models and observational data have demonstrated promising activity for many of these agents, and they are now being studied in prospective trials. We review the relevant published data regarding the therapeutic effects of metformin, statins, nonsteroidal anti-inflammatory drugs, beta-blockers, and itraconazole in NSCLC, with a focus on the putative mechanisms of action and clinical data. As these drugs are increasingly being tested in clinical trials, we aim to highlight the salient challenges and future strategies to optimize this approach. IMPLICATIONS FOR PRACTICE: The staggering failure rates, exorbitant costs, and lengthy approval process associated with drug development in lung cancer warrants exploration of alternative strategies. The repositioning of approved noncancer medications to treat non-small cell lung cancer (NSCLC) represents a unique opportunity to improve outcomes by delivering an effective drug at lower costs with manageable toxicity. Several such agents have demonstrated antineoplastic activity and are being studied in NSCLC patient populations. The present review highlights the relevant literature regarding these agents' therapeutic effects and reports on the challenges in implementing this strategy moving forward, including a discussion of ongoing phase I, II, and III trials.
PMCID:4524771
PMID: 26156329
ISSN: 1549-490x
CID: 1739902

The time for low-dose computed tomography screening is now: a medical oncologist perspective

Levy, Benjamin P; Becker, Daniel J
PMID: 25381211
ISSN: 0890-9091
CID: 1500992

A randomized, phase 2 trial of Docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic non-small-cell lung cancer

Levy, Benjamin; Spira, Alexander; Becker, Daniel; Evans, Tracey; Schnadig, Ian; Camidge, D Ross; Bauman, Julie E; Hausman, Diana; Walker, Luke; Nemunaitis, John; Rudin, Charles M; Halmos, Balazs; Bowles, Daniel W
INTRODUCTION: The phosphotidylinositol-3 kinase/serine-threonine kinase (AKT)/mammalian target of rapamycin signaling pathway is frequently altered in non-small-cell lung cancer (NSCLC). PX-866 is an oral, irreversible, pan-isoform inhibitor of phosphotidylinositol-3 kinase. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory NSCLC. METHODS: Patients with locally advanced, recurrent, or metastatic NSCLC who had received at least one and no more than two prior systemic treatment regimens were randomized (1:1) to a combination of docetaxel (75 mg/m intravenous every 21 days) with or without PX-866 (8 mg orally daily; arms A and B, respectively). The primary end point was progression-free survival (PFS). Secondary end points included objective response rate, overall survival (OS), toxicity, and correlation of biomarker analyses with efficacy outcomes. RESULTS: A total of 95 patients were enrolled. Median PFS was 2 months in arm A and 2.9 months in arm B (p = 0.65). Objective response rates were 6% and 0% in arms A and B, respectively (p = 0.4). There was no difference in OS between the two arms (7.0 versus 9.2 months; p = 0.9). Grade 3 or higher adverse events were infrequent, but more common in the combination arm with respect to diarrhea (7% versus 2%), nausea (4% versus 0%), and vomiting (7% versus 0%). PIK3CA mutations or PTEN loss were infrequently observed. CONCLUSION: The addition of PX-866 to docetaxel did not improve PFS, response rate, or OS in patients with advanced, refractory NSCLC without molecular preselection.
PMID: 24926548
ISSN: 1556-1380
CID: 1521442

Double trouble: a case of concurrent de novo T790M and L858R EGFR mutations in treatment-naive advanced non-small-cell lung cancer [Case Report]

Saxena, Ashish; Nagasaka, Misako; Li, Zujun; Becker, Daniel J; Levy, Benjamin P
PMID: 25134330
ISSN: 0890-9091
CID: 1499462

Treatment of cancer-associated retinopathy with rituximab [Case Report]

Dy, Irene; Chintapatla, Rangaswamy; Preeshagul, Isabel; Becker, Daniel
Cancer-associated retinopathy (CAR) is a rare autoimmune condition associated with various cancers, causing significant visual impairment. Visual symptoms in CAR may or may not correlate with the extent of systemic disease or its response to chemotherapy, and must be addressed separately from the management of systemic malignancy. Steroids have been the mainstay of CAR therapy. Various immunomodulatory therapies have also been described with varying responses, but the overall visual prognosis remains poor. Rituximab is a monoclonal antibody used in the treatment of non-Hodgkin's B-cell lymphoma and many autoimmune disorders. This case report describes a patient with small cell uterine cancer who initially presented with visual impairment associated with CAR. The patient's deteriorating visual symptoms were successfully halted for an extended, clinically meaningful period with rituximab.
PMID: 24225966
ISSN: 1540-1413
CID: 3891302