Daniel Morgensztern

Changing Epidemiology of Small-Cell Lung Cancer in the United States Over the Last 30 Years: Analysis of the Surveillance, Epidemiologic, and End Results Database

PURPOSE Small-cell lung cancer (SCLC) is a histologic subtype of lung cancer with a distinct biology and clinical course. It has been observed that the incidence of SCLC has been decreasing over the last several years. METHODS We used the Surveillance, Epidemiologic, and End Results (SEER) database to determine the incidence of SCLC over the last 30 years. In addition, we sought to determine sex- and stage-based differences in the incidence and survival of SCLC among a proportion of reported cases of lung cancer over the last 30 years (1973 to 2002). Joinpoint analyses were applied to test the trends in annual percentage change for statistical significance. RESULTS The proportion of SCLC (among all lung cancer histologic types) decreased from 17.26% in 1986 to 12.95% in 2002. Of all patients with SCLC, the proportion of women with SCLC increased from 28% in 1973% to 50% in 2002. A modest but statistically significant improvement in 2- and 5-year survival was noted among both limited-stage SCLC and extensive-stage SCLC cohorts during the study period. CONCLUSION Our analysis indicates that the incidence of SCLC is decreasing in the United States, and only modest improvements have been seen in survival over the last 30 years. Possible explanations for the decreasing incidence include the decrease in the percentage of smokers and the change to low-tar filter cigarettes. Despite trends toward modest improvement in survival, the outcome remains very poor.

Prognostic Biomarkers in Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkins lymphoma. Although it represents a curable disease, less than half of the patients are cured with conventional chemotherapy. The highly variable outcome reflects a heterogeneous group of tumors, with different genetic abnormalities and response to therapy. The International Prognostic Index (IPI) is useful in predicting the outcome of DLBCL patients. However, patients with identical IPI still exhibit marked variability in survival, suggesting the presence of significant residual heterogeneity within each IPI category. The discovery of specific genetic alterations and the assessment of protein expression led to the identification of multiple novel single molecular markers capable of predicting the outcome of DLBCL patients independently of clinical variables. The recent application of DNA microarrays and tissue array technologies allowed a better understanding of the biology of lymphoma and the development of novel diagnostic tools capable of improving the current models for outcome prediction. However, much confusion exists in the literature regarding the importance of different prognostic biomarkers and their applicability in routine practice. This review summarizes the recent advances in our understanding of prognostic biomarkers in DLBCL and discusses whether this is the right time for biomarkers-guided risk-adjusted therapy.

Trends in Stage Distribution for Patients with Non-small Cell Lung Cancer: A National Cancer Database Survey

Introduction: We examined the recent changes in stage distribution in newly diagnosed patients with non-small cell lung cancer (NSCLC) using a national database to assess the impact of recent advances in imaging modalities. Methods: We searched the National Cancer Database for patients with NSCLC diagnosed between the calendar years 1998 and 2006 for which staging information was available. Results: Among the 877,518 patients diagnosed with NSCLC during the study period, staging information was available for 813,302 patients (92.6%). We observed a change in stage distribution between the years 2000 and 2001, with a decrease in stage I, from 27.5 to 24.8%, and a corresponding increase in stage IV, from 35.4 to 38.8%. No significant changes in stage distribution were noted after 2002. Conclusion: Our study showed a recent and significant stage migration in patients with NSCLC. It is likely that increased acceptance and widespread use of 18fluorodeoxyglucose-positron emission tomography scan and routine brain imaging could account for these changes.

Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study

BACKGROUND Rovalpituzumab tesirine is a first-in-class antibody-drug conjugate directed against delta-like protein 3 (DLL3), a novel target identified in tumour-initiating cells and expressed in more than 80% of patients with small-cell lung cancer. We aimed to assess the safety and activity of rovalpituzumab tesirine in patients who progressed after one or more previous regimen. METHODS We conducted a phase 1 open-label study at ten cancer centres in the USA. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed small-cell lung cancer or large-cell neuroendocrine tumours with progressive measurable disease (according to Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1) previously treated with one or two chemotherapeutic regimens, including a platinum-based regimen. We assigned patients to dose-escalation or expansion cohorts, ranging from 0·05 mg/kg to 0·8 mg/kg rovalpituzumab tesirine intravenously every 3 weeks or every 6 weeks, followed by investigation of the dose schedules 0·3 mg/kg and 0·4 mg/kg every 6 weeks and 0·2 mg/kg every 3 weeks. Primary objectives were to assess the safety of rovalpituzumab tesirine, including the maximum tolerated dose and dose-limiting toxic effects. The primary activity endpoint was objective response by intention-to-treat analysis. This study is registered with ClinicalTrials.gov, number NCT01901653. The study is closed to enrolment; this report focuses on the cohort with small-cell lung cancer. FINDINGS Between July 22, 2013, and Aug 10, 2015, 82 patients were enrolled, including 74 patients with small-cell lung cancer and eight with large-cell neuroendocrine carcinoma, all of whom received at least one dose of rovalpituzumab tesirine. Dose-limiting toxic effects of rovalpituzumab tesirine occurred at a dose of 0·8 mg/kg every 3 weeks, including grade 4 thrombocytopenia (in two of two patients at that dose level) and grade 4 liver function test abnormalities (in one patient). The most frequent grade 3 or worse treatment-related adverse events in 74 patients with small-cell lung cancer were thrombocytopenia (eight [11%]), pleural effusion (six [8%]), and increased lipase (five [7%]). Drug-related serious adverse events occurred in 28 (38%) of 74 patients. The maximum tolerated dose of rovalpituzumab tesirine was 0·4 mg/kg every 3 weeks; the recommended phase 2 dose and schedule is 0·3 mg/kg every 6 weeks. At active doses of rovalpituzumab tesirine (0·2 mg/kg or 0·4 mg/kg every 3 weeks or 0·3 mg/kg or 0·4 mg/kg every 6 weeks), 11 (18%) of 60 assessable patients had a confirmed objective response. 11 (18%) of 60 assessable patients had a confirmed objective response, including ten (38%) of 26 patients confirmed to have high DLL3 expression (expression in 50% or more of tumour cells). INTERPRETATION Rovalpituzumab tesirine shows encouraging single-agent antitumour activity with a manageable safety profile. Further development of rovalpituzumab tesirine in DLL3-expressing malignant diseases is warranted. FUNDING Stemcentrx Inc.

Clinical next-generation sequencing in patients with non-small cell lung cancer.

A clinical assay was implemented to perform next‐generation sequencing (NGS) of genes commonly mutated in multiple cancer types. This report describes the feasibility and diagnostic yield of this assay in 381 consecutive patients with non–small cell lung cancer (NSCLC).

Distinctive Characteristics of Non-small Cell Lung Cancer (NSCLC) in the Young: A Surveillance, Epidemiology, and End Results (SEER) Analysis

Background: The median age of patients with newly diagnosed non-small cell lung cancer (NSCLC) at presentation is 71 years. We conducted an analysis of Surveillance, Epidemiology, and End Results data to assess whether the presentation and outcomes of NSCLC in younger patients (age ≤40 years) are different from that in older patients (age >40 years). Methods: We obtained the demographic, clinical, and outcomes data for all patients diagnosed with NSCLC from 1988 to 2003 in the Surveillance, Epidemiology, and End Results registry. Patients were grouped by age at diagnosis into younger than or equal to 40 years (younger cohort) or older than 40 years (older cohort). Results: During the period analyzed, we identified 2775 patients with NSCLC in the younger cohort and 236,313 patients in the older cohort. Compared with the older group, the younger group had greater proportion of African Americans (19.2% versus 10.9%; p < 0.0001), Asian or Pacific Islander (10.3% versus 5.9%; p < 0.0001), women (48.7% versus 41.9%; p < 0.0001), and patients with stage IV disease (57.4% versus 43.0%; p < 0.0001). Adenocarcinoma was more common in younger patients than in the older patients (57.5% versus 45.2%; p < 0.0001). Squamous cell carcinoma was less prevalent in the younger cohort than in older cohort (12.5% versus 26.4%; p < 0.0001). Five-year overall survival and cancer specific survival were significantly better for younger patients than for older patients across all stages. Conclusions: There is a greater representation of African Americans, Asians or Pacific Islanders, women, and adenocarcinoma histology in the younger cohort of patients with NSCLC compared with the older cohort. Despite presenting with stage IV disease more often, the overall and cancer-specific survivals are better in younger cohort than in the older cohort.

Molecularly Targeted Therapies in Non–Small-Cell Lung Cancer Annual Update 2014

There have been significant advances in the understanding of the biology and treatment of non-small-cell lung cancer (NSCLC) during the past few years. A number of molecularly targeted agents are in the clinic or in development for patients with advanced NSCLC. We are beginning to understand the mechanisms of acquired resistance after exposure to tyrosine kinase inhibitors in patients with oncogene addicted NSCLC. The advent of next-generation sequencing has enabled to study comprehensively genomic alterations in lung cancer. Finally, early results from immune checkpoint inhibitors are very encouraging. This review summarizes recent advances in the area of cancer genomics, targeted therapies, and immunotherapy.

Genomic alterations in lung adenocarcinoma

Treatment for non-small-cell lung cancer is evolving from the use of cytotoxic chemotherapy to personalised treatment based on molecular alterations. This past decade has witnessed substantial progress in the treatment of patients with EGFR mutations and ALK rearrangements, and it is now possible to study complex genomic alterations in cancer using next-generation sequencing. Sequencing data from large-scale consortia, such as The Cancer Genome Atlas, as well as several independent groups, have helped identify novel drivers and potentially targetable alterations in lung adenocarcinomas. These data clearly suggest that lung adenocarcinoma is associated with distinct genomic alterations compared with other lung cancer subtypes, and highlight the widespread molecular heterogeneity that underlies the disease. In this Review, we discuss some of the key findings from genomic studies of lung adenocarcinoma.

Postoperative Radiotherapy for Pathologic N2 Non–Small-Cell Lung Cancer Treated With Adjuvant Chemotherapy: A Review of the National Cancer Data Base

PURPOSE To investigate the impact of modern postoperative radiotherapy (PORT) on overall survival (OS) for patients with N2 non-small-cell lung cancer (NSCLC) treated nationally with surgery and adjuvant chemotherapy. PATIENTS AND METHODS Patients with pathologic N2 NSCLC who underwent complete resection and adjuvant chemotherapy from 2006 to 2010 were identified from the National Cancer Data Base and stratified by use of PORT (≥ 45 Gy). A total of 4,483 patients were identified (PORT, n = 1,850; no PORT, n = 2,633). The impact of patient and treatment variables on OS was explored using Cox regression. RESULTS Median follow-up time was 22 months. On univariable analysis, improved OS correlated with younger age, treatment at an academic facility, female sex, urban population, higher income, lower Charlson comorbidity score, smaller tumor size, multiagent chemotherapy, resection with at least a lobectomy, and PORT. On multivariable analysis, improved OS remained independently predicted by younger age, female sex, urban population, lower Charlson score, smaller tumor size, multiagent chemotherapy, resection with at least a lobectomy, and PORT (hazard ratio, 0.886; 95% CI, 0.798 to 0.988). Use of PORT was associated with an increase in median and 5-year OS compared with no PORT (median OS, 45.2 v 40.7 months, respectively; 5-year OS, 39.3% [95% CI, 35.4% to 43.5%] v 34.8% [95% CI, 31.6% to 38.3%], respectively; P = .014). CONCLUSION For patients with N2 NSCLC after complete resection and adjuvant chemotherapy, modern PORT seems to confer an additional OS advantage beyond that achieved with adjuvant chemotherapy alone.

Improving Survival for Stage IV Non-small Cell Lung Cancer: A Surveillance, Epidemiology, and End Results Survey from 1990 to 2005

Background: Although there has been a significant survival improvement for patients with metastatic NSCLC enrolled in randomized trials, it is not clear whether a similar benefit is seen in an unselected group of patients. Therefore, we conducted a study to evaluate for survival changes in a large national cancer registry database. Patients and Methods: The Surveillance, Epidemiology, and End Results (SEER) registry was queried for patients with NSCLC stage IV, aged 21 years or older, and diagnosed between 1990 and 2005. We analyzed four equally divided time periods between 1990 and 2005 (1990 to 1993 or period 1, 1994 to 1997 or period 2, 1998 to 2001 or period 3, and 2002 to 2005 or period 4) to determine changes in overall survival for all patients and according to histology. Results: We identified 129,337 patients meeting eligibility criteria. There was a significant improvement in overall survival since period 1. One-year and 2-year overall survival increased from 13.2 and 4.5%, respectively, in period 1 to 19.4% and 7.8%, respectively, in period 4. On multivariate analysis, survival for adenocarcinoma was increased compared with squamous cell carcinoma only in period 4 (p = 0.02). Conclusions: There has been a modest but statistically significant improvement in overall survival for stage IV NSCLC over the past 16 years. The recent differences in outcomes based on histology observed in period 4 may reflect the increased activity of epidermal growth factor receptor tyrosine kinase inhibitors in adenocarcinoma compared with squamous cell carcinoma.