Racial differences in lung cancer

Although race, in and of itself, is not a relevant biologic variable, racial differences in disease characteristics and outcomes have been reported in many malignancies, including lung cancer. The lung cancer incidence rate in blacks has been consistently higher than that in whites for many years. This racial disparity is seen primarily in men and is significantly greater in younger age groups. The reason for higher lung cancer incidence rates in blacks remains unclear, but racial differences in smoking habits, socioeconomic variables, and the metabolism of tobacco carcinogens may all play an important role. Blacks are also more likely than whites to present with squamous cell carcinoma and with advanced-stage disease. A significant racial difference in survival rates has developed over the past 30 years, with a poorer prognosis noted in black patients, particularly those with local- and regional-stage disease. This disparity appears to be due to a lack of improvement in the survival of black patients with lung cancer, but the biological and/or societal basis for racial variations in survival have not been determined. In summary, significant racial differences exist in lung cancer incidence and survival rates. Further research is required to determine the factors responsible for these differences and to develop effective preventative and therapeutic interventions that will impact favorably on the incidence and prognosis of this disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44537/1/10555_2004_Article_5111825.pd

Phase II Study of Celecoxib and Docetaxel in Non-small Cell Lung Cancer (NSCLC) Patients with Progression after Platinum-Based Therapy

IntroductionTo evaluate the efficacy and toxicity of the combination of celecoxib and docetaxel in patients with advanced non-small cell lung cancer after failure of platinum-based therapy.MethodsPatients with relapsed non-small cell lung cancer received celecoxib 400 mg orally twice daily beginning 7 days before the first cycle of docetaxel and the celecoxib was continued with no interruption. Docetaxel 75 mg/m2 was administered intravenously on a 21-day cycle. The primary end point of the study was the 6-month survival rate.ResultsTwenty-four patients were enrolled and twenty patients were treated (median age 60, M:F 16:8). Most patients had a baseline performance status of 1. The objective response rate was 10% (95% confidence interval [CI], 0–25%) and the 6-month survival rate was 59% (95% CI 37–80%). Median survival time was 6.9 months (95% CI, 2.8–15.2 months) and the 1- and 2-year survival rates were 36% (95% CI, 15–57%) and 1% (95% CI, 0–10%), respectively. The most frequent grade ≥3 adverse events were neutropenia (58%) and neutropenic fever (21%) which resulted in early closure of the trial.ConclusionsThe addition of celecoxib to docetaxel did not seem to improve the response rate and survival compared with docetaxel alone. The combination demonstrated considerable neutropenia and complications from febrile neutropenia that suggests celecoxib may enhance the marrow toxicity of docetaxel

Doses of radiation to the pericardium, instead of heart, are significant for survival in patients with non-small cell lung cancer

Background and purpose: Higher cardiac dose was associated with worse overall survival in the RTOG0617 study. Pericardial effusion (PCE) is a common cardiac complication of thoracic radiation therapy (RT). We investigated whether doses of radiation to the heart and pericardium are associated with PCE and overall survival in patients treated with thoracic radiation for non-small cell lung cancer (NSCLC). Materials and Methods: A total of 94 patients with medically inoperable/unresectable NSCLC treated with definitive RT in prospective studies were reviewed for this secondary analysis. Heart and pericardium were contoured consistently according to the RTOG1106 Atlas, with the great vessels and thymus of the upper mediastinal structures included in the upper part of pericardium, only heart chambers included in the heart structure. Clinical factors and dose-volume parameters associated with PCE or survival were identified via Cox proportional hazards modeling. The risk of PCE and death were mapped using DVH atlases. Results: Median follow-up for surviving patients was 58 months. The overall rate of PCE was 40.4%. On multivariable analysis, dosimetric factors of heart and pericardium were significantly associated with the risk of PCE. Pericardial V30 and V55 were significantly correlated with overall survival, but presence of PCE and heart dosimetric factors were not. Conclusion: PCE was associated with both heart and pericardial doses. The significance of pericardial dosimetric parameters, but not heart chamber parameters, on survival suggests the potential significance of radiation damage to the cranial region of pericardium

Molecular Testing Guideline for the Selection of Patients With Lung Cancer for Treatment With Targeted Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Clinical Practice Guideline Update

Purpose In response to advances in the field, the College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) recently updated their recommendations for molecular testing for the selection of patients with lung cancer for treatment with targeted tyrosine kinase inhibitors. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. Methods The molecular testing guideline was reviewed for developmental rigor by methodologists. Then an ASCO Expert Panel reviewed the content and the recommendations. Results The ASCO Expert Panel determined that the recommendations from the CAP/IASLC/AMP molecular testing guideline are clear, thorough, and based upon the most relevant scientific evidence. ASCO endorsed the guideline with minor modifications. Recommendations This update clarifies that any sample with adequate cellularity and preservation may be tested and that analytical methods must be able to detect mutation in a sample with as little as 20% cancer cells. It strongly recommends against evaluating epidermal growth factor receptor (EGFR) expression by immunohistochemistry for selection of patients for EGFR-targeted therapy. New for 2018 are recommendations for stand-alone ROS1 testing with additional confirmation testing in all patients with advanced lung adenocarcinoma, and RET, ERBB2 (HER2), KRAS, and MET testing as part of larger panels. ASCO also recommends stand-alone BRAF testing in patients with advanced lung adenocarcinoma. Recommendations are also provided for testing methods for lung cancers that have a nonadenocarcinoma non-small-cell component, for patients with targetable mutations who have relapsed on targeted therapy, and for testing the presence of circulating cell-free DNA. Additional information is available at www.asco.org/thoracic-cancer-guidelines and www.asco.org/guidelineswiki

Prediction of Radiation Esophagitis in Non-Small Cell Lung Cancer Using Clinical Factors, Dosimetric Parameters, and Pretreatment Cytokine Levels

Radiation esophagitis (RE) is a common adverse event associated with radiotherapy for non-small cell lung cancer (NSCLC). While plasma cytokine levels have been correlated with other forms of radiation-induced toxicity, their association with RE has been less well studied. We analyzed data from 126 patients treated on 4 prospective clinical trials. Logistic regression models based on combinations of dosimetric factors [maximum dose to 2 cubic cm (D2cc) and generalized equivalent uniform dose (gEUD)], clinical variables, and pretreatment plasma levels of 30 cytokines were developed. Cross-validated estimates of area under the receiver operating characteristic curve (AUC) and log likelihood were used to assess prediction accuracy. Dose-only models predicted grade 3 RE with AUC values of 0.750 (D2cc) and 0.727 (gEUD). Combining clinical factors with D2cc increased the AUC to 0.779. Incorporating pretreatment cytokine measurements, modeled as direct associations with RE and as potential interactions with the dose-esophagitis association, produced AUC values of 0.758 and 0.773, respectively. D2cc and gEUD correlated with grade 3 RE with odds ratios (ORs) of 1.094/Gy and 1.096/Gy, respectively. Female gender was associated with a higher risk of RE, with ORs of 1.09 and 1.112 in the D2cc and gEUD models, respectively. Older age was associated with decreased risk of RE, with ORs of 0.992/year and 0.991/year in the D2cc and gEUD models, respectively. Combining clinical with dosimetric factors but not pretreatment cytokine levels yielded improved prediction of grade 3 RE compared to prediction by dose alone. Such multifactorial modeling may prove useful in directing radiation treatment planning

High-Throughput Label-Free Isolation of Heterogeneous Circulating Tumor Cells and CTC Clusters from Non-Small-Cell Lung Cancer Patients.

(1) Background: Circulating tumor cell (CTC) clusters are emerging as clinically significant harbingers of metastases in solid organ cancers. Prior to engaging these CTC clusters in animal models of metastases, it is imperative for technology to identify them with high sensitivity. These clusters often present heterogeneous surface markers and current methods for isolation of clusters may fall short. (2) Methods: We applied an inertial microfluidic Labyrinth device for high-throughput, biomarker-independent, size-based isolation of CTCs/CTC clusters from patients with metastatic non-small-cell lung cancer (NSCLC). (3) Results: Using Labyrinth, CTCs (PanCK+/DAPI+/CD45-) were isolated from patients (n = 25). Heterogeneous CTC populations, including CTCs expressing epithelial (EpCAM), mesenchymal (Vimentin) or both markers were detected. CTCs were isolated from 100% of patients (417 +/- 1023 CTCs/mL). EpCAM- CTCs were significantly greater than EpCAM+ CTCs. Cell clusters of \u3e/=2 CTCs were observed in 96% of patients-of which, 75% were EpCAM-. CTCs revealed identical genetic aberrations as the primary tumor for RET, ROS1, and ALK genes using fluorescence in situ hybridization (FISH) analysis. (4) Conclusions: The Labyrinth device recovered heterogeneous CTCs in 100% and CTC clusters in 96% of patients with metastatic NSCLC. The majority of recovered CTCs/clusters were EpCAM-, suggesting that these would have been missed using traditional antibody-based capture methods

Effect of Midtreatment PET/CT-Adapted Radiation Therapy With Concurrent Chemotherapy in Patients With Locally Advanced Non–Small-Cell Lung Cancer

IMPORTANCE Our previous studies demonstrated that tumors significantly decrease in size and metabolic activity after delivery of 45 Gy of fractionated radiatiotherapy (RT), and that metabolic shrinkage is greater than anatomic shrinkage. This study aimed to determine whether 18F-fludeoxyglucose–positron emission tomography/computed tomography (FDG-PET/CT) acquired during the course of treatment provides an opportunity to deliver higher-dose radiation to the more aggressive areas of the tumor to improve local tumor control without increasing RT-induced lung toxicity (RILT), and possibly improve survival. OBJECTIVE To determine whether adaptive RT can target high-dose radiation to the FDG-avid tumor on midtreatment FDG-PET to improve local tumor control of locally advanced non–small-cell lung cancer (NSCLC). DESIGN, SETTING, AND PARTICIPANTS A phase 2 clinical trial conducted at 2 academic medical centers with 42 patients who had inoperable or unresectable stage II to stage III NSCLC enrolled from November 2008, to May 2012. Patients with poor performance, more than 10% weight loss, poor lung function, and/or oxygen dependence were included, providing that the patients could tolerate the procedures of PET scanning and RT. INTERVENTION Conformal RT was individualized to a fixed risk of RILT (grade >2) and adaptively escalated to the residual tumor defined on midtreatment FDG-PET up to a total dose of 86 Gy in 30 daily fractions. Medically fit patients received concurrent weekly carboplatin plus paclitaxel followed by 3 cycles of consolidation. MAIN OUTCOMES AND MEASURES The primary end point was local tumor control. The trial was designed to achieve a 20% improvement in 2-year control from 34% of our prior clinical trial experience with 63 to 69 Gy in a similar patient population. RESULTS The trial reached its accrual goal of 42 patients: median age, 63 years (range, 45–83 years); male, 28 (67%); smoker or former smoker, 39 (93%); stage III, 38 (90%). Median tumor dose delivered was 83 Gy (range, 63–86 Gy) in 30 daily fractions. Median follow-up for surviving patients was 47 months. The 2-year rates of infield and overall local regional tumor controls (ie, including isolated nodal failure) were 82% (95% CI, 62%–92%) and 62% (95% CI, 43%–77%), respectively. Median overall survival was 25 months (95% CI, 12–32 months). The 2-year and 5-year overall survival rates were 52% (95% CI, 36%–66%) and 30% (95% CI, 16%–45%), respectively. CONCLUSIONS AND RELEVANCE Adapting RT-escalated radiation dose to the FDG-avid tumor detected by midtreatment PET provided a favorable local-regional tumor control. The RTOG 1106 trial is an ongoing clinical trial to validate this finding in a randomized fashion. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT0119052

Radiation-induced lung toxicity in non-small-cell lung cancer: Understanding the interactions of clinical factors and cytokines with the dose-toxicity relationship

BACKGROUND AND PURPOSE: Current methods to estimate risk of radiation-induced lung toxicity (RILT) rely on dosimetric parameters. We aimed to improve prognostication by incorporating clinical and cytokine data, and to investigate how these factors may interact with the effect of mean lung dose (MLD) on RILT. MATERIALS AND METHODS: Data from 125 patients treated from 2004 to 2013 with definitive radiotherapy for stages I-III NSCLC on four prospective clinical trials were analyzed. Plasma levels of 30 cytokines were measured pretreatment, and at 2 and 4weeks midtreatment. Penalized logistic regression models based on combinations of MLD, clinical factors, and cytokine levels were developed. Cross-validated estimates of log-likelihood and area under the receiver operating characteristic curve (AUC) were used to assess accuracy. RESULTS: In prognosticating grade 3 or greater RILT by MLD alone, cross-validated log-likelihood and AUC were -28.2 and 0.637, respectively. Incorporating clinical features and baseline cytokine levels increased log-likelihood to -27.6 and AUC to 0.669. Midtreatment cytokine data did not further increase log-likelihood or AUC. Of the 30 cytokines measured, higher levels of 13 decreased the effect of MLD on RILT, corresponding to a lower odds ratio for RILT per Gy MLD, while higher levels of 4 increased the association. CONCLUSIONS: Although the added prognostic benefit from cytokine data in our model was modest, understanding how clinical and biologic factors interact with the MLD-RILT relationship represents a novel framework for understanding and investigating the multiple factors contributing to radiation-induced toxicity