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Journal of Thoracic Oncology:
doi: 10.1097/JTO.0000000000000057
In This Issue

In This Issue

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The Central Nervous System as a Sanctuary Site in ALK-Positive Non–Small-Cell Lung Cancer

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The metastatic development in the central nervous system (CNS) has been recognized as an emerging complication in non–small-cell lung cancer (NSCLC) patients with anaplastic lymphoma kinase (ALK) gene rearrangements receiving the ALK inhibitor crizotinib treatment. In this report, Gainor and colleagues presented a series of ALK-positive patients with two distinct types of metastatic involvement of the CNS: intramedullary spinal cord metastasis (ISCM) and leptomeningeal carcinomatosis (LC). It is the first report of ISCM in a patient with ALK-positive NSCLC. From a retrospective chart review of 96 ALK-positive patients, the authors identified ISCM in 4.17% of them and LC in 5.21%. These patients with CNS complications were previously treated or still undergoing treatment with crizotinib at the time of diagnosis. The time from diagnosis of NSCLC to development of ISCM (> 15 months) and LC (≥ 9 months) indicated that these are potentially late complications. Optimal treatments for patients with ISCM and LC have not yet been defined. The authors recommend clinicians to use neuroimaging in ALK-positive patients presenting with neurologic symptoms. This report also underscores the need to develop next-generation ALK inhibitors with enhanced CNS penetration and antitumor activity. (p. 1570)

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Phase II Trial of Carboplatin, Paclitaxel, Cetuximab, and Bevacizumab Followed by Cetuximab and Bevacizumab in Advanced Nonsquamous Non–Small-Cell Lung Cancer: SWOG 0536

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Whether combining cetuximab and bevacizumab with carboplatin and paclitaxel will benefit chemotherapy-naive patients with advanced nonsquamous non–small-cell lung cancer was investigated in this phase II study. Patients underwent six cycles of the treatment and were then given maintenance cetuximab and bevacizumab until disease progression. The primary endpoint was safety (i.e., frequency and severity of hemorrhagic toxicities). The secondary endpoints were response rate, progression-free survival, overall survival, and toxicity. Association between clinical outcomes and biomarkers such as EGFR and KRAS mutation status, and EGFR protein H score were also explored but no statistically significant associations were observed, except for circulating cytokine-angiogenesis factors. In 110 patients enrolled, 2% had grade 4 or higher hemorrhage and there were four treatment-related deaths including hemorrhage and infection. With a median progression-free survival of 7 months, median overall survival of 15 months, response rate of 56%, and 77% of overall disease control rate, the regimen was demonstrated to be safe, effective, and feasible as a first-line treatment for this study population. A phase III trial for further assessment is underway. (p. 1519)

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Clinician Perceptions of Care Difficulty, Quality of Life, and Symptom Reports for Lung Cancer Patients: An Analysis from ECOG E2Z02 (Symptom Outcomes and Practice Patterns)

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To investigate the potential clinician perception differences for their lung cancer patients compared with other patients having breast, prostate, and colon cancer, the authors specifically evaluated care difficulty, quality of life (QoL), and symptom reports from clinicians’ responses. Analysis from the Eastern Cooperative Oncology Group Symptom Outcomes and Practice Patterns study (E2Z02) was reported, which included clinician ratings of 3106 patients with solid tumors. The findings revealed that clinicians perceived lung cancer patients as more difficult to treat and as having poorer QoL and higher symptom reports versus other solid tumor patients. To further assess the possibility of nihilism and perception bias, the persistence of the disease-specific differences was observed after other explanatory covariates (stage, performance status, and patient reports) were included. For lung cancer patients, lower QoL was perceived with an odds ratio of 3.6 (p < 0.0001) whereas weight gain/loss difficulties with an odds ratio of 3.2 (p = 0.0004). To conclude, clinicians were more pessimistic about the well-being of their lung cancer patients versus others with solid tumors. Perception differences of patient QoL and weight difficulties persisted after adjusting for covariates. The study suggested that subtle and possible physician nihilism and perception bias could affect treatment options and disease management; further studies are required to confirm these findings and gain better understanding. (p. 1474)

Photo credit: Mike Blackburn ( http://www.flickr.com/photos/mikeblackburn/5520196331/)

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The IASLC/ITMIG Thymic Malignancies Staging Project: Development of a Stage Classification for Thymic Malignancies

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The International Association for the Study of Lung Cancer and the International Thymic Malignancies Interest Group joined effort in forming a Thymic Malignancies Domain of the Staging and Prognostic Factors Committee, responsible for the development of proposals for the American Joint Committee on Cancer/Union for International Cancer Control 8th edition of stage classification system for thymic malignancies. This article outlines the structure of this project and the plans designed to achieve the goal. To foster global collaboration in thymic malignancies, retrospective and prospective databases were created, with over 10,000 cases worldwide being assembled for analysis. Careful evaluation of characteristics, guiding principles, and the process for the development of a thymic stage classification system were discussed. The development of a prognostic model for thymic malignancies to guide treatment was also proposed. (p. 1467)

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RESEARCH WATCH

ACRIN 6668/RTOG 0235 Trial: Prognostic value of [18F]Fluorodeoxyglucose Positron Emission Tomography in Patients with Locally Advanced Non–Small-Cell Lung Cancer Receiving Chemoradiation Therapy

Machtay et al. evaluated the association of standardized uptake value (SUV) on posttreatment [18F]fluorodeoxyglucose positron emission tomography with survival of stage III non–small-cell lung cancer patients. Patients did not receive surgery but underwent conventional concurrent platinum-based chemoradiotherapy. The primary endpoint was peak SUV (SUVpeak). The study population of 250 patients had a 2-year survival rate of 42.5%. No association with survival was found with pretreatment SUVpeak and SUVmax (mean, 10.3 and 13.1, respectively) whereas a higher posttreatment tumor SUV (SUVpeak or SUVmax) is linked to poorer survival in these patients (hazard ratio: 1.087; p = 0.020). In exploratory analyses, a link to survival was found when a SUVpeak cutoff of 5.0 (p = 0.041) or 7.0 (p < 0.001) was used. Similar findings were found by using SUVmax. The study suggests that there is a prognostic value of SUV in these patients although more studies are warranted to determine a clear cutoff value for its use in routine clinics.

Machtay M, Duan F, Siegel BA, et al. Prediction of survival by [18F]fluorodeoxyglucose positron emission tomography in patients with locally advanced non-small-cell lung cancer undergoing definitive chemoradiation therapy: results of the ACRIN 6668/RTOG 0235 Trial. J Clin Oncol, doi:10.1200/jco.2012.47.5947 (2013).

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ATLAS: Maintenance Bevacizumab with or without Erlotinib for Advanced Non–Small-Cell Lung Cancer After First-Line Bevacizumab Treatment

This randomized, double-blind, placebo-controlled, phase IIIb study aimed to determine whether adding erlotinib to bevacizumab maintenance therapy after first-line chemotherapy regimen with bevacizumab would benefit patients with advanced non–small-cell lung cancer (stage IIIB with malignant pleural effusion, stage IV, or recurrent). In the study population of 743 patients randomized to receive bevacizumab with or without erlotinib postchemotherapy, addition of erlotinib to bevacizumab significantly improved progression-free survival: 3.7 months with bevacizumab/placebo versus 4.8 months with bevacizumab/erlotinib (hazard ratio, 0.71; p < 0.001). But no significant improvement was observed in overall survival: 13.3 versus 14.4 months, respectively (hazard ratio, 0.92; p = 0.5341). Increased toxicity was also found in the bevacizumab/erlotinib arm. The results of this study did not provide sufficient evidence to support the addition of erlotinib to bevacizumab maintenance as a new standard of care.

Johnson BE, Kabbinavar F, Fehrenbacher L, et al. ATLAS: randomized, double-blind, placebo-controlled, phase IIIB trial comparing bevacizumab therapy with or without erlotinib, after completion of chemotherapy, with bevacizumab for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol, doi:10.1200/jco.2012.47.3983 (2013).

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Randomized Phase II Trial of Onartuzumab in Combination with Erlotinib in Patients with Advanced Non–Small-Cell Lung Cancer Based on MET Status

The authors evaluated the clinical benefit of inhibiting MET/epidermal growth factor receptor in patients with non–small-cell lung cancer, in which up-regulated hepatocyte growth factor/MET activity has been shown to link to poor prognosis and resistance to anti–epidermal growth factor receptor therapy. Onartuzumab/erlotinib or placebo/erlotinib was randomly assigned to patients with recurrent non–small-cell lung cancer. MET status was determined by immunohistochemistry on tumor tissues. No improvement of progression-free survival (PFS) and overall survival (OS) was observed in the intent-to-treat population (n = 137, hazard ratio [HR], 1.09; p = 0.69; OS HR, 0.80; p = 0.34) whereas prolonged PFS and OS were found in MET-positive patients receiving onartuzumab/erlotinib (PFS HR, 0.53; p = 0.04; OS HR, 0.37; p= 0.002). Onartuzumab/erlotinib-treated MET-negative patients had worse PFS (HR, 1.82; p = 0.05) and OS (HR, 1.78; p = 0.16). Worse PFS (HR, 1.71; p = 0.06) and OS (HR, 2.61; p = 0.004) were found in MET-positive control versus MET-negative control patients. Taken together, the findings demonstrated that MET-positive patients receiving onartuzumab/erlotinib showed better clinical outcomes, and underscore the importance of MET status testing in optimizing treatment outcomes. A phase III study is ongoing.

Spigel DR, Ervin TJ, Ramlau RA, et al. Randomized phase II Trial of onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol, doi:10.1200/jco.2012.47.4189 (2013).

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NEWS IN BRIEF

European Cancer Congress (ECC) 2013: New Anti–PD-L1 Antibody Shows Efficacy in Metastatic NSCLC Patients Including Smokers
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A phase I trial study evaluating the novel anti–PD-L1 antibody, MPDL3280A, showed promising results in the treatment of patients with metastatic non–small-cell lung cancer, including smokers and nonsmokers, with squamous and adenoma tumors. The non–small-cell lung cancer cohort is the largest group under anti–PD-L1 treatment to date, with 138 patients evaluable for safety and efficacy, and 81% of current or former smokers. Objective response rate (ORR) of 23% was achieved in this cohort; the 24-week progression-free survival rate of 44% was observed in patients with squamous tumors and 46% in nonsquamous tumors. Smoking status and PD-L1 expression on immunohistochemistry were predictive of response. Higher level of PD-L1 expression was associated with increased ORR and decreased progressive disease. Former smokers showed a 26% ORR whereas never-smokers demonstrated a 10% ORR. The treatment seemed to be well tolerated, with generally grade 1 and 2 adverse events.

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American Society of Therapeutic Radiology Oncology (ASTRO) 2013: PET Could Identify High-Risk Early Lung Cancer
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At the American Society of Therapeutic Radiology Oncology meeting, Mancini and colleagues presented the findings from their retrospective study on the use of positron emission tomography imaging to identify prognostic markers for patients with inoperable, early non–small-cell lung cancer before and after stereotactic body radiation therapy (SBRT). Of the 171 patients with T1-3 N0M0 non–small-cell lung cancer treated with SBRT, median survival was 14.65 months at a median follow-up of 14 months. The absolute reduction in SUVmax, the maximum change in standardized uptake value, was one of the four independent predictors of any SBRT failure (hazard ratio, 0.856, p=0.005). Other predictors were age, tumor size, and squamous-cell histology. A lower pretreatment SUV was associated with prolonged overall survival (hazard ratio, 1.132, p=0.001). These findings, if confirmed in prospective studies with standardized positron emission tomography protocol, could stratify low- and high-risk patients for clinical decision making.

Photo source: National Institutes of Health

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Anesthesiology™ 2013 Annual Meeting: Simple Blood Test May Diagnose Lung and Other Cancers
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According to the data presented by Daniel I. Sessler from The Cleveland Clinic, a blood test that measures serum free fatty acids and their metabolites could differentiate patients with lung cancer (55) and prostate cancer (40) from propensity-matched controls. Up to sixfold higher levels of serum free fatty acids and metabolites were observed in lung cancer patients versus controls (areas under the receiver operating characteristics curve: 0.71–0.82, p<0.001). Levels of these markers dropped by three to 10 times within 24 hours after lung tumor resections. Dr. Sessler suggested that this test, rather than widespread screening, could potentially be useful in high-risk patients and be used in parallel with other tests, for example, computed tomography screening. It is also considered most useful in monitoring recurrence postresection. A prospective trial will be underway to validate the blood test as a biomarker for recurrence.

Photo source: CDC

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Outdoor Air Pollution a Leading Environmental Cause of Cancer Deaths ( http://ecancer.org/news/4616-outdoor-air-pollution-a-leading-environmental-cause-of-cancer-deaths.php)
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Outdoor air pollution has been classified as carcinogenic by the International Agency for Research on Cancer of WHO. More than 1000 scientific literature articles on analysis of carcinogenicity of air pollutants across Europe, Asia, and North and South America were reviewed. Particulate matter and transportation-related pollution were among the air pollutants analyzed. Strong evidence from the review demonstrated significantly increased risk of developing lung cancer in people exposed to outdoor air pollution. An association of exposure to air pollution with increased risk of bladder cancer was also observed. This is the first time that experts have classified outdoor air pollution as a cause of cancer, and it should serve as a strong message for prompt measures in reducing air pollution worldwide.

Copyright © 2013 by the International Association for the Study of Lung Cancer

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