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Medical Abstracts
Keyword: lung cancer
Publication Date from 2010/03/01 to 2010/03/31
1. Pathobiology. 2010;77(2):53-63. Epub 2010 Mar 22.
Key genes in lung cancer translational research: a meta-analysis.
Amelung JT, Bührens R, Beshay M, Reymond MA.
Westfalian Wilhelms University Münster, Münster, Germany.
In lung cancer, integrating translational data from various histologies obtained
in different patients under different conditions can increase their robustness.
This is a meta-analysis of cDNA array data obtained in 688 tumor patients (541
non-small cell lung cancer, 33 small cell lung cancer and 114 others) and 205
controls. 1,206 genes were found to be dysregulated in one of the 12
transcriptomics studies available. 748 results (62%) were obtained only once and
might be questioned. 38% of observations could be reproduced twice or more. 346
genes were reported twice, 80 three times, 27 four and 5 five times. A common set
of genes dysregulated in lung cancer was obtained, including BPA1, DUSP6, ASCL1,
RNAS1 and S100P. p63 and CK 5/6 p63 are useful for differentiating adenocarcinoma
and small cell lung cancer from squamous cell carcinoma. TFF-3 and MUC1 are
over-expressed in adenocarcinoma. INSM1, SGNE1 and H2AFZ are typical for small
cell lung cancer. Using a meta-analysis approach, it was possible to detect a
robust set of genes differentially expressed in lung cancer and to determine a
limited number of key genes linked to subtypes in lung cancer molecular
pathology.
PMID: 20332665 [PubMed - in process]
2. Cancer Res. 2010 Apr 1;70(7):2779-88. Epub 2010 Mar 23.
Aberrant DNA methylation links cancer susceptibility locus 15q25.1 to apoptotic
regulation and lung cancer.
Paliwal A, Vaissière T, Krais A, Cuenin C, Cros MP, Zaridze D, Moukeria A,
International Agency for Research on Cancer, Lyon, France.
Nicotinic acetylcholine receptor (nAChR) genes form a highly conserved gene
cluster at the lung cancer susceptibility locus 15q25.1. In this study, we show
that the CHRNalpha3 gene encoding the nAChRalpha3 subunit is a frequent target of
aberrant DNA hypermethylation and silencing in lung cancer, whereas the adjacent
CHRNbeta4 and CHRNalpha5 genes exhibit moderate and no methylation, respectively.
Treatment of cancer cells exhibiting CHRNalpha3 hypermethylation with DNA
methylation inhibitors caused demethylation of the CHRNalpha3 promoter and gene
reactivation. Restoring CHRNalpha3 levels through ectopic expression induced
apoptotic cell death. Small hairpin RNA-mediated depletion of nAChRalpha3 in
CHRNalpha3-expressing lung cancer cells elicited a dramatic Ca(2+) influx
response in the presence of nicotine, followed by activation of the Akt survival
pathway. CHRNalpha3-depleted cells were resistant to apoptosis-inducing agents,
underscoring the importance of epigenetic silencing of the CHRNalpha3 gene in
human cancer. In defining a mechanism of epigenetic control of nAChR expression
in nonneuronal tissues, our findings offer a functional link between
susceptibility locus 15q25.1 and lung cancer, and suggest nAChRs to be
theranostic targets for cancer detection and chemoprevention.
PMID: 20332232 [PubMed - in process]
3. JAMA. 2010 Mar 17;303(11):1070-6.
Stereotactic body radiation therapy for inoperable early stage lung cancer.
Timmerman R, Paulus R, Galvin J, Michalski J, Straube W, Bradley J, Fakiris A,
Department of Radiation Oncology, University of Texas Southwestern Medical
Center, Dallas, TX 75390, USA. robert.timmerman@utsouthwestern.edu
CONTEXT: Patients with early stage but medically inoperable lung cancer have a
poor rate of primary tumor control (30%-40%) and a high rate of mortality (3-year
survival, 20%-35%) with current management. OBJECTIVE: To evaluate the toxicity
and efficacy of stereotactic body radiation therapy in a high-risk population of
patients with early stage but medically inoperable lung cancer. DESIGN, SETTING,
AND PATIENTS: Phase 2 North American multicenter study of patients aged 18 years
or older with biopsy-proven peripheral T1-T2N0M0 non-small cell tumors (measuring
<5 cm in diameter) and medical conditions precluding surgical treatment. The
prescription dose was 18 Gy per fraction x 3 fractions (54 Gy total) with entire
treatment lasting between 1(1/2) and 2 weeks. The study opened May 26, 2004, and
closed October 13, 2006; data were analyzed through August 31, 2009. MAIN OUTCOME
MEASURES: The primary end point was 2-year actuarial primary tumor control;
secondary end points were disease-free survival (ie, primary tumor, involved
lobe, regional, and disseminated recurrence), treatment-related toxicity, and
overall survival. RESULTS: A total of 59 patients accrued, of which 55 were
evaluable (44 patients with T1 tumors and 11 patients with T2 tumors) with a
median follow-up of 34.4 months (range, 4.8-49.9 months). Only 1 patient had a
primary tumor failure; the estimated 3-year primary tumor control rate was 97.6%
(95% confidence interval [CI], 84.3%-99.7%). Three patients had recurrence within
the involved lobe; the 3-year primary tumor and involved lobe (local) control
rate was 90.6% (95% CI, 76.0%-96.5%). Two patients experienced regional failure;
the local-regional control rate was 87.2% (95% CI, 71.0%-94.7%). Eleven patients
experienced disseminated recurrence; the 3-year rate of disseminated failure was
22.1% (95% CI, 12.3%-37.8%). The rates for disease-free survival and overall
survival at 3 years were 48.3% (95% CI, 34.4%-60.8%) and 55.8% (95% CI,
41.6%-67.9%), respectively. The median overall survival was 48.1 months (95% CI,
29.6 months to not reached). Protocol-specified treatment-related grade 3 adverse
events were reported in 7 patients (12.7%; 95% CI, 9.6%-15.8%); grade 4 adverse
events were reported in 2 patients (3.6%; 95% CI, 2.7%-4.5%). No grade 5 adverse
events were reported. CONCLUSION: Patients with inoperable non-small cell lung
cancer who received stereotactic body radiation therapy had a survival rate of
55.8% at 3 years, high rates of local tumor control, and moderate
treatment-related morbidity.
PMID: 20233825 [PubMed - indexed for MEDLINE]
4. J Clin Oncol. 2010 Apr 10;28(11):1942-9. Epub 2010 Mar 8.
Are the most distressing concerns of patients with inoperable lung cancer
adequately assessed? A mixed-methods analysis.
Tishelman C, Lövgren M, Broberger E, Hamberg K, Sprangers MA.
Stockholms Sjukhem, FoUU-enheten, Karolinska Institutet, Mariebergsgatan 22,
11235 Stockholm, Sweden. carol.tishelman@ki.se
PURPOSE Standardized questionnaires for patient-reported outcomes are generally
composed of specified predetermined items, although other areas may also cause
patients distress. We therefore studied reports of what was most distressing for
343 patients with inoperable lung cancer (LC) at six time points during the first
year postdiagnosis and how these concerns were assessed by three quality-of-life
and symptom questionnaires. PATIENTS AND METHODS Qualitative analysis of
patients' responses to the question "What do you find most distressing at
present?" generated 20 categories, with 17 under the dimensions of "bodily
distress," "life situation with LC," and "iatrogenic distress." Descriptive and
inferential statistical analyses were conducted. RESULTS The majority of
statements reported as most distressing related to somatic and psychosocial
problems, with 26% of patients reporting an overarching form of distress instead
of specific problems at some time point. Twenty-seven percent reported some facet
of their contact with the health care system as causing them most distress. While
55% to 59% of concerns reported as most distressing were clearly assessed by the
European Organisation for Research and Treatment for Cancer Quality of Life
Questionnaire Core-30 and Lung Cancer Module instruments, the Memorial Symptom
Assessment Scale, and the modified Distress Screening Tool, iatrogenic distress
is not specifically targeted by any of the three instruments examined. CONCLUSION
Using this approach, several distressing issues were found to be commonly
reported by this patient group but were not assessed by standardized
questionnaires. This highlights the need to carefully consider choice of
instrument in relation to study objectives and characteristics of the sample
investigated and to consider complementary means of assessment in clinical
practice.
PMID: 20212257 [PubMed - in process]
5. Curr Opin Oncol. 2010 Mar;22(2):102-11.
Adjuvant or neoadjuvant chemotherapy in minimal N2 stage IIIA nonsmall cell lung
cancer.
De Craene S, Surmont V, van Meerbeeck JP.
Department of Respiratory Medicine and Thoracic Oncology, University Hospital
Ghent, Belgium.
PURPOSE OF REVIEW: In the last decade, numerous randomized trials have evaluated
the benefit of (neo-)adjuvant chemotherapy in nonsmall cell lung cancer. This
article will review the recent data on perioperative chemotherapy in stage III
A-N2 nonsmall cell lung cancer and future research opportunities are presented.
RECENT FINDINGS: Four retrospective series, two phase 2 and four phase 3 trials
in the neoadjuvant setting and one retrospective series, two phase 2 trials and
two phase 3 trials in the adjuvant setting are retrieved and discussed. SUMMARY:
The available evidence does not allow to change the current recommendation
regarding the management of patients presenting with biopsy-proven clinical stage
IIIA-N2 nonsmall cell lung cancer: their preferred treatment is
chemoradiotherapy. Surgery with neoadjuvant or adjuvant chemotherapy is not
proven superior to radiotherapy. The patient occasionally presenting with
unforeseen pN2 despite adequate preoperative mediastinal staging should be
offered adjuvant cisplatin-based chemotherapy and possibly postoperative
radiotherapy.
PMID: 20180283 [PubMed - in process]
6. Clin Cancer Res. 2010 Mar 1;16(5):1452-65. Epub 2010 Feb 23.
Comparative profiling of the novel epothilone, sagopilone, in xenografts derived
from primary non-small cell lung cancer.
Hammer S, Sommer A, Fichtner I, Becker M, Rolff J, Merk J, Klar U, Hoffmann J.
Bayer Schering Pharma AG, Global Drug Discovery, Berlin, Germany.
stefanie.hammer@bayerhealthcare.com
PURPOSE: Characterization of new anticancer drugs in a few xenograft models
derived from established human cancer cell lines frequently results in the
discrepancy between preclinical and clinical results. To take the heterogeneity
of tumors into consideration more thoroughly, we describe here a preclinical
approach that may allow a more rational clinical development of new anticancer
drugs. EXPERIMENTAL DESIGN: We tested Sagopilone, an optimized fully synthetic
epothilone, in 22 well-characterized patient-derived non-small cell lung cancer
models and correlated results with mutational and genome-wide gene expression
analysis. RESULTS: Response analysis according to clinical trial criteria
revealed that Sagopilone induced overall responses in 64% of the xenograft models
(14 of 22), with 3 models showing stable disease and 11 models showing partial
response. A comparison with response rates for established drugs showed the
strong efficacy of Sagopilone in non-small cell lung cancer. In gene expression
analyses, Sagopilone induced tubulin isoforms in all tumor samples, but genes
related to mitotic arrest only in responder models. Moreover, tumors with high
expression of genes involved in cell adhesion/angiogenesis as well as of
wild-type TP53 were more likely to be resistant to Sagopilone therapy. As
suggested by these findings, Sagopilone was combined with Bevacizumab and
Sorafenib, drugs targeting vascular endothelial growth factor signaling, in
Sagopilone-resistant models and, indeed, antitumor activity could be restored.
CONCLUSION: Analyses provided here show how preclinical studies can provide
hypotheses for the identification of patients who more likely will benefit from
new drugs as well as a rationale for combination therapies to be tested in
clinical trials.
PMID: 20179216 [PubMed - in process]
7. Radiology. 2010 Mar;254(3):949-56.
Perifissural nodules seen at CT screening for lung cancer.
Ahn MI, Gleeson TG, Chan IH, McWilliams AM, Macdonald SL, Lam S, Atkar-Khattra S,
Department of Radiology, Vancouver General Hospital, 899 W 12th Ave, Vancouver,
BC, Canada V5Z 1M9.
Purpose: To describe and characterize the potential for malignancy of
noncalcified lung nodules adjacent to fissures that are often found in current or
former heavy smokers who undergo computed tomography (CT) for lung cancer
screening. Materials and Methods: Institutional review board approval and
informed consent were obtained. Baseline and follow-up thin-section multidetector
CT scans obtained in 146 consecutive subjects at high risk for lung cancer (age
range, 50-75 years; > 30 pack-year smoking history) were retrospectively
reviewed. Noncalcified nodules (NCNs) were categorized according to location
(parenchymal, perifissural), shape, septal connection, manually measured
diameter, diameter change, and lung cancer outcome at 7(1/2) years. Results:
Retrospective review of images from 146 baseline and 311 follow-up CT
examinations revealed 837 NCNs in 128 subjects. Of those 837 nodules, 234 (28%),
in 98 subjects, were adjacent to a fissure and thus classified as perifissural
nodules (PFNs). Multiple (range, 2-14) PFNs were seen in 47 subjects. Most PFNs
were triangular (102/234, 44%) or oval (98/234, 42%), were located inferior to
the carina (196/234, 84%), and had a septal connection (171/234, 73%). The mean
maximal length was 3.2 mm (range, 1-13 mm). During 2-year follow-up in 71
subjects, seven of 159 PFNs increased in size on one scan but were then stable.
The authors searched a lung cancer registry 7(1/2) years after study entry and
found 10 lung cancers in 139 of 146 study subjects who underwent complete
follow-up; none of these cancers had originated from a PFN. Conclusion: PFNs are
frequently seen on screening CT scans obtained in high-risk subjects. Although
PFNs may show increased size at follow-up CT, the authors in this study found
none that had developed into lung cancer; this suggests that the malignancy
potential of PFNs is low. (c) RSNA, 2010.
PMID: 20177105 [PubMed - indexed for MEDLINE]
8. Ann Surg. 2010 Mar;251(3):550-4.
Limited resection for the treatment of patients with stage IA lung cancer.
Wisnivesky JP, Henschke CI, Swanson S, Yankelevitz DF, Zulueta J, Marcus S,
Division of General Internal Medicine, Mount Sinai School of Medicine, New York,
NY, USA. juan.wisnivesky@mssm.edu
OBJECTIVE: Lobectomy is the standard of care for stage IA lung cancer. Some small
retrospective studies have suggested similar results after limited resection for
tumors < or =2 cm in size. The objective of the study was to compare survival
after lobectomy and limited resection among Medicare patients with lung cancer.
METHODS: Using the Surveillance, Epidemiology, and End Results registry, linked
to Medicare records, we identified 1165 cases of stage I lung cancer < or =2 cm
in size that underwent lobectomy or limited resection (segmentectomy or wedge
resection). We used logistic regression to determine propensity scores for
undergoing limited resection based on the patients' preoperative characteristics.
Overall and lung cancer-specific survival of patients treated with lobectomy or
limited resection was compared after adjusting for their propensity score.
RESULTS: Overall, 196 (17%) patients underwent limited resection. For the entire
sample, the adjusted hazard ratio for all cause mortality (1.09; 95% confidence
interval: 0.85-1.40) or lung cancer-specific death (hazard ratio: 1.39; 95%
confidence interval: 0.97-2.01) for patients undergoing limited resection were
not significantly different from those having lobectomy. Similarly, we found no
significant differences in overall or lung cancer-specific survival for patients
treated with limited resection compared with lobectomy when data was analyzed
stratifying and matching patients by their propensity scores. CONCLUSIONS: These
results suggest that survival of patients >65 years of age undergoing limited
resection or lobectomy for stage IA tumors < or =2 cm appears to be similar.
Although these findings should be confirmed in prospective trials, our results
suggest that limited resection may be an effective therapeutic alternative for
these patients.
PMID: 20160639 [PubMed - indexed for MEDLINE]
9. J Clin Oncol. 2010 Mar 20;28(9):1527-33. Epub 2010 Feb 16.
Phase 1b study of dulanermin (recombinant human Apo2L/TRAIL) in combination with
paclitaxel, carboplatin, and bevacizumab in patients with advanced non-squamous
non-small-cell lung cancer.
Soria JC, Smit E, Khayat D, Besse B, Yang X, Hsu CP, Reese D, Wiezorek J,
Service des Innovations, Thérapeutiques Précoces, Département de Médecine,
Institut Gustave Roussy, Villejuif, France. jean-charles.soria@igr.fr
PURPOSE: To determine the safety, pharmacokinetics (PK), and maximum-tolerated
dose (MTD) up to a prespecified target dose of dulanermin in combination with
paclitaxel, carboplatin, and bevacizumab (PCB) in patients with previously
untreated, nonsquamous, stage IIIb (with pleural effusion)/IV or recurrent
non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: In this phase 1b study,
patients (n = 24) received PCB on day 1 of each 21-day cycle then dulanermin at 4
or 8 mg/kg/d for 5 consecutive days or 15 or 20 mg/kg/d for 2 consecutive days
per assigned treatment cohort. Incidence of dose-limiting toxicities (DLTs),
adverse events, and antidulanermin antibodies were assessed. PK parameters were
recorded for each agent. Tumor response was measured by modified Response
Evaluation Criteria in Solid Tumors. RESULTS: Twenty-four patients received at
least one dose of dulanermin plus PCB, six in each treatment cohort. There were
no DLTs. An MTD was not reached, and the drug combination was well tolerated.
Treatment-emergent adverse events were generally as expected for the PCB regimen.
Adverse events attributed to dulanermin were grade 1/2; no significant
hepatotoxicity occurred. There was minimal impact of PCB on the PK of dulanermin.
There was one confirmed complete response and 13 confirmed partial responses. The
overall response rate was 58% (95% CI, 37 to 78). Median progression-free
survival was 7.2 months (95% CI, 4.7 to 10.3). CONCLUSION: Dulanermin plus PCB
was well tolerated with no occurrence of DLTs and demonstrated antitumor activity
in this patient population. Dulanermin at 8 mg/kg/d for 5 days and 20 mg/kg/d for
2 days every 3 weeks in combination with PCB is being studied in a phase II
trial.
PMID: 20159815 [PubMed - in process]
10. Int J Oncol. 2010 Mar;36(3):635-40.
Secreted form of EphA7 in lung cancer.
Tsuboi M, Mori H, Bunai T, Kageyama S, Suzuki M, Okudela K, Takamochi K, Ogawa H,
Department of Pathology, Hamamatsu University School of Medicine, Higashi-ward,
Hamamatsu 431-3192, Japan.
EPHA7 is a member of the EPHA family of receptor kinases, among which several
members are known to be involved in human lung carcinogenesis. We report here a
novel spliced variant, the so-called secreted form of EPHA7, recently reported in
malignant lymphoma, in human lung cancer cell lines and primary lung cancer. In
contrast to the EPHA7 down-regulation in colorectal cancer by promoter
hypermethylation, EPHA7 is expressed at a substantial level in most human lung
cancers and the secreted form of EPHA7 mRNA was found in a fraction of primary
lung cancer tissues, lung cancer cell lines, and immortalized bronchogenic
epithelial cell lines. Interestingly, the secreted form of EPHA7 message was
predominantly detected in non-adeno type lung carcinoma. The mechanistic role of
the secreted form of EPHA7 in human lung carcinogenesis is not clear, but the
presence of this form could distinctly exclude adenocarcinoma of the lung from
the other categories, i.e., squamous cell carcinoma, small cell carcinoma and
large cell carcinoma, which have strong association with smoking. This is the
first study to detect the secreted form of EPHA7 in human epithelial tissues.
EPHA7 warrants further investigation to determine its possible involvement in
smoking related lung carcinogenesis.
PMID: 20126984 [PubMed - in process]
11. Eur J Pharm Sci. 2010 Mar 18;39(5):402-11. Epub 2010 Jan 25.
In vivo assessment of temozolomide local delivery for lung cancer inhalation
therapy.
Wauthoz N, Deleuze P, Hecq J, Roland I, Saussez S, Adanja I, Debeir O,
Laboratoire de Pharmacie Galénique et de Biopharmacie, Institut de Pharmacie,
Université Libre de Bruxelles , boulevard du triomphe, CP207, 1050 Brussels,
Belgium. nawautho@ulb.ac.be
The aim of this study was to compare the efficacy of local drug delivery by
inhalation to intravenous delivery in a B16F10 melanoma metastatic lung model.
Temozolomide was formulated as a suspension, which was elaborated and evaluated
in terms of particle size, shape and agglomeration. An endotracheal
administration device was used to aerosolise the suspension. This mode of
delivery was evaluated at different temozolomide concentrations and was optimized
for the uniformity of delivered dose, the droplet size distribution and the
distribution of droplets in vivo. Of the particles in the stabilised suspension,
79% were compatible with the human respirable size range, and this formulation
retained 100% in vitro anticancer activity as compared to temozolomide alone in
three distinct cancer cell lines. The pulmonary delivery device provided good
reproducibility in terms of both the dose delivered and the droplet size
distribution. Most of the lung tissues that were exposed to aerosol droplets
contained the particles, as revealed by fluorescent microscopy techniques. The
global in vivo antitumour activity of the inhaled temozolomide provided a median
survival period similar to that for intravenous temozolomide delivery, and three
out of 27 mice (11%) survived with almost complete eradication of the lung
tumours. The present study thus shows that inhalation of a simple liquid
formulation is well tolerated and active against a very biologically aggressive
mouse melanoma pulmonary pseudo-metastatic model. This inhalation delivery could
be used to deliver other types of anticancer drugs. Copyright 2010 Elsevier B.V.
All rights reserved.
PMID: 20109545 [PubMed - in process]
12. Cancer. 2010 Mar 15;116(6):1518-25.
Five-year lung cancer survival: which advanced stage nonsmall cell lung cancer
patients attain long-term survival?
Wang T, Nelson RA, Bogardus A, Grannis FW Jr.
Department of Thoracic Surgery, City of Hope National Medical Center, Duarte, CA
91010, USA.
BACKGROUND: The core strategy of American College of Chest Physicians lung cancer
guidelines is identification of the earliest symptoms of lung cancer and the
immediate initiation of diagnosis and treatment. In the absence of screening,
most symptomatic lung cancer is discovered at advanced stages, with the goal of
long-term survival entirely dependent on effective treatment of stage III and IV
lung cancer. METHODS: In a retrospective review, all patients diagnosed with
stage IIIA, IIIB, and IV nonsmall cell lung cancer (NSCLC) between the years 1986
and 2001 at City of Hope National Medical Center who survived 5 years or longer
were analyzed to identify parameters that might predict long-term survival.
RESULTS: Of 846 patients presenting with stage III or IV disease, 56 (6.6%)
survived 5 years or longer. Sixteen patients died of primary tumor progression
beyond 5 years. Two 5-year survivors died of second tobacco-caused neoplasms, and
16 died from medical conditions potentially related to prior treatment. A
substantial majority of survivors were from specific pathologic subsets
including: 1) resectable N2 disease (n = 17, 30.4%), 2) multiple lung tumors (n =
7, 12.5%), 3) T3N0 (n = 5, 8.1%), and 4) single site distant metastasis (n = 8,
14.2%). CONCLUSIONS: Despite aggressive multimodality therapy, 5-year survival in
patients with advanced stage NSCLC was very poor and limited to small
pathological subsets. Patients with advanced stage NSCLC who did not belong to 1
of these subsets had a small chance of long-term survival.
PMID: 20108308 [PubMed - in process]
13. Cancer Metastasis Rev. 2010 Mar;29(1):61-72.
Evidence for self-renewing lung cancer stem cells and their implications in tumor
initiation, progression, and targeted therapy.
Sullivan JP, Minna JD, Shay JW.
Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center,
Dallas, TX, 75390, USA. james.sullivan@utsouthwestern.edu
The discovery of rare tumor cells with stem cell features first in leukemia and
later in solid tumors has emerged as an important area in cancer research. It has
been determined that these stem-like tumor cells, termed cancer stem cells, are
the primary cellular component within a tumor that drives disease progression and
metastasis. In addition to their stem-like ability to self-renew and
differentiate, cancer stem cells are also enriched in cells resistant to
conventional radiation therapy and to chemotherapy. The immediate implications of
this new tumor growth paradigm not only require a re-evaluation of how tumors are
initiated, but also on how tumors should be monitored and treated. However,
despite the relatively rapid pace of cancer stem cell research in solid tumors
such as breast, brain, and colon cancers, similar progress in lung cancer remains
hampered in part due to an incomplete understanding of lung epithelial stem cell
hierarchy and the complex heterogeneity of the disease. In this review, we
provide a critical summary of what is known about the role of normal and
malignant lung stem cells in tumor development, the progress in characterizing
lung cancer stem cells and the potential for therapeutically targeting pathways
of lung cancer stem cell self-renewal.
PMID: 20094757 [PubMed - in process]
14. Cancer. 2010 Mar 1;116(5):1155-64.
Implications of key trials in advanced nonsmall cell lung cancer.
Bonomi PD.
Division of Hematology/Oncology, Rush University Medical Center, Chicago, IL,
USA. philip_bonomi@rsh.net
Many different targeted therapies with varying mechanisms of action have been
added to standard first-line chemotherapy doublets in an effort to improve
survival of patients with advanced nonsmall cell lung cancer (NSCLC). Only 2
targeted therapies-bevacizumab and cetuximab-have been associated with superior
survival in phase 3 first-line studies. For both agents, the decision to enter
phase 3 was based on results from randomized phase 2 trials, unlike other
targeted therapies where the decision was made using either phase 1 or single
study arm phase 2 results. There is also mounting evidence that patient selection
will play a key role in the successful development of any targeted agent.
Bevacizumab is indicated for patients with nonsquamous NSCLC who do not have
certain comorbidities. Use of cetuximab is not restricted by safety factors, but
may be focused on patients whose tumors are epidermal growth factor receptor
(EGFR)-dependent; whether EGFR expression or absence of KRAS mutations are
appropriate markers is still under study. By including randomized phase 2 trials
in the development pathway, and by improving patient selection for individual
agents (enriching trials with patients most likely to respond), it may be
possible to enhance the success rate of future phase 3 clinical trials and, in
turn, define future clinical practice with improved patient outcomes.
PMID: 20087963 [PubMed - indexed for MEDLINE]
15. Curr Opin Oncol. 2010 Mar;22(2):79-85.
Antiangiogenic agents in the treatment of nonsmall cell lung cancer: reality and
hope. Ramalingam SS, Belani CP.
Emory University, Winship Cancer Institute, Atlanta, Georgia, USA.
PURPOSE OF REVIEW: Angiogenesis is critical for tumor growth and progression.
Strategies to inhibit angiogenesis have gained a strong foothold for the
treatment of a variety of malignancies. This review will provide the relevant
interventions targeted against specific angiogenesis pathways with or without
known effective therapies for nonsmall cell lung cancer (NSCLC). RECENT FINDINGS:
Bevacizumab, a mAb against the vascular endothelial growth factor, has been
approved by the U.S. Food and Drug Administration for the treatment of patients
with advanced stage nonsquamous NSCLC in combination with the
carboplatin-paclitaxel regimen. This has prompted the evaluation of a variety of
novel agents for the treatment of NSCLC. Agents that inhibit the vascular
endothelial growth factor receptor tyrosine kinase are currently under extensive
investigation, but the initial results with combination strategies have not been
encouraging. Identification of predictive biomarkers for antiangiogenic agents
continues to be elusive and remains a major focus of ongoing research. Apart from
vascular endothelial growth factor, other targets within the angiogenic pathway
are also being evaluated in the clinical setting. SUMMARY: In this article, we
review the recent data with antiangiogenic agents in NSCLC and their implications
for clinical use and future research.
PMID: 20009926 [PubMed - in process]
16. Am J Respir Crit Care Med. 2010 Mar 1;181(5):478-85. Epub 2009 Dec 10.
Fluorescence in situ hybridization testing algorithm improves lung cancer
detection in bronchial brushing specimens.
Voss JS, Kipp BR, Halling KC, Henry MR, Jett JR, Clayton AC, Rickman OB.
Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation,
Rochester, Minnesota, USA.
RATIONALE: Bronchoscopically collected cytology specimens are commonly used to
obtain a diagnosis of cancer in patients with pulmonary lesions. However, the
sensitivity of cytology is suboptimal, especially for peripheral lesions less
than 2 cm in diameter. OBJECTIVES: We assessed the performance of a testing
algorithm using cytology and fluorescence in situ hybridization (FISH) as part of
clinical practice. METHODS: Bronchial brushing specimens (n = 343) were obtained
from patients undergoing bronchoscopy for indeterminate pulmonary lesions.
Routine cytology was performed and specimens without a positive diagnosis (n =
294) were analyzed by FISH, using residual brushing material. Pathology-confirmed
lung cancer or clinical/radiographic evidence of disease was considered
diagnostic of malignancy. MEASUREMENTS AND MAIN RESULTS: Routine cytology had a
sensitivity and specificity of 41% (23 of 56) and 100% (45 of 45) for central
lesions and 20% (26 of 133) and 100% (109 of 109) for peripheral nodules,
respectively. FISH detected an additional 32% of lung cancers (18 central and 43
peripheral) not detectable by cytology alone, while producing false positive
diagnoses in 22% (10 of 45) and 6% (6 of 109) benign central and peripheral
lesions, respectively. In peripheral nodules, FISH detected (relative to routine
cytology) an additional 44% (15 of 34) and 28% (25 of 91) of lung cancers less
than 2 cm and 2 cm or more in size, respectively. A positive FISH result had a
likelihood ratio of 1.45 and 5.87 for central and peripheral lesions and 3.44 and
15.38 for peripheral nodules less than 2 cm and 2 cm or more in size,
respectively. CONCLUSIONS: FISH testing significantly increases the detection of
lung cancer over routine cytology alone. It is especially useful for peripheral
nodules.
PMID: 20007925 [PubMed - indexed for MEDLINE]
17. Oncogene. 2010 Mar 11;29(10):1421-30. Epub 2009 Dec 7.
Genomic and functional analysis identifies CRKL as an oncogene amplified in lung
cancer.
Kim YH, Kwei KA, Girard L, Salari K, Kao J, Pacyna-Gengelbach M, Wang P,
Hernandez-Boussard T, Gazdar AF, Petersen I, Minna JD, Pollack JR.
Department of Pathology, Stanford University, Stanford, CA 94305-5176, USA.
DNA amplifications, leading to the overexpression of oncogenes, are a cardinal
feature of lung cancer and directly contribute to its pathogenesis. To uncover
such novel alterations, we performed an array-based comparative genomic
hybridization survey of 128 non-small-cell lung cancer cell lines and tumors.
Prominent among our findings, we identified recurrent high-level amplification at
cytoband 22q11.21 in 3% of lung cancer specimens, with another 11% of specimens
exhibiting low-level gain spanning that locus. The 22q11.21 amplicon core
contained eight named genes, only four of which were overexpressed (by transcript
profiling) when amplified. Among these, CRKL encodes an adapter protein
functioning in signal transduction, best known as a substrate of the BCR-ABL
kinase in chronic myelogenous leukemia. RNA-interference-mediated knockdown of
CRKL in lung cancer cell lines with (but not without) amplification led to
significantly decreased cell proliferation, cell-cycle progression, cell
survival, and cell motility and invasion. In addition, overexpression of CRKL in
immortalized human bronchial epithelial cells led to enhanced growth
factor-independent cell growth. Our findings indicate that amplification and
resultant overexpression of CRKL contribute to diverse oncogenic phenotypes in
lung cancer, with implications for targeted therapy, and highlight a role of
adapter proteins as primary genetic drivers of tumorigenesis.
PMID: 19966867 [PubMed - in process]
18. Respir Med. 2010 Mar;104(3):434-9. Epub 2009 Nov 12.
Trends in chemotherapy for elderly patients with advanced non-small-cell lung
cancer.
Kim YH, Yoh K, Niho S, Goto K, Ohmatsu H, Kubota K, Nishiwaki Y.
Division of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1
Kashiwanoha, Kashiwa, Chiba 277-8577, Japan. ekim@kuhp.kyoto-u.ac.jp
BACKGROUND: In approximately the year 2000, the results of a number of important
studies of non-small-cell lung cancer (NSCLC) were published. METHODS: Between
July 1992 and December 2003, 223 patients with NSCLC aged > or = 70 years
received chemotherapy alone as their initial treatment at the National Cancer
Center Hospital East. These patients were divided into 2 groups: those that began
treatment between 1992 and 1999 (group A) and between 2000 and 2003 (group B).
The details of chemotherapy regimens and outcomes were compared. RESULTS: In
group A, 83% of patients received platinum-based chemotherapy, two-thirds of
these regimens comprised platinumplus second-generation combination chemotherapy.
In contrast, although 55% of patients received platinum-based chemotherapy in
group B, 41% of patients received non-platinum-based chemotherapy. Among patients
in group B, performance status was significantly associated with the selection of
platinum-based or non-platinum-based chemotherapy; age was marginally associated
with this selection. Median survival time (MST), 1-year survival rate, and 2-year
survival rate were 6.7 months, 14%, and 7%, respectively, in group A, and 8.1
months, 35%, and 20% in group B (p=0.0109). Multivariate analysis revealed that
clinical stage and administration of salvage chemotherapy were independent
prognostic factors. CONCLUSIONS: In and after the year 2000, chemotherapy
regimens changed greatly and survival of elderly patients significantly improved
in our institute, and this improvement appears to be attributable mostly to the
effect of salvage chemotherapy. These results suggest that even elderly patients
should be offered salvage chemotherapy regardless of age, if possible. Crown
Copyright 2009. Published by Elsevier Ltd. All rights reserved.
PMID: 19913397 [PubMed - in process]
19. Eur J Cardiothorac Surg. 2010 Mar;37(3):540-5. Epub 2009 Aug 21.
Quality study of a lung cancer committee: study of agreement between preoperative
and pathological staging.
Macia I, Moya J, Escobar I, Ramos R, Masuet C, Gamez C, Llatjos R,
Department of Thoracic Surgery, Lung Functional Unit, Hospital Universitari de
Bellvitge and Hospital Duran i Reynals-Institut Català d'Oncologia, L'Hospitalet
de Llobregat, Barcelona, Spain. ivanmacia@yahoo.com
OBJECTIVE: Accurate preoperative staging is essential to provide the best
treatment for lung cancer. The objective of the present study was to determine
agreement between preoperative and surgical-pathological staging and to analyse
the impact of any disparity on treatment. METHODS: This is a descriptive study of
a series of 176 lung cancer cases treated by surgery between 2005 and 2007.
Preoperative staging was based on clinical information and computed tomography
(CT), positron emission tomography (PET), PET-CT, bronchoscopy and
mediastinoscopy. In all cases, surgical-pathological staging was based on the
analysis of surgical samples and the findings during surgery. Both preoperative
and pathological stage determination were based on the TNM (tumour, node,
metastasis) classification established in 1997. Concordance was measured by
calculating agreement rates and the kappa value. RESULTS: Preoperative and
surgical-pathological staging agreed in 102 cases, an agreement rate of 58% and
kappa value of 0.54 (95% confidence interval (CI) 0.44-0.63). The highest kappa
value (0.68, 95% CI 0.53-0.82) was obtained in stage IA patients. Patients who
underwent PET or PET-CT had a better kappa index (0.56, 95% CI 0.45-0.67, vs
0.39, 95% CI 0.21-0.56). Surgical-pathological staging validated surgery in 145
cases (82%), while 21 (12%) were revised to stage IIIA N2 and 10 (6%) to
non-surgical stages. CONCLUSIONS: Global agreement between preoperative and
surgical-pathological staging was moderate. The best agreement was found in
stages IV and IA. Copyright (c) 2009 European Association for Cardio-Thoracic
Surgery. Published by Elsevier B.V. All rights reserved.
PMID: 19699648 [PubMed - in process]
20. Eur J Radiol. 2010 Mar;73(3):510-7. Epub 2009 Feb 25.
Thin-section CT of the mediastinum in preoperative N-staging of non-small cell
lung cancer: comparison with FDG PET.
Nambu A, Kato S, Motosugi U, Araki T, Okuwaki H, Nishikawa K, Saito A,
Department of Radiology, University of Yamanashi, Shimokawato, Chuo-shi,
Yamanashi Prefecture, Japan. nambu-a@gray.plala.or.jp
PURPOSE: To compare diagnostic capability of preoperative N-staging of lung
cancer between thin-section CT of the mediastinum and FDG PET, and 5mm slice
thickness CT. MATERIALS AND METHODS: The subjects were 34 patients with lung
carcinoma who were examined by both CT and PET, and subsequently underwent
surgery between May 2005 and January 2007. CT was carried out with a 16 detector
row helical CT scanner. The raw data were reconstructed into 5 mm slice thickness
and 1mm slice thickness (thin-section CT). A total of 251 lymph node stations
were retrospectively assessed for the presence of lymph node metastasis with
thin-section CT, 5 mm CT and PET. In the interpretations of thin-section CT and 5
mm CT, we employed multi-criteria as follows: nodular calcification and
intranodal fat as benign criteria, and short-axis diameter more than 10 mm (size
criterion), focal low density other than fat, surrounding fat infiltration and
convex margin in hilar lymph nodes, as malignant criteria. On PET, maximum
standardized uptake value (SUVmax) of 2.5 or more was used as the criterion of
malignancy. Sensitivity and specificity were compared between these examinations
using McNemar test. RESULTS: Sensitivities and specificities of thin-section CT,
5 mm CT and PET were 25%, 25%, 25%, and 97%, 94%, 98%, respectively. The
statistical analysis revealed that the specificity of 5 mm CT was significantly
lower than those of thin-section CT (p=0.039) and PET (p=0.006), while no
difference was present between thin-section CT and PET. CONCLUSION: Thin-section
CT of the mediastinum using multiple criteria was comparable to PET in
preoperative N-staging of lung cancer. Copyright 2009 Elsevier Ireland Ltd. All
rights reserved.
PMID: 19246170 [PubMed - in process]
21. Med Oncol. 2010 Mar;27(1):152-7. Epub 2009 Feb 26.
Concomitant chemoradiotherapy with cisplatin and docetaxel followed by surgery
and consolidation chemotherapy in patients with unresectable locally advanced
non-small cell lung cancer.
Kaya AO, Buyukberber S, Benekli M, Coskun U, Sevinc A, Akmansu M, Yildiz R,
Department of Medical Oncology, Gazi University Faculty of Medicine, Ankara,
Turkey.
AIMS: To evaluate preoperative concomitant chemoradiation using cisplatin plus
docetaxel followed by consolidation chemotherapy in patients with unresectable
locally advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS:
Medical records of patients with locally advanced unresectable NSCLC (stage IIIA
and IIIB) treated with concomitant chemoradiotherapy using cisplatin + docetaxel
combination followed by consolidation chemotherapy were retrospectively
evaluated. All the patients were consecutively treated. Chemotherapy consisted of
weekly cisplatin 20 mg/m(2) and docetaxel 20 mg/m(2) during radiotherapy.
Radiotherapy dose was 58-66 Gy given in 2 Gy fractions, 5 days per week. The
patients were subsequently referred to surgery if adequately downstaged.
Consolidation chemotherapy using cisplatin and docetaxel both at doses 75 mg/m(2)
every 3 weeks followed local therapy in all patients. RESULTS: A total of 54
patients were evaluated (49 males, 5 females with a median age of 58 years; 41
[75.9%] stage IIIB and 13 [24.1%] IIIA). Twelve patients (22.2%) achieved
pathologic complete response and 20 (37%) partial response. Downstaging was
possible in 32 patients (59.3%). Twenty-six patients (48.1%) were operated after
concomitant chemoradiotherapy (pneumonectomy [n = 2], lobectomy [n = 12], and
wedge resection [n = 12]). Toxicity was tolerable. Median progression-free
survival and overall survival (OS) for the entire cohort were 14 and 22 months,
respectively. In resected patients (n = 26), median PFS and OS have not been
reached with a median follow-up duration of 24 months. CONCLUSION: Preoperative
concomitant chemoradiation using weekly cisplatin and docetaxel followed by
surgery and consolidation chemotherapy is effective and well tolerated in
patients with unresectable locally advanced NSCLC.
PMID: 19242825 [PubMed - in process]
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