Lung cancer stem cells as a target for therapy.

Gorelik E, Lokshin A, Levina V.

University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.

levinav@upmc.edu.

Despite significant efforts in diagnosing and treating lung cancer, therapeutic

resistance remains a major unresolved clinical and scientific problem. Cancer

stem cells (CSCs) are thought to be responsible for the failure of current

chemotherapy of lung cancer. The concept of CSCs has radically changed the view

of cancer therapy. Today a majority of current treatment modalities target the

differentiated cancer cells and avoid the drug resistant cancer-initiating stem

cells. This review summarizes our understanding of lung CSCs and their role in

metastasis formation and growth of non- small-cells lung cancer (NSCLC). High

tumorigenic and metastatic properties of lung CSCs are associated with the

efficient cytokine network production and with the specific signaling pathways.

This review underlines the experimental evidence indicating that the stem cell

factor (SCF) and its receptor c-kit (CD117) play an important role in survival

and proliferation of lung CSCs. Thus, molecularly targeting key cytokine network

axes of such highly tumorigenic and metastatic CSCs must be considered for

improving the current anti-cancer strategy efficacy. Standard chemotherapy in

combination with specific axis of cytokine network targeting, such as SCF-c-kit,

could eliminate both bulk tumor cells and CSCs, and therefore to be truly

curative therapies. This review provides a summary of some of the developments in

the field of lung CSCs targeting and highlights aspects which could help in the

drug discovery process.

PMID: 20184538 [PubMed - in process]

 

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]

 

Economic analysis: randomized placebo-controlled clinical trial of erlotinib in

advanced non-small cell lung cancer.

Bradbury PA, Tu D, Seymour L, Isogai PK, Zhu L, Ng R, Mittmann N, Tsao MS, Evans

WK, Shepherd FA, Leighl NB; NCIC Clinical Trials Group Working Group on Economic

Analysis.

NCIC Clinical Trials Group, Kingston, ON, Canada.

Comment in:

    J Natl Cancer Inst. 2010 Mar 3;102(5):287-8.

BACKGROUND: The NCIC Clinical Trials Group conducted the BR.21 trial, a

randomized placebo-controlled trial of erlotinib (an epidermal growth factor

receptor tyrosine kinase inhibitor) in patients with previously treated advanced

non-small cell lung cancer. This trial accrued patients between August 14, 2001,

and January 31, 2003, and found that overall survival and quality of life were

improved in the erlotinib arm than in the placebo arm. However, funding

restrictions limit access to erlotinib in many countries. We undertook an

economic analysis of erlotinib treatment in this trial and explored different

molecular and clinical predictors of outcome to determine the cost-effectiveness

of treating various populations with erlotinib. METHODS: Resource utilization was

determined from individual patient data in the BR.21 trial database. The trial

recruited 731 patients (488 in the erlotinib arm and 243 in the placebo arm).

Costs arising from erlotinib treatment, diagnostic tests, outpatient visits,

acute hospitalization, adverse events, lung cancer-related concomitant

medications, transfusions, and radiation therapy were captured. The incremental

cost-effectiveness ratio was calculated as the ratio of incremental cost (in 2007

Canadian dollars) to incremental effectiveness (life-years gained). In

exploratory analyses, we evaluated the benefits of treatment in selected

subgroups to determine the impact on the incremental cost-effectiveness ratio.

RESULTS: The incremental cost-effectiveness ratio for erlotinib treatment in the

BR.21 trial population was $94,638 per life-year gained (95% confidence interval

= $52,359 to $429,148). The major drivers of cost-effectiveness included the

magnitude of survival benefit and erlotinib cost. Subgroup analyses revealed that

erlotinib may be more cost-effective in never-smokers or patients with high EGFR

gene copy number. CONCLUSION: With an incremental cost-effectiveness ratio of $94

638 per life-year gained, erlotinib treatment for patients with previously

treated advanced non-small cell lung cancer is marginally cost-effective. The use

of molecular predictors of benefit for targeted agents may help identify more or

less cost-effective subgroups for treatment.

PMID: 20160168 [PubMed - in process]

 

Association of polymorphisms in AKT1 and EGFR with clinical outcome and toxicity

in non-small cell lung cancer patients treated with gefitinib.

Giovannetti E, Zucali PA, Peters GJ, Cortesi F, D'Incecco A, Smit EF, Falcone A,

Department of Medical Oncology, VU University Medical Center, Cancer Center

Amsterdam-CCA 1.52, Amsterdam, the Netherlands. elisa.giovannetti@gmail.com

EGFR mutations are strongly predictive of epidermal growth factor receptor

(EGFR)-tyrosine kinase inhibitor activity in non-small cell lung cancer (NSCLC),

but resistance mechanisms are not completely understood. The interindividual

variability in toxicity also points out to the need of novel pharmacogenetic

markers to select patients before therapy. Therefore, we evaluated the

associations between EGFR and AKT1 polymorphisms and outcome/toxicity in

gefitinib-treated NSCLC patients. Polymorphic loci in EGFR, and AKT1, and EGFR

and K-Ras mutations were assessed in DNA isolated from blood samples and/or

paraffin-embedded tumor from 96 gefitinib-treated NSCLC patients. Univariate and

multivariate analyses compared genetic variants with clinical efficacy and

toxicity using Fisher's, log-rank test, and Cox's proportional hazards model.

AKT1-SNP4 association with survival was also evaluated in 127

chemotherapy-treated/gefitinib-naive patients, whereas its relationship with AKT1

expression and gefitinib cytotoxicity was studied in 15 NSCLC cell lines.

AKT1-SNP4 A/A genotype was associated with shorter time-to-progression (P = 0.04)

and overall survival (P = 0.007). Multivariate analyses and comparison with the

gefitinib-nontreated population underlined its predictive significance, whereas

the in vitro studies showed the association of lower AKT1 mRNA levels with

gefitinib resistance. In contrast, EGFR-activating mutations were significantly

correlated with response, longer time-to-progression, and overall survival,

whereas EGFR -191C/A (P < 0.001), -216 G/T (P < 0.01), and R497K (P = 0.02)

polymorphisms were strongly associated with grade >1 diarrhea. AKT1-SNP4 A/A

genotype seems to be a candidate biomarker of primary resistance, whereas EGFR

-191C/A, -216G/T, and R497K polymorphisms are associated with diarrhea when using

gefitinib in NSCLC patients, thus offering potential new tools for treatment

optimization.

PMID: 20159991 [PubMed - in process]

 

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,

SITEP, 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]

 

Limited-stage small cell lung cancer: current chemoradiotherapy treatment

paradigms.

Stinchcombe TE, Gore EM.

Lineberger Comprehensive Cancer Center at University of North Carolina at Chapel

Hill, North Carolina 27599-7305, USA. Thomas_Stinchcombe@med.unc.edu

In the U.S., the prevalence of small cell lung cancer (SCLC) is declining,

probably reflecting the decreasing prevalence of tobacco use. However, a

significant number of patients will receive a diagnosis of SCLC, and

approximately 40% of patients with SCLC will have limited-stage (LS) disease,

which is potentially curable with the combination of chemotherapy and radiation

therapy. The standard therapy for LS-SCLC is concurrent chemoradiotherapy, and

the 5-year survival rate observed in clinical trials is approximately 25%. The

standard chemotherapy remains cisplatin and etoposide, but carboplatin is

frequently used in patients who cannot tolerate or have a contraindication to

cisplatin. Substantial improvements in survival have been made through

improvements in radiation therapy. Concurrent chemoradiotherapy is the preferred

therapy for patients who are appropriate candidates. The optimal timing of

concurrent chemoradiotherapy is during the first or second cycle, based on data

from meta-analyses. The optimal radiation schedule and dose remain topics of

debate, but 1.5 Gy twice daily to a total of 45 Gy and 1.8-2.0 Gy daily to a

total dose of 60-70 Gy are commonly used treatments. For patients who obtain a

near complete or complete response, prophylactic cranial radiation reduces the

incidence of brain metastases and improves overall survival. The ongoing

Radiation Therapy Oncology Group and Cancer and Leukemia Group B and the European

and Canadian phase III trials will investigate different radiation treatment

paradigms for patients with LS-SCLC, and completion of these trials is critical.

PMID: 20145192 [PubMed - in process]

 

Mature results of an individualized radiation dose prescription study based on

normal tissue constraints in stages I to III non-small-cell lung cancer.

van Baardwijk A, Wanders S, Boersma L, Borger J, Ollers M, Dingemans AM, Bootsma

G, Geraedts W, Pitz C, Lunde R, Lambin P, De Ruysscher D.

Department of RadiationOncology (MAASTRO), GROWResearch Institute, Maastricht

UniversityMedical Center, Maastricht. angela.vanbaardwijk@maastro.nl

PURPOSE: We previously showed that individualized radiation dose escalation based

on normal tissue constraints would allow safe administration of high radiation

doses with low complication rate. Here, we report the mature results of a

prospective, single-arm study that used this individualized tolerable dose

approach. PATIENTS AND METHODS: In total, 166 patients with stage III or

medically inoperable stage I to II non-small-cell lung cancer, WHO performance

status 0 to 2, a forced expiratory volume at 1 second and diffusing capacity of

lungs for carbon monoxide >or= 30% were included. Patients were irradiated using

an individualized prescribed total tumor dose (TTD) based on normal tissue dose

constraints (mean lung dose, 19 Gy; maximal spinal cord dose, 54 Gy) up to a

maximal TTD of 79.2 Gy in 1.8 Gy fractions twice daily. Only sequential

chemoradiation was administered. The primary end point was overall survival (OS),

and the secondary end point was toxicity according to Common Terminology Criteria

of Adverse Events (CTCAE) v3.0. RESULTS: The median prescribed TTD was 64.8 Gy

(standard deviation, +/- 11.4 Gy) delivered in 25 +/- 5.8 days. With a median

follow-up of 31.6 months, the median OS was 21.0 months with a 1-year OS of 68.7%

and a 2-year OS of 45.0%. Multivariable analysis showed that only a large gross

tumor volume significantly decreased OS (P < .001). Both acute (grade 3, 21.1%;

grade 4, 2.4%) and late toxicity (grade 3, 4.2%; grade 4, 1.8%) were acceptable.

CONCLUSION: Individualized prescribed radical radiotherapy based on normal tissue

constraints with sequential chemoradiation shows survival rates that come close

to results of concurrent chemoradiation schedules, with acceptable acute and late

toxicity. A prospective randomized study is warranted to further investigate its

efficacy.

PMID: 20142596 [PubMed - in process]

 

Pharmacokinetic study of gemcitabine, given as prolonged infusion at fixed dose

rate, in combination with cisplatin in patients with advanced non-small-cell lung

cancer.

Caffo O, Fallani S, Marangon E, Nobili S, Cassetta MI, Murgia V, Sala F, Novelli

A, Mini E, Zucchetti M, Galligioni E.

Medical Oncology Department, Santa Chiara Hospital, Trento, Italy,

orazio.caffo@apss.tn.it.

INTRODUCTION: Although some studies have suggested that gemcitabine delivered as

a fixed dose rate (FDR) infusion of 10 mg/m(2)/min could be more effective than

when administered as the standard 30-min infusion, the available pharmacokinetic

data are still too limited to draw definitive conclusions. This study is aimed to

investigate the plasmatic and intracellular pharmacokinetics of gemcitabine given

as FDR at doses of 600 and 1,200 mg/m(2) in combination with 75 mg/m(2) of

cisplatin in advanced non-small-cell lung cancer (NSCLC) patients. PATIENTS AND

METHOD: The patients were divided into two groups receiving different initial

doses of the drug: 4 patients received 600 mg/m(2) gemcitabine 60-min i.v.

infusion and 4 patients 1,200 mg/m(2) gemcitabine 120-min i.v. infusion both as a

FDR of 10 mg/m(2)/min on days 1 and 8 of a 21-day cycle (at first cycle). At the

second cycle, all patients were treated with gemcitabine at 1,200 mg/m(2) 120-min

i.v. infusion (FDR of 10 mg/m(2)/min) on days 1 and 8 of a 21-day cycle. At each

cycle, gemcitabine was administered alone on day one, and in combination with 75

mg/m(2) of cisplatin on day 8. Plasmatic and intracellular pharmacokinetic

analyses were performed on blood samples collected at defined time points before,

during and after gemcitabine infusion. RESULTS: The plasmatic pharmacokinetic

parameters were clearly different when the patients received a higher gemcitabine

dose in the second cycle compared to the lower dose of the first course; in the

same time, the intracellular drug levels were not modified. Comparing the

pharmacokinetic parameters of different patients treated at different dose

levels, the results appeared to be quite similar. CONCLUSIONS: A substantially

higher accumulation of metabolites in peripheral blood mononuclear cells was

observed when the longer infusion time was employed, suggesting a pharmacological

advantage for this treatment schedule.

PMID: 20140616 [PubMed - in process]

 

Classification of the thoroughness of mediastinal staging of lung cancer.

Detterbeck F, Puchalski J, Rubinowitz A, Cheng D.

Section of Thoracic Surgery, Yale University School of Medicine, Yale Thoracic

Oncology Program, New Haven, CT 06520-8062, USA. frank.detterbeck@yale.edu

There are many complementary techniques for mediastinal staging of lung cancer.

It is increasingly apparent that the accuracy of mediastinal staging depends not

only on which test is used but also on technical factors of how the procedure is

performed. This article reviews data regarding such technical factors and

proposes a classification schema of the thoroughness of execution of mediastinal

staging tests. Such a schema is needed for a thoughtful discussion of how

mediastinal staging tests should be integrated and for the development of

standards of good quality care for patients with non-small cell lung cancer.

PMID: 20133290 [PubMed - indexed for MEDLINE]

 

Phase II trial of a trimodality regimen for stage III non-small-cell lung cancer

using chemotherapy as induction treatment with concurrent hyperfractionated

chemoradiation with carboplatin and paclitaxel followed by subsequent resection:

a single-center study.

Friedel G, Budach W, Dippon J, Spengler W, Eschmann SM, Pfannenberg C,

FETCS, Department of Thoracic Surgery, Robert-Bosch-Hospital Klinik

Schillerhoehe, Thoracic Center, D-70839 Stuttgart-Gerlingen, Germany.

godehard.friedel@klinik-schillerhoehe.de

PURPOSE We started a phase II trial of induction chemotherapy and concurrent

hyperfractionated chemoradiotherapy followed by either surgery or boost

chemoradiotherapy in patients with advanced, stage III disease. The purpose is to

achieve better survival in the surgery group with minimum morbidity and

mortality. PATIENTS AND METHODS Patients treated from 1998 to 2002 with

neoadjuvant chemoradiotherapy and surgical resection for stage III NSCLC were

analyzed. The treatment consisted of four cycles of induction chemotherapy with

carboplatin/paclitaxel followed by chemoradiotherapy with a reduced dose of

carboplatin/paclitaxel and accelerated hyperfractionated radiotherapy with 1.5 Gy

twice daily up to 45 Gy. After restaging, operable patients underwent

thoracotomy. Inoperable patients received chemoradiotherapy up to 63 Gy. Study

end points included resectability, pathologic response, and survival. Results One

hundred twenty patients were enrolled; 25% patients had stage IIIA, 73% had stage

IIIB, and 2% stage IV. After treatment, 47.5% had downstaging, 29.2% had stable

disease, and 23.3% had progressive disease. Thirty patients (25%) were not

eligible for operation because of progressive disease, stable disease, and/or

functional deterioration with one treatment-related death. The 30-day mortality

was 5% in patients who underwent operation. The 5-year survival rate for 120

patients was 21.7%, and it was 43.1% in patients with complete resection. In

postoperative patients with stage N0 disease, 5-year survival was 53.3%; if stage

N2 or N3 disease was still present, 5-year survival was 33.3%. CONCLUSION Staging

and treatment with chemoradiotherapy and complete resection performed in

experienced centers achieve acceptable morbidity and mortality.

PMID: 20100967 [PubMed - in process]

 

Cetuximab and first-line taxane/carboplatin chemotherapy in advanced

non-small-cell lung cancer: results of the randomized multicenter phase III trial

BMS099.

Lynch TJ, Patel T, Dreisbach L, McCleod M, Heim WJ, Hermann RC, Paschold E,

Yale School of Medicine, 333 Cedar St, PO Box 208028, New Haven, CT 06520, USA.

thomas.lynch@yale.edu

PURPOSE To evaluate the efficacy of cetuximab plus taxane/carboplatin (TC) as

first-line treatment of advanced non-small-cell lung cancer (NSCLC). PATIENTS AND

METHODS This multicenter, open-label, phase III study enrolled 676

chemotherapy-naïve patients with stage IIIB (pleural effusion) or IV NSCLC,

without restrictions by histology or epidermal growth factor receptor expression.

Patients were randomly assigned to cetuximab/TC or TC. TC consisted of paclitaxel

(225 mg/m(2)) or docetaxel (75 mg/m(2)), at the investigator's discretion, and

carboplatin (area under the curve = 6) on day 1 every 3 weeks for < or = six

cycles; cetuximab (400 mg/m(2) on day 1, 250 mg/m(2) weekly) was administered

until progression or unacceptable toxicity. The primary end point was

progression-free survival assessed by independent radiologic review committee

(PFS-IRRC); overall response rate (ORR), overall survival (OS), quality of life

(QoL), and safety were key secondary end points. PFS and ORR assessed by

investigators were also evaluated. Results Median PFS-IRRC was 4.40 months with

cetuximab/TC versus 4.24 months with TC (hazard ratio [HR] = 0.902; 95% CI, 0.761

to 1.069; P = .236). Median OS was 9.69 months with cetuximab/TC versus 8.38

months with TC (HR = 0.890; 95% CI, 0.754 to 1.051; P = .169). ORR-IRRC was 25.7%

with cetuximab/TC versus 17.2% with TC (P = .007). The safety profile of this

combination was manageable and consistent with its individual components.

CONCLUSION The addition of cetuximab to TC did not significantly improve the

primary end point, PFS-IRRC. There was significant improvement in ORR by IRRC.

The difference in OS favored cetuximab but did not reach statistical

significance.

PMID: 20100966 [PubMed - in process]

 

Microenvironmental modulation of asymmetric cell division in human lung cancer

cells.

Pine SR, Ryan BM, Varticovski L, Robles AI, Harris CC.

Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer

Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Normal tissue homeostasis is maintained through asymmetric cell divisions that

produce daughter cells with differing self-renewal and differentiation

potentials. Certain tumor cell subfractions can self-renew and repopulate the

heterogeneous tumor bulk, suggestive of asymmetric cell division, but an equally

plausible explanation is that daughter cells of a symmetric division subsequently

adopt differing cell fates. Cosegregation of template DNA during mitosis is one

mechanism by which cellular components are segregated asymmetrically during cell

division in fibroblast, muscle, mammary, intestinal, and neural cells. Asymmetric

cell division of template DNA in tumor cells has remained elusive, however.

Through pulse-chase experiments with halogenated thymidine analogs, we determined

that a small population of cells within human lung cancer cell lines and primary

tumor cell cultures asymmetrically divided their template DNA, which could be

visualized in single cells and in real time. Template DNA cosegregation was

enhanced by cell-cell contact. Its frequency was density-dependent and modulated

by environmental changes, including serum deprivation and hypoxia. In addition,

we found that isolated CD133(+) lung cancer cells were capable of tumor cell

repopulation. Strikingly, during cell division, CD133 cosegregated with the

template DNA, whereas the differentiation markers prosurfactant protein-C and

pan-cytokeratins were passed to the opposing daughter cell, demonstrating that

segregation of template DNA correlates with lung cancer cell fate. Our results

demonstrate that human lung tumor cell fate decisions may be regulated during the

cell division process. The characterization and modulation of asymmetric cell

division in lung cancer can provide insight into tumor initiation, growth, and

maintenance.

PMCID: PMC2836660 [Available on 2010/8/2]

PMID: 20080668 [PubMed - indexed for MEDLINE]

 

XIAP-mediated protection of H460 lung cancer cells against cisplatin.

Cheng YJ, Jiang HS, Hsu SL, Lin LC, Wu CL, Ghanta VK, Hsueh CM.

Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.

Molecular mechanism(s) responsible for drug resistance of non-small cell lung

cancer (NSCLC) cells to cisplatin was investigated. Results showed that cisplatin

(50muM)-induced cell death (apoptosis) was more significant in CH27 and A549 cell

lines than in H460. The high protein levels of X-linked inhibitor-of-apoptosis

protein (XIAP) observed in H460 cells appeared to play a key role in the

regulation of cisplatin resistance of H460 cells. XIAP can bind to and suppress

the activities of caspase 3 in H460 cells and lead to apoptosis inhibition of

these cells. Blockade of XIAP activity by Embelin (XIAP inhibitor) or siRNA has

increased caspase 3 activities and promoted cisplatin-induced cell death of H460

cells. The results indicate a therapeutic value of Embelin and/or XIAP siRNA in

the control of cisplatin-resistant NSCLC cells (H460). Copyright (c) 2009

Elsevier B.V. All rights reserved.

PMID: 19903469 [PubMed - in process]

 

Phase II trial of pemetrexed plus bevacizumab for second-line therapy of patients

with advanced non-small-cell lung cancer: NCCTG and SWOG study N0426.

Adjei AA, Mandrekar SJ, Dy GK, Molina JR, Adjei AA, Gandara DR, Ziegler KL,

Roswell Park Cancer Institute, Buffalo, NY 14263, USA. alex.adjei@roswellpark.org

Comment in:

    J Clin Oncol. 2010 Mar 10;28(8):e131; author reply e132.

PURPOSE: To evaluate the efficacy and toxicity of pemetrexed combined with

bevacizumab as second-line therapy for patients with advanced non-small-cell lung

cancer (NSCLC) and to correlate allelic variants in pemetrexed-metabolizing genes

with clinical outcome. PATIENTS AND METHODS: Patients with previously treated

NSCLC received pemetrexed (500 mg/m(2) intravenous) combined with bevacizumab (15

mg/kg intravenous) every 3 weeks. The primary end point, evaluated using a

one-stage Fleming design for detecting a true success rate of at least 70%, was

the proportion of patients who were progression free and on treatment at 3

months. Polymorphisms in genes responsible for pemetrexed transport (reduced

folate carrier [SLC19A1]) and metabolism (folylpolyglutamate synthase [FPGS] and

gamma-glutamyl hydrolase [GGH]) evaluated in germline DNA (blood) were correlated

with treatment outcome. RESULTS: Forty-eight evaluable patients (14 females and

34 males) received a median of four cycles (range, one to 20 cycles). The most

common grade 3 or 4 nonhematologic adverse events (AEs) were fatigue (13%),

dyspnea (10%), and thrombosis (10%). Grade 3 or 4 hematologic AEs were

neutropenia (19%) and lymphopenia (13%). Twenty-four (57%; 95% CI, 41% to 72%) of

the first 42 patients met the success criteria. Median overall survival (OS) and

progression-free survival (PFS) times were 8.6 and 4.0 months, respectively. The

exon 6 (2522)C-->T polymorphism in SLC19A1 correlated with 3-month

progression-free status (P = .01) and with PFS (P = .05). The IVS1(1307)C-->T

polymorphism in GGH correlated with OS (P = .04). CONCLUSION: The study did not

meet its primary end point. However, the median PFS time of 4 months is

promising. Pharmacogenetic studies in larger cohorts are needed to definitively

identify polymorphisms that predict for survival and toxicity of pemetrexed.

PMCID: PMC2815996 [Available on 2011/2/1]

PMID: 19841321 [PubMed - indexed for MEDLINE]

 

Does video-assisted thoracoscopic lobectomy for lung cancer provide improved

functional outcomes compared with open lobectomy?

Handy JR Jr, Asaph JW, Douville EC, Ott GY, Grunkemeier GL, Wu Y.

Providence Cancer Center, Providence Health & Services, Portland, OR 97213, USA.

jhandy@orclinic.com

OBJECTIVE: We evaluated video-assisted thoracic surgery (VATS) and open (OPEN)

lobectomy for lung cancer and impact upon 6-month postoperative (postop)

functional health status and quality of life. METHODS: In this retrospective

analysis of prospective, observational data, anatomic lobectomy with staging

thoracic lymphadenectomy was performed with curative intent for lung cancer. OPEN

consisted of either thoracotomy (TH) or median sternotomy (MS). Technique was

selected on the basis of anatomic imperative (OPEN: larger or central; VATS

smaller or peripheral tumours) and/or surgical skills (VATS lobectomy initiated

in 2001). All patients completed the Short Form 36 Health Survey (SF36) and

Ferrans and Powers quality-of-life index (QLI) preoperatively (preop) and 6

months postop. RESULTS: A total of 241 patients underwent lobectomy (OPEN, 192;

VATS, 49). OPEN included MS 128 and TH 64. Comparison of MS and TH patient

demographics, co-morbidities, pulmonary variables, intra-operative variables,

stage and cell type, postop complications and 6-month clinical outcomes found no

differences, allowing grouping together into OPEN. The VATS group had better

pulmonary function testing (PFT), more adenocarcinoma and lower stage. The VATS

and OPEN groups did not differ regarding operating time, postop complications and

operative or 6-month mortality. The VATS group had less blood loss, transfusion,

intra-operative fluid administration and shorter length of stay. Comparing within

each group's preop to 6-month postop data, VATS patients were either the same or

better in all SF36 categories (physical functioning, role functioning - physical,

role functioning - emotional, social functioning, bodily pain, mental health,

energy and general health). The OPEN group, however, was significantly worse in

SF36 categories physical functioning, role functioning - physical and social

functioning. The preop and 6 months postop VATS versus OPEN QLI scores were not

different. At 6 months postop, hospital re-admission and use of pain medication

was less in the VATS group. In addition, the VATS group had better preservation

of preop performance status. CONCLUSIONS: VATS lobectomy for curative lung cancer

resection appears to provide a superior functional health recovery compared with

OPEN techniques. Copyright 2009 European Association for Cardio-Thoracic Surgery.

Published by Elsevier B.V. All rights reserved.

PMID: 19747837 [PubMed - in process]

 

Vorinostat increases carboplatin and paclitaxel activity in non-small-cell lung

cancer cells.

Owonikoko TK, Ramalingam SS, Kanterewicz B, Balius TE, Belani CP, Hershberger PA.

University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.

We observed a 53% response rate in non-small cell lung cancer (NSCLC) patients

treated with vorinostat plus paclitaxel/carboplatin in a Phase I trial. Studies

were undertaken to investigate the mechanism (s) underlying this activity. Growth

inhibition was assessed in NSCLC cells by MTT assay after 72 hr of continuous

drug exposure. Vorinostat (1 microM) inhibited growth by: 17% +/- 7% in A549, 28%

+/- 6% in 128-88T, 39% +/- 8% in Calu1 and 41% +/- 7% in 201T cells. Vorinostat

addition to carboplatin or paclitaxel led to significantly greater growth

inhibition than chemotherapy alone in all 4 cell lines. Vorinostat (1 microM)

synergistically increased the growth inhibitory effects of carboplatin/paclitaxel

in 128-88T cells. When colony formation was measured after drug withdrawal,

vorinostat significantly increased the effects of carboplatin but not paclitaxel.

The % colony formation was control 100%; 1 microM vorinostat, 83% +/- 10%; 5

microM carboplatin, 41% +/- 11%; carboplatin/vorinostat, 8% +/- 4%; 2 nM

paclitaxel, 53% +/- 11%; paclitaxel/vorinostat, 46% +/- 21%. In A549 and 128-88T,

vorinostat potentiated carboplatin induction of gamma-H2AX (a DNA damage marker)

and increased alpha-tubulin acetylation (a marker for stabilized mictrotubules).

In A549, combination of vorinostat with paclitaxel resulted in a synergistic

increase in alpha-tubulin acetylation, which reversed upon drug washout. We

conclude that vorinostat interacts favorably with carboplatin and paclitaxel in

NSCLC cells, which may explain the provocative response observed in our clinical

trial. This likely involves a vorinostat-mediated irreversible increase in DNA

damage in the case of carboplatin and a reversible increase in microtubule

stability in the case of paclitaxel.

PMCID: PMC2795066

PMID: 19621389 [PubMed - indexed for MEDLINE]

 

Oral second- and third-line lomustine-etoposide-cyclophosphamide chemotherapy for

small cell lung cancer.

Lebeau B, Chouaïd C, Baud M, Masanès MJ, Febvre M.

Department of Lung Diseases, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux

de Paris, Université Pierre et Marie Curie Paris VI, France.

bernard.lebeau@sat.aphp.fr

PURPOSE: There is no standard therapy for progressive or recurrent small cell

lung cancer (SCLC). Lomustine, etoposide and cyclophosphamide oral chemotherapy

were evaluated in a feasibility study of efficacy survival and toxicity. PATIENTS

AND METHODS: 71 patients were included in this study, 36 in second-line and 35 in

third-line chemotherapy. They received lomustine (CCNU) 80 or 120mg on D1 only,

etoposide 100mg from D1 until D6 up to D14 and cyclophosphamide 100mg from D1

until D6 up to D14 every 4 weeks. The dosages of CCNU and duration of

administration of the other two drugs were adapted to an original therapeutic

risk level table on D1 and throughout treatment. Evaluation based on clinical

status, response and weekly blood counts was performed before each cycle until

progression. RESULTS: 70 patients were evaluable. They received between 1 and 20

cycles of treatment (mean=3.7 for second-line and 3.0 for third-line treatment).

Complete responses were observed for 3 patients in each line, and partial

responses were noted in 13 patients in second-line and 8 patients in third-line,

resulting in a total response rate of 27/70=38%. Median-survival time estimated

from the start of second- or third-line treatment was the same in the two

subgroups: 4.4 months, but the patients in two subgroups presented different

clinical characteristics. Haematological toxicity was severe with three toxic

deaths as frequently observed in this setting, but hospitalisations were uncommon

during this fully oral treatment that provided a very good quality of life for

these out-patients. Consumption of health care resources for this low-cost and

ambulatory treatment was limited. CONCLUSION: The similar efficacy with

acceptable safety, the ease of administration in out-patients and the economical

advantages justify comparison of this oral chemotherapy with conventional

intravenous chemotherapy. A randomised phase II trial is on-going in France for

second-line SCLC patients on this theme. Copyright 2009 Elsevier Ireland Ltd. All

rights reserved.

PMID: 19394109 [PubMed - in process]