Management of patients with advanced non-small cell lung cancer: current and

emerging options.

Triano LR, Deshpande H, Gettinger SN.

Yale Cancer Center/Yale University School of Medicine, New Haven, Connecticut,

USA.

Systemic therapy for advanced non-small cell lung cancer (NSCLC) has evolved over

the last two decades, with modest improvements in quality of life and overall

survival. A plateau has been reached with traditional chemotherapy, and efforts

are now being directed at developing molecularly targeted agents. To date, three

such agents have been found to improve overall survival in advanced NSCLC.

Erlotinib, a small-molecule inhibitor of the epidermal growth factor receptor,

was approved by the US FDA in 2004 as second- or third-line treatment for

advanced NSCLC. Bevacizumab, an antibody to vascular endothelial growth factor, a

key mediator of angiogenesis, received approval in 2006, after a randomized trial

reported a median survival of 1 year when bevacizumab was added to first-line

chemotherapy. More recently, cetuximab, an antibody to the epidermal growth

factor receptor, was found to improve outcome when added to chemotherapy, and FDA

approval is anticipated. Several additional agents are currently being evaluated

in randomized trials, with encouraging results from early studies. These and

other studies are prospectively investigating predictive clinical and molecular

characteristics, with the ultimate goal of individualizing therapy in advanced

NSCLC.

PMID: 20108990 [PubMed - in process]

 

Concurrent chemoradiation therapy with docetaxel/cisplatin followed by docetaxel

consolidation therapy in inoperable stage IIIA/B non-small-cell lung cancer:

results of a phase I study.

Huber RM, Borgmeier A, Flentje M, Willner J, Schmidt M, Manegold C, Bramlage P,

Pneumology, Department of Medicine, Innenstadt, University of Munich, Germany.

huber@med.uni-muenchen.de

INTRODUCTION: Docetaxel consolidation therapy (DCT) after concurrent

cisplatin/docetaxel chemoradiation therapy (CRT) produces high tumor control in

non-small-cell lung cancer (NSCLC); toxicity is, however, considerable. We aimed

to determine the maximally tolerated dose (MTD) for DCT. PATIENTS AND METHODS:

Patients with inoperable stage IIIB NSCLC received docetaxel 20 mg/m2 and

cisplatin 25 mg/m2 on days 1, 8, 15, 22, 29, and 36, with concurrent radiation

therapy 5 days per week for a total dose of 66 Gy. Patients achieving stable

disease, partial response, or complete response were given DCT on days 71, 92,

and 113. DCT was started with 75 mg/m2 and titrated depending on tolerability.

The MTD of docetaxel was defined as the dose preceding that at which 3 or more

patients experienced dose-limiting toxicity (DLT). RESULTS: Of 23 patients

enrolled (median age, 58.8 years +/- 7.3 years), 19 received complete CRT (4

withdrew because of toxicity). Of the patients receiving complete CRT, 1 patient

died and 1 became operable, leaving 17 patients eligible for DCT starting at 75

mg/m2. After the third patient with DLT, dose was reduced to 60 mg/m2. Median

survival was 27.6 months +/- 23.1 months. Median TTP was 12.4 months +/- 10.7

months. CONCLUSION: The MTD of DCT after concurrent cisplatin/docetaxel CRT was

determined to be 60 mg/m2, but toxicity was considerable. The benefit-risk ratio

of DCT has, however, been questioned by a placebo-controlled phase III trial.

Further phase III trials need to consider further stratification factors

(pretreatment forced expiratory volume [FEV]1, hemoglobin, performance, and

stage) to define a role for DCT in patients with NSCLC.

PMID: 20085867 [PubMed - in process]

 

Oxaliplatin in first-line therapy for advanced non-small-cell lung cancer.

Raez LE, Kobina S, Santos ES.

University of Miami Miller School of Medicine, Miami, FL 33136, USA.

lraez@med.miami.edu

Platinum doublets are the recommended standard first-line chemotherapy for stage

IIIB/IV non-small-cell lung cancer (NSCLC). As efficacy outcomes associated with

currently approved agents (cisplatin and carboplatin) are broadly similar, the

decision about which platinum-based doublet to use is based on other factors such

as toxicity. The goals for new platinum agents are to maintain and perhaps

improve current efficacy and to improve toxicity. The aim of this article is to

review the available clinical data from studies investigating the

third-generation platinum analogue oxaliplatin in patients with advanced NSCLC.

Information was obtained from the PubMed database and from recent presentations

at national and international meetings. Oxaliplatin has been studied as

monotherapy and in combination with a wide range of other chemotherapies (vinca

alkaloids, taxanes, gemcitabine, and pemetrexed), mainly in phase II trials.

Preliminary results from studies in which oxaliplatin-based doublets have been

combined with targeted agents (eg, bevacizumab) are now available. In general,

the clinical activity observed with oxaliplatin-based therapy is similar to that

seen with other currently used platinum regimens, although outcomes vary between

individual trials (response rates, 23%-48%; median progression-free survival,

2.7-7.3 months; median overall survival, 7.3-13.7 months). The toxicity profile

of oxaliplatin, particularly when compared with cisplatin, makes it an

alternative treatment, especially in patients unable to tolerate cisplatin.

However, well-conducted randomized phase III trials will be needed to clarify

which particular groups of patients with NSCLC may benefit from oxaliplatin-based

therapy.

PMID: 20085863 [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.

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.

PMID: 20080668 [PubMed - in process]

 

High-resolution computed tomography screening for lung cancer: unexpected

findings and new controversies regarding adenocarcinogenesis.

Chirieac LR, Flieder DB.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School,

Boston, Massachusetts, USA.

CONTEXT: Recent advances in human imaging technologies reawakened interest in

lung cancer screening. Although historic and current preliminary and

noncontrolled studies have not shown a decrease in lung cancer mortality in

screened populations, many explanations have been proffered while the lung cancer

community awaits the results of several large controlled population studies.

OBJECTIVE: To critically review the current model of adenocarcinoma development

against the background of lung cancer screening results combined with

observational pathologic and radiographic studies. DATA SOURCES: Published

articles pertaining to lung cancer screening, lung adenocarcinoma pathology, and

radiology accessible through PubMed form the basis for this review. CONCLUSIONS:

The current adenocarcinogenesis model is probably valid for many but not all lung

adenocarcinomas. Screening data combined with radiographic and pathologic studies

suggest that not all lung adenocarcinomas are clinically aggressive, and it is

uncertain whether all aggressive adenocarcinomas arise from identified

precursors.

PMID: 20073604 [PubMed - indexed for MEDLINE]

 

Do we have enough evidence to implement particle therapy as standard treatment in

lung cancer? A systematic literature review.

Pijls-Johannesma M, Grutters JP, Verhaegen F, Lambin P, De Ruysscher D.

Maastricht Radiation Oncology (MAASTRO) Clinic, Dr. Tanslaan 12, 6229 ET

Maastricht, The Netherlands. madelon.pijls@maastro.nl

BACKGROUND: The societal burden of lung cancer is high because of its high

incidence and high lethality. From a theoretical point of view, radiotherapy with

beams of protons and heavier charged particles, for example, carbon ions

(C-ions), should lead to superior results, compared with photon beams. In this

review, we searched for clinical evidence to justify implementation of particle

therapy as standard treatment in lung cancer. METHODS: A systematic literature

review based on an earlier published comprehensive review was performed and

updated through November 2009. RESULTS: Eleven fully published studies, all

dealing with non-small cell lung cancer (NSCLC), mainly stage I, were identified.

No phase III trials were found. For proton therapy, 2- to 5-year local tumor

control rates varied in the range of 57%-87%. The 2- and 5-year overall survival

(OS) and 2- and 5-year cause-specific survival (CSS) rates were 31%-74% and 23%

and 58%-86% and 46%, respectively. Radiation-induced pneumonitis was observed in

about 10% of patients. For C-ion therapy, the overall local tumor control rate

was 77%, but it was 95% when using a hypofractionated radiation schedule. The

5-year OS and CSS rates were 42% and 60%, respectively. Slightly better results

were reported when using hypofractionation, 50% and 76%, respectively.

CONCLUSION: The present results with protons and heavier charged particles are

promising. However, the current lack of evidence on the clinical

(cost-)effectiveness of particle therapy emphasizes the need to investigate the

efficiency of particle therapy in an adequate manner. Until these results are

available for lung cancer, charged particle therapy should be considered

experimental.

PMID: 20067947 [PubMed - in process]

 

A rigorous and comprehensive validation: common genetic variations and lung

cancer.

Yang P, Li Y, Jiang R, Cunningham JM, Zhang F, de Andrade M.

Department of 1Health Sciences Research, Mayo Clinic College of Medicine,

Rochester, MN, 55905, USA. yang.ping@mayo.edu

BACKGROUND: Multiple recent genome-wide studies of single nucleotide

polymorphisms (SNP) reported associations between candidate chromosome loci and

lung cancer susceptibility. We evaluated five of the top candidate SNPs

(rs402710, rs2736100, rs4324798, rs16969968, and rs8034191) for their effects on

lung cancer risk and overall survival. METHODS: Over 1,700 cases and 2,200

controls were included in this study. Seven independent, complementary

case-control data sets were tested for risk assessment encompassing cigarette

smokers and never smokers, using unrelated controls and unaffected full-sibling

controls. Five patient groups were tested for survival prediction stratified by

smoking status, histology subtype, and treatment. RESULTS: After considering a

history of chronic obstructive pulmonary disease as a risk factor altering lung

cancer risk and comparing to sibling controls, none of the five SNPs remained

significant. However, the variant rs4324798 was significant in predicting overall

survival (hazard ratio, 0.46; 95% confidence interval, 0.30-0.73; P = 0.001) in

small cell lung cancer. CONCLUSIONS: None of the five candidate SNPs in lung

cancer risk can be confirmed in our study. The previously reported association

could be explained by disparity in tobacco smoke exposure and chronic obstructive

pulmonary disease history between cases and controls. Instead, we found rs4324798

to be an independent predictor in small cell lung cancer survival, warranting

further elucidation of the underlying mechanisms.

PMCID: PMC2805461 [Available on 2011/1/1]

PMID: 20056643 [PubMed - in process]

 

Elimination of human lung cancer stem cells through targeting of the stem cell

factor-c-kit autocrine signaling loop.

Levina V, Marrangoni A, Wang T, Parikh S, Su Y, Herberman R, Lokshin A,

University of Pittsburgh Cancer Institute and Department of Medicine, University

of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.

levinav@upmc.edu

Cancer stem cells (CSC) are thought to be responsible for tumor initiation and

tumor regeneration after chemotherapy. Previously, we showed that chemotherapy of

non-small cell lung cancer (NSCLC) cells lines can select for outgrowth of highly

tumorigenic and metastatic CSCs. The high malignancy of lung CSCs was associated

with an efficient cytokine network. In this study, we provide evidence that

blocking stem cell factor (SCF)-c-kit signaling is sufficient to inhibit CSC

proliferation and survival promoted by chemotherapy. CSCs were isolated from

NSCLC cell lines as tumor spheres under CSC-selective conditions and their stem

properties were confirmed. In contrast to other tumor cells, CSCs expressed c-kit

receptors and produced SCF. Proliferation of CSCs was inhibited by

SCF-neutralizing antibodies or by imatinib (Gleevec), an inhibitor of c-kit.

Although cisplatin treatment eliminated the majority of tumor cells, it did not

eliminate CSCs, whereas imatinib or anti-SCF antibody destroyed CSCs.

Significantly, combining cisplatin with imatinib or anti-SCF antibody prevented

the growth of both tumor cell subpopulations. Our findings reveal an important

role for the SCF-c-kit signaling axis in self-renewal and proliferation of lung

CSCs, and they suggest that SCF-c-kit signaling blockade could improve the

antitumor efficacy of chemotherapy of human NSCLC.

PMID: 20028869 [PubMed - indexed for MEDLINE]

 

Phase 1b study of motesanib, an oral angiogenesis inhibitor, in combination with

carboplatin/paclitaxel and/or panitumumab for the treatment of advanced non-small

cell lung cancer.

Blumenschein GR Jr, Reckamp K, Stephenson GJ, O'Rourke T, Gladish G, McGreivy J,

The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

gblumens@mdanderson.org

PURPOSE: Motesanib is a small-molecule antagonist of vascular endothelial growth

factor receptor 1, 2, and 3, platelet-derived growth factor receptor, and Kit.

This phase 1b study assessed the safety, maximum tolerated dose (MTD), and

pharmacokinetics, and explored the objective response of motesanib plus

carboplatin/paclitaxel and/or the fully human anti-epidermal growth factor

receptor monoclonal antibody panitumumab in advanced non-small cell lung cancer

(NSCLC). EXPERIMENTAL DESIGN: Patients with unresectable NSCLC received

sequentially escalating doses of motesanib [50, 125 mg once daily; 75 mg twice

daily] orally continuously plus carboplatin/paclitaxel (arm A; first line) or

panitumumab (arm B; first and second line) once every 21-day cycle or 125 mg once

daily plus carboplatin/paclitaxel and panitumumab (arm C; first line). RESULTS:

Forty-five patients received motesanib. Three dose-limiting toxicities occurred:

grade 4 pulmonary embolism (n = 1; arm A, 50 mg once daily) and grade 3 deep vein

thrombosis (n = 2; arm A, 125 mg once daily; arm C). The MTD was 125 mg once

daily. Common motesanib-related adverse events were fatigue (60% of patients),

diarrhea (53%), hypertension, (38%), anorexia (27%), and nausea (22%). Three

cases of cholecystitis occurred but only in the 75-mg twice-daily schedule, which

was subsequently discontinued. At 125 mg once daily, motesanib pharmacokinetics

were not markedly changed with carboplatin/paclitaxel coadministration; however,

exposure to paclitaxel was moderately increased. The objective response rates

were 17%, 0%, and 17% in arms A, B, and C, respectively. CONCLUSIONS: Treatment

with motesanib was tolerable when combined with carboplatin/paclitaxel and/or

panitumumab, with little effect on motesanib pharmacokinetics at the 125-mg once

daily dose level. This dose is being investigated in an ongoing phase 3 study in

NSCLC.

PMID: 20028752 [PubMed - in process]

 

A small-cell lung cancer genome with complex signatures of tobacco exposure.

Pleasance ED, Stephens PJ, O'Meara S, McBride DJ, Meynert A, Jones D, Lin ML,

Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.

Cancer is driven by mutation. Worldwide, tobacco smoking is the principal

lifestyle exposure that causes cancer, exerting carcinogenicity through >60

chemicals that bind and mutate DNA. Using massively parallel sequencing

technology, we sequenced a small-cell lung cancer cell line, NCI-H209, to explore

the mutational burden associated with tobacco smoking. A total of 22,910 somatic

substitutions were identified, including 134 in coding exons. Multiple mutation

signatures testify to the cocktail of carcinogens in tobacco smoke and their

proclivities for particular bases and surrounding sequence context. Effects of

transcription-coupled repair and a second, more general, expression-linked repair

pathway were evident. We identified a tandem duplication that duplicates exons

3-8 of CHD7 in frame, and another two lines carrying PVT1-CHD7 fusion genes,

indicating that CHD7 may be recurrently rearranged in this disease. These

findings illustrate the potential for next-generation sequencing to provide

unprecedented insights into mutational processes, cellular repair pathways and

gene networks associated with cancer.

PMID: 20016488 [PubMed - in process]

 

Erlotinib: a pharmacoeconomic review of its use in advanced non-small cell lung

cancer.

Lyseng-Williamson KA.

Adis, a Wolters Kluwer Business, Auckland, New Zealand. demail@adis.co.nz

Erlotinib (Tarceva), an oral epidermal growth factor receptor tyrosine kinase

inhibitor, is associated with modest improvements in survival in patients with

advanced non-small cell lung cancer (NSCLC) who have previously received one or

more prior chemotherapy regimens. In a well designed clinical trial in this

patient population, median overall survival and progression-free survival were

significantly longer in patients receiving erlotinib 150 mg/day than in those

receiving placebo. Erlotinib is generally well tolerated, with most adverse

events being of mild to moderate severity. A large body of modelled

pharmacoeconomic data suggests that second- or third-line erlotinib 150 mg/day is

a cost-saving option relative to treatment with the approved second-line

intravenous chemotherapies of docetaxel and pemetrexed in patients with advanced

NSCLC. In patients who had received at least one prior chemotherapy regimen,

erlotinib was predicted to be dominant (i.e. more effective and less costly) or

cost saving (i.e. equally effective and less costly) relative to docetaxel or

pemetrexed with regard to the cost per QALY or life-year gained in

cost-effectiveness analyses. Although the effect of erlotinib on overall survival

was generally assumed to be equivalent to that of the chemotherapies, the

estimated amount of QALYs gained was slightly greater with erlotinib than with

docetaxel. In cost-minimization and national budgetary impact analyses, estimated

total direct costs with erlotinib were lower than those with docetaxel and

pemetrexed, because of the generally lower drug acquisition, administration and

adverse event management costs associated with erlotinib. Cost advantages with

erlotinib were predicted across analyses, regardless of the type of model

developed, specific costs that were included, country that the study was

conducted in and year of costing. Sensitivity analyses consistently showed that

these results were robust to plausible changes in the key model assumptions. In

conclusion, in patients with advanced NSCLC, second- or third-line treatment with

erlotinib is clinically effective in improving survival. Available

pharmacoeconomic data from several countries, despite some inherent limitations,

support the use of erlotinib as a cost-saving treatment relative to chemotherapy

with docetaxel or pemetrexed in this patient population.

PMID: 20014878 [PubMed - in process]

 

Small cell lung cancer: are we making progress?

Dowell JE.

Hematology/Oncology, Veterans Affairs North Texas Healthcare System, Dallas,

Texas, USA. jonathan.dowell@utsouthwestern.edu

Although the incidence of small cell lung cancer (SCLC) has declined during the

past 30 years, it remains a significant cause of cancer mortality in the United

States and across the world. With appropriate treatment, about 20% of patients

who present with limited stage SCLC can be cured of their disease. Unfortunately,

the outcome for the remainder of patients is extremely poor. The only significant

advance in extensive stage SCLC in the past 2 decades is the recent discovery

that prophylactic cranial irradiation improves survival in those patients whose

disease has responded to initial chemotherapy. Numerous attempts to enhance the

antitumor effects of traditional chemotherapy for SCLC have not been successful.

As the understanding of the biology of SCLC increased, a number of rational

molecular targets for therapy have been identified. Although initial attempts at

"targeted therapy" in SCLC have been unsuccessful, several newly identified

targets hold promise and give hope that significant improvements in therapy for

this challenging disease are not far away.

PMID: 19996730 [PubMed - indexed for MEDLINE]

 

Cryptogenic fibrosing alveolitis and lung cancer: the BTS study.

Harris JM, Johnston ID, Rudd R, Taylor AJ, Cullinan P.

Occupational and Environmental Medicine, National Heart & Lung Institute,

Imperial College, 1B Manresa Road, London SW3 6LR, UK.

jessica.harris@imperial.ac.uk

BACKGROUND: The risk of lung cancer is often reported to be increased for

patients with cryptogenic fibrosing alveolitis (CFA). METHODS: Vital status was

sought for all 588 members of the British Thoracic Society (BTS) cryptogenic

fibrosing alveolitis (CFA) study 11 years after entry to the cohort. Observed

deaths due to lung cancer were compared with expected deaths using age-, sex- and

period-adjusted national rates. The roles of reported asbestos exposure and

smoking were also investigated. RESULTS: 488 cohort members (83%) had died; 46

(9%) were certified to lung cancer (ICD9 162). The standardised mortality ratio

(SMR) was 7.4 (95% CI 5.4 to 9.9). Stratified analysis showed increased lung

cancer mortality among younger subjects, men and ever smokers. Using an

independent expert panel, 25 cohort members (4%) were considered to have at least

moderate exposure to asbestos; the risk of lung cancer was increased for these

subjects (SMR 13.1 (95% CI 3.6 to 33.6)) vs 7.2 (95% CI 5.2 to 9.7) for those

with less or no asbestos exposure). Ever smoking was reported by 448 (73%) of the

cohort and was considerably higher in men than in women (92% vs 49%; p<0.001).

Most persons who died from lung cancer were male (87%), and all but two (96%) had

ever smoked. Ever smokers presented at a younger age (mean 67 vs 70 years;

p<0.001) and with less breathlessness (12% smokers reported no breathlessness vs

5% never smokers; p = 0.02). CONCLUSIONS: These findings confirm an association

between CFA and lung cancer although this relationship may not be causal. The

high rate of smoking and evidence that smokers present for medical attention

earlier than non-smokers suggest that smoking could be confounding this

association.

PMID: 19996344 [PubMed - in process]

 

Long-term results of the international adjuvant lung cancer trial evaluating

adjuvant Cisplatin-based chemotherapy in resected lung cancer.

Arriagada R, Dunant A, Pignon JP, Bergman B, Chabowski M, Grunenwald D,

Institut Gustave-Roussy, rue Camille Desmoulins, Villejuif 94800, France.

Rodrigo.Arriagada@ki.se

PURPOSE Based on 5-year or shorter-term follow-up data in recent randomized

trials, adjuvant cisplatin-based chemotherapy is now generally recommended after

complete surgical resection for patients with non-small-cell lung cancer (NSCLC).

We evaluated the results of the International Adjuvant Lung Cancer Trial study

with three additional years of follow-up. PATIENTS AND METHODS Patients with

completely resected NSCLC were randomly assigned to three or four cycles of

cisplatin-based chemotherapy or to observation. Cox models were used to evaluate

treatment effect according to follow-up duration. Results The trial included

1,867 patients with a median follow-up of 7.5 years. Results showed a beneficial

effect of adjuvant chemotherapy on overall survival (hazard ratio [HR], 0.91; 95%

CI, 0.81 to 1.02; P = .10) and on disease-free survival (HR, 0.88; 95% CI, 0.78

to 0.98; P = .02). However, there was a significant difference between the

results of overall survival before and after 5 years of follow-up (HR, 0.86; 95%

CI, 0.76 to 0.97; P = .01 v HR, 1.45; 95% CI, 1.02 to 2.07; P = .04) with P =

.006 for interaction. Similar results were observed for disease-free survival.

The analysis of non-lung cancer deaths for the whole period showed an HR of 1.34

(95% CI, 0.99 to 1.81; P = .06). CONCLUSION These results confirm the significant

efficacy of adjuvant chemotherapy at 5 years. The difference in results beyond 5

years of follow-up underscores the need for the long-term follow-up of other

adjuvant lung cancer trials and for a better identification of patients deriving

long-term benefit from adjuvant chemotherapy.

PMID: 19933916 [PubMed - indexed for MEDLINE]

 

Carboplatin and Paclitaxel in combination with either vorinostat or placebo for

first-line therapy of advanced non-small-cell lung cancer.

Ramalingam SS, Maitland ML, Frankel P, Argiris AE, Koczywas M, Gitlitz B, Thomas

S, Espinoza-Delgado I, Vokes EE, Gandara DR, Belani CP.

Emory University, Winship Cancer Institute, 1365 Clifton Rd, C-3090, Atlanta, GA

30322, USA. suresh.ramalingam@emory.edu

PURPOSE Vorinostat, a histone deacetylase inhibitor, exerts anticancer effects by

both histone and nonhistone-mediated mechanisms. It also enhances the anticancer

effects of platinum compounds and taxanes in non-small-cell lung cancer (NSCLC)

cell lines. This phase II randomized, double-blinded, placebo-controlled study

evaluated the efficacy of vorinostat in combination with carboplatin and

paclitaxel in patients with advanced-stage NSCLC. PATIENTS AND METHODS Patients

with previously untreated stage IIIB (ie, wet) or IV NSCLC were randomly assigned

(2:1) to carboplatin (area under the curve, 6 mg/mL x min) and paclitaxel (200

mg/m(2) day 3) with either vorinostat (400 mg by mouth daily) or placebo.

Vorinostat or placebo was given on days 1 through 14 of each 3-week cycle to a

maximum of six cycles. The primary end point was comparison of the response rate.

Results Ninety-four patients initiated protocol therapy. Baseline patient

characteristics were similar between the two arms. The median number of cycles

was four for both treatment arms. The confirmed response rate was 34% with

vorinostat versus 12.5% with placebo (P = .02). There was a trend toward

improvement in median progression-free survival (6.0 months v 4.1 months; P =

.48) and overall survival (13.0 months v 9.7 months; P = .17) in the vorinostat

arm. Grade 4 platelet toxicity was more common with vorinostat (18% v 3%; P <

.05). Nausea, emesis, fatigue, dehydration, and hyponatremia also were more

frequent with vorinostat. CONCLUSION Vorinostat enhances the efficacy of

carboplatin and paclitaxel in patients with advanced NSCLC. HDAC inhibition is a

promising therapeutic strategy for treatment of NSCLC.

PMCID: PMC2799233 [Available on 2011/1/1]

PMID: 19933908 [PubMed - indexed for MEDLINE]

 

Randomized, double-blind trial of carboplatin and paclitaxel with either daily

oral cediranib or placebo in advanced non-small-cell lung cancer: NCIC clinical

trials group BR24 study.

Goss GD, Arnold A, Shepherd FA, Dediu M, Ciuleanu TE, Fenton D, Zukin M, Walde D,

FCP(SA), FRCPC, The Ottawa Hospital Cancer Centre, 501 Smyth Rd, Ottawa ON K1H

8L6, Canada. ggoss@ottawahospital.on.ca

PURPOSE This phase II/III double-blind study assessed efficacy and safety of

cediranib with standard chemotherapy as initial therapy for advanced

non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Paclitaxel (200 mg/m(2))

and carboplatin (area under the serum concentration-time curve 6) were given

every 3 weeks, with daily oral cediranib or placebo at 30 mg (first 45 patients

received 45 mg). Progression-free survival (PFS) was the primary outcome of the

phase II interim analysis; phase III would proceed if the hazard ratio (HR) for

PFS < or = 0.77 and toxicity were acceptable. Results A total of 296 patients

were enrolled, 251 to the 30-mg cohort. The phase II interim analysis

demonstrated a significantly higher response rate (RR) for cediranib than for

placebo, HR of 0.77 for PFS, no excess hemoptysis, and a similar number of deaths

in each arm. The study was halted to review imbalances in assigned causes of

death. In the primary phase II analysis (30-mg cohort), the adjusted HR for PFS

was 0.77 (95% CI, 0.56 to 1.08) with a higher RR for cediranib than for placebo

(38% v 16%; P < .0001). Cediranib patients had more hypertension, hypothyroidism,

hand-foot syndrome, and GI toxicity. Hypoalbuminemia, age > or = 65 years, and

female sex predicted increased toxicity. Survival update (N = 296) 10 months

after study unblinding favored cediranib over placebo (median of 10.5 months v

10.1 months; HR, 0.78; 95% CI, 0.57 to 1.06; P = .11). Causes of death in the

cediranib 30-mg cohort were NSCLC (81%), protocol toxicity +/- NSCLC (13%), and

other (6%); for the placebo group, they were 98%, 0%, and 2%, respectively.

CONCLUSION The addition of cediranib to carboplatin/paclitaxel results in

improved response and PFS, but does not appear tolerable at a 30-mg dose.

Consequently, the National Cancer Institute of Canada Clinical Trials Group and

the Australasian Lung Cancer Trials Group initiated a randomized, double-blind,

placebo-controlled trial of cediranib 20 mg with carboplatin and paclitaxel in

advanced NSCLC.

PMID: 19917841 [PubMed - indexed for MEDLINE]

 

Real-time imaging of single cancer-cell dynamics of lung metastasis.

Kimura H, Hayashi K, Yamauchi K, Yamamoto N, Tsuchiya H, Tomita K, Kishimoto H,

AntiCancer, Inc., 7917 Ostrow Street, San Diego, California 92111, USA.

We have developed a new in vivo mouse model to image single cancer-cell dynamics

of metastasis to the lung in real-time. Regulating airflow volume with a novel

endotracheal intubation method enabled controlling lung expansion adequate for

imaging of the exposed lung surface. Cancer cells expressing green fluorescent

protein (GFP) in the nucleus and red fluorescent protein (RFP) in the cytoplasm

were injected in the tail vein of the mouse. The right chest wall was then opened

in order to image metastases on the lung surface directly. After each

observation, the chest wall was sutured and the air was suctioned in order to

re-inflate the lung, in order to keep the mice alive. Observations have been

carried out for up to 8 h per session and repeated up to six times per mouse thus

far. The seeding and arresting of single cancer cells on the lung, accumulation

of cancer-cell emboli, cancer-cell viability, and metastatic colony formation

were imaged in real-time. This new technology makes it possible to observe

real-time monitoring of cancer-cell dynamics of metastasis in the lung and to

identify potential metastatic stem cells.

PMID: 19911396 [PubMed - in process]

 

The role of pemetrexed combined with targeted agents for non-small cell lung

cancer.

Konopa K, Jassem J.

Dept. of Oncology and Radiotherapy, Medical University of Gdańsk, Poland.

Pemetrexed is a novel third-generation multitargeted antifolate agent used in the

first- and second-line treatment of unresectable pleural mesothelioma and

advanced non-small cell lung cancer (NSCLC). Owing to its mild toxicity, this

compound is a preferred partner in the multidrug regimens. In the last few

decades, better understanding of molecular oncology and genetics has allowed for

the development of an array of molecular targeted agents, many of which have been

found active in NSCLC. It has been hoped that these compounds will disrupt tumor

signaling pathways complementary to those targeted by chemotherapy. This review

outlines the current preclinical and clinical studies using pemetrexed in

combination with targeted agents in advanced NSCLC. Clinical experience with the

use of these combinations is still limited and mostly includes phase I and II

trials. These investigations have mainly focused on compounds previously shown to

be active in NSCLC: anti-angiogenic agents (bevacizumab and small molecule

tyrosine kinase inhibitors) and inhibitors of epidermal growth factor receptor

(cetuximab and erlotinib). Preliminary results have shown the feasibility of

these combinations and their promising activity but large phase III studies are

warranted to verify the real value of this strategy. Combinations of pemetrexed

with other targeted agents, such as mTOR inhibitors and compounds targeting

proteasome are still at early stages of development.

PMID: 19839932 [PubMed - in process]

 

Pharmacological aspects of the enzastaurin-pemetrexed combination in non-small

cell lung cancer (NSCLC).

Giovannetti E, Honeywell R, Hanauske AR, Tekle C, Kuenen B, Sigmond J, Giaccone

G, Peters GJ.

Dept of Medical Oncology, VU University Medical Center, Amsterdam, The

Netherlands.

Conventional regimens have limited impact against NSCLC. Current research is

focusing on multiple pathways as potential targets, and this review describes

pharmacological aspects underlying the combination of the PKCbeta-inhibitor

enzastaurin with the multitargeted antifolate pemetrexed. Pemetrexed is commonly

used, alone or combined with platinum compounds, in NSCLC treatment, and ongoing

studies are evaluating its target, thymidylate synthase (TS), as predictor of

drug activity. Enzastaurin is a biological targeted agent being actively

investigated against different tumors as single agent or in combination. All the

downstream events following PKCbeta inhibition by enzastaurin are not completely

known, and assays to evaluate possible biomarkers, such as expression of PKC,

VEGF and GSK3beta, in tissues and/or in blood samples, are being developed.

Enzastaurin-pemetrexed combination was synergistic in preclinical models,

including NSCLC cells, where enzastaurin reduced phosphoCdc25C, resulting in

G2/M-checkpoint abrogation, and Akt and GSK3beta; phosphorylation, favoring

apoptosis induction in pemetrexed-damaged cells. Enzastaurin also significantly

reduced VEGF secretion and pemetrexed-induced upregulation of TS expression,

possibly via E2F-1 reduction, while the combination decreased TS activity.

Similarly, the accumulation of deoxyuridine (a marker of TS inhibition) and the

reduction of GSK3beta phosphorylation were detectable in clinical samples from a

phase-Ib trial of pemetrexed-enzastaurin combination. In conclusion, the

favorable toxicity profile and the multiple effects of enzastaurin on signaling

pathways involved in cell cycle control, apoptosis and angiogenesis, as well as

on proteins involved in pemetrexed activity, provide experimental basis for

future studies on enzastaurin-pemetrexed combination and their possible

pharmacodynamic markers in NSCLC patients.

PMID: 19839931 [PubMed - in process]

 

Gene profiling of clinical routine biopsies and prediction of survival in

non-small cell lung cancer.

Baty F, Facompré M, Kaiser S, Schumacher M, Pless M, Bubendorf L, Savic S, Marrer

E, Budach W, Buess M, Kehren J, Tamm M, Brutsche MH.

Pneumologie, Kantonsspital St. Gallen, CH-9007 St. Gallen, Switzerland.

RATIONALE: Global gene expression analysis provides a comprehensive molecular

characterization of non-small cell lung cancer (NSCLC). OBJECTIVES: To evaluate

the feasibility of integrating expression profiling into routine clinical work-up

by including both surgical and minute bronchoscopic biopsies and to develop a

robust prognostic gene expression signature. METHODS: Tissue samples from 41

chemotherapy-naive patients with NSCLC and 15 control patients with inflammatory

lung diseases were obtained during routine clinical work-up and gene expression

profiles were gained using an oligonucleotide array platform (NovaChip; 34'207

transcripts). Gene expression signatures were analyzed for correlation with

histological and clinical parameters and validated on independent published data

sets and immunohistochemistry. MEASUREMENTS AND MAIN RESULTS: Diagnostic

signatures for adenocarcinoma and squamous cell carcinoma reached a sensitivity

of 80%/80% and a specificity of 83%/94%, respectively, dependent on the

proportion of tumor cells. Sixty-seven of the 100 most discriminating genes were

validated with independent observations from the literature. A 13-gene metagene

refined on four external data sets was built and validated on an independent data

set. The metagene was a strong predictor of survival in our data set (hazard

ratio = 7.7, 95% CI [2.8-21.2]) and in the independent data set (hazard ratio =

1.6, 95% CI [1.2-2.2]) and in both cases independent of the International Union

against Cancer staging. Vascular endothelial growth factor-beta, one of the key

prognostic genes, was further validated by immunohistochemistry on 508

independent tumor samples. CONCLUSIONS: Integration of functional genomics from

small bronchoscopic biopsies allows molecular tumor classification and prediction

of survival in NSCLC and might become a powerful adjunct for the daily clinical

practice.

PMID: 19833826 [PubMed - indexed for MEDLINE]