Lung Cancer

Editorial Board

2012-02-01

PET scans in radiotherapy planning of lung cancer

Dirk De Ruysscher, Ursula Nestle, Robert Jeraj, Michael MacManus — 2011-09-19

Abstract: Accurate delineation of the primary tumor and of involved lymph nodes is a key requisite for successful curative radiotherapy in non-small cell lung cancer (NSCLC). In recent years, it has become clear that the incorporation of FDG PET-CT scan information into the related processes of patient selection and radiotherapy planning has lead to significant improvements for patients with NSCLC. The use of FDG PET-CT information in radiotherapy planning allows better target volume definition, reduces inter-observer variability and encourages selective irradiation of involved mediastinal lymph nodes. PET-CT also opens the door for innovative radiotherapy delivery and the development of new concepts. However, care must be taken to avoid a variety of technical pitfalls and specific education is necessary, for clinicians and physicists alike.

Implementation of hypoxia measurement into lung cancer therapy

Xue Meng, Feng-Ming (Spring) Kong, Jinming Yu — 2011-10-17

Abstract: Tumor hypoxia has been found to be a characteristic feature in lung cancer. It has been shown to decrease the therapeutic efficacy of radiotherapy and some forms of chemotherapy. New methods for qualitative and quantitative assessment of tumor oxygenation have made it possible to establish the prognostic significance of tumor hypoxia. The ability to determine the degree and extent of hypoxia in lung cancer is not only important prognostically, but also in the selection of patients for hypoxia-modifying treatments. To provide the best attainable quality of life for individual patients it is of increasing importance that tools be developed that allow a better selection of patients for these intensified treatment strategies. Although some markers and combinations have shown potential benefit and are associated with treatment outcome, their clinical usefulness needs to be validated in prospective trials. A review of published studies was carried out, focusing on the assessment of tumor hypoxia and the possibilities to overcome hypoxia during treatment in lung cancer.

Cancer mortality among Chinese chrysotile asbestos textile workers

2011-07-28

Abstract: To determine mortality associated with exposure to chrysotile asbestos, a cohort of asbestos workers from an asbestos textile factory in China was followed prospectively from 1972 to 2008. A total 577 workers were successfully followed, achieving a follow-up rate of 98.5% over 37 years. Employment data and smoking information were obtained from factory and individual workers. Vital status was ascertained from factory personnel records and the municipal death registry. Workers were categorized into high, medium and low exposure groups in terms of their job titles and workshops. Follow-up generated 17,508 person-years, with 259 deaths from all causes, 96 all cancers and 53 lung cancers and 2 mesotheliomas. The highest cancer mortality was observed in the high exposure group, with 1.5-fold age-adjusted mortality from all cancers and 2-fold from lung cancer compared to the low exposure group. Age and smoking adjusted hazard ratio in the high exposure group was 2.99 (95%CI, 1.30, 6.91) for lung cancer and 2.04 (1.12, 3.71) for all cancers. Both smokers and nonsmokers at the high exposure level had a high death risk of lung cancer, with a clearer exposure-response trend seen in smokers. This study confirmed increased mortality from lung cancer and all cancers in asbestos workers, and the cancer mortality was associated with exposure level.

Smoking history and lung carcinoma: KRAS mutation is an early hit in lung adenocarcinoma development

2011-08-12

Abstract: Background: In a European multicenter prospective study patients with lung cancer were interviewed for smoking history and biological samples centrally collected. The aim of this study was to compare KRAS mutation analysis with smoking status at the time of diagnosis.Methods: A nested case-study was performed on 233 non-small cell lung carcinomas. Cases were selected on the basis of progressive disease or disease-free post surgery based on specific criteria. KRAS mutation analysis was performed with the point-EXACCT method.Results: KRAS mutations were found in 39 adenocarcinomas and 1 squamous cell carcinoma in the 233 NSCLC. The median quitting smoking time (QST) for patients with and without KRAS mutations was 9 years, interquartile range [IQR 16–38] and 3 years, IQR [13–50], respectively (p=0.039). No difference was found for age at initiation of smoking, duration of smoking, average tobacco consumption, and smoking status at the time of diagnosis.Conclusion: The QST was longer for patients with KRAS mutations, supporting the notion that the presence of a KRAS mutation is a dominant early effect, supporting its role as a driver oncogen.

The anti-proliferative effect of heat shock protein 90 inhibitor, 17-DMAG, on non-small-cell lung cancers being resistant to EGFR tyrosine kinase inhibitor

2011-07-18

Abstract: Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, is frequently observed after initiation of TKIs therapy. Non-small-cell lung cancers (NSCLC) with activating EGFR mutations were reported to be sensitive to heat shock protein 90 (Hsp90) inhibitors regardless of the secondary TKI-resistant T790M mutation. We established EGFR-TKI resistant clones for PC-9 cell lines, harboring EGFR exon 19 deletions, with or without the secondary T790M mutation. We examined the anti-proliferative effect of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), an orally active Hsp90 inhibitor, on the growth of NSCLC cell lines in vitro and in vivo. In MTS assay, the IC50 values of 17-DMAG for 13 EGFR-mutant cell lines including eight EGFR-TKI resistant cell lines ranged from 0.04 to 0.16μM while those for seven EGFR-wild type cell lines ranged from 1.6 to 27.4μM. Western blot analysis revealed that phospho-EGFR, phospho-Akt, phospho-MAPK, cdk4, and cyclin D1 were more readily depleted by 17-DMAG treatment in EGFR-mutant cell lines than in EGFR-wild type cell lines. Cleaved PARP expression confirmed apoptosis in response to 17-DMAG treatment in EGFR-mutant cell lines but not in EGFR-wild type cell lines. In mice xenograft models, 17-DMAG significantly reduced the growth of EGFR-mutant lines irrespective of T790M mutation. These results suggested that 17-DMAG is a potential novel therapeutic agent for NSCLC patients with EGFR mutations with or without EGFR-TKI resistance.

Mesenchymal stem cells enhance lung cancer initiation through activation of IL-6/JAK2/STAT3 pathway

2011-07-29

Abstract: Background: The role of mesenchymal stem cells (MSCs) and IL-6 in lung cancer has not been well-addressed. We aimed to determine if MSCs can enhance the ability of tumor initiation of lung cancer cells, and link MSCs with activation of the IL-6/JAK2/STAT3 signaling pathway.Materials and methods: Lung cancer cell lines A549 and CL1-5 were directly or indirectly cocultured with MSCs. Spheres were defined as cell colonies with >50% area showing 3-dimensional structure and blurred cell margins. Cells without and with MSCs were injected into NOD/SCID mice. The percentage of tumor formation was determined. The influence of the IL-6/JAK2/STAT3 signaling pathway in cancer cell sphere formation and tumor growth were investigated.Results: A very small number of lung cancer cells, when mixed with otherwise non-tumorigenic MSCs, obtained de novo tumorigenicity when injected subcutaneously and allowed to form a tumor xenograft. Secretion of IL-6 from MSCs increased activation of the JAK2/STAT3 pathway in cancer cells, and enhanced sphere formation and tumor initiation. A reduced capacity of tumor formation of A549 and CL1-5 lung cancer cells when IL-6 was inhibited in MSCs or STAT3 was silenced in A549 and CL1-5 admixed with MSCs.Conclusions: Culture of A549 or CL1-5 lung cancer cells with MSCs increased sphere formation, drug resistance, and overexpression of pluripotency markers through activation of the IL-6/JAK2/STAT3 pathway. MSCs enhanced the capability of A549 and CL1-5 lung cancer cells to form tumors in immunodeficient mice. Blockade of the IL-6/JAK2/STAT3 pathway attenuated the capability of A549 and CL1-5 cells to form tumors.

Exhaled breath condensate pH in patients with lung cancer

Balazs Antus, Imre Barta — 2011-08-10

Abstract: Assessment of exhaled breath condensate (EBC) pH is a promising method for investigating and monitoring airway pathology in a number of lung diseases. In this cross-sectional study we tested whether development of lung cancer is associated with acidification of EBC. EBC was collected in 43 smoking patients with lung cancer (squamous cell carcinoma: 17 patients, adenocarcinoma: 16 patients, and small cell lung cancer: 10 patients) before receiving any anticancer treatment and in 20 healthy smokers without any clinical and radiological evidence of pulmonary tumor. EBC pH was measured by CO2 gas standardization, the most reliable and accurate method at present. EBC pH in patients with pulmonary tumor (6.68±0.02) and in controls (6.63±0.05) was similar (p>0.05). Results were affected neither by the histological subtype nor the stage of the tumors. Our data suggest that assessment of EBC pH is of limited value for the diagnosis and/or screening of lung cancer.

Abnormality of the hepatocyte growth factor/MET pathway in pulmonary adenocarcinogenesis

2011-08-29

Abstract: Background: Signaling mediated by hepatocyte growth factor (HGF)/MET promotes multiple biological activities, including cell proliferation, motility, invasion, angiogenesis, and morphogenesis. Overexpression of HGF and MET and an increase of the MET gene copy number have recently been found in various cancers that had a poor outcome. Here we investigated the copy number of the MET gene and expression of MET and HGF in small pulmonary adenocarcinomas.Methods: Tumor tissues were obtained from 106 pulmonary small adenocarcinomas 2cm or less in diameter. MET gene copy number, and the expression of MET and HGF, were analyzed using fluorescence in situ hybridization (FISH) and immunohistochemistry, respectively.Results: MET FISH-positive signals were observed in 11 (10.4%) of 106 cases. One case (0.9%) showed gene amplification and 10 (9.4%) exhibited high polysomy. High immunoreactivity for MET and HGF in tumor cells was found in 30 (28.3%) and 19 cases (17.9%), respectively. HGF was also expressed in stromal cells in 32 cases (30.2%). No cases of non-invasive adenocarcinoma (adenocarcinoma in situ, localized bronchioloalveolar carcinoma) showed MET FISH-positive signals or high expression of HGF in the tumor cells. Expression of both MET and stromal HGF was stronger in invasive than in non-invasive adenocarcinoma. MET FISH-positive signals and high immunoreactivity for MET and HGF in tumor cells were associated with factors indicative of poor prognosis such as pleural invasion, vascular invasion, lymphatic permeation, lymph node metastasis, and nuclear grading. Univariate and multivariate analyses that included these factors showed that all statuses except for MET and HGF immunoreactivity were significantly associated with an increased risk of death. However, multivariate analysis revealed no independent factors related to poor prognosis.Conclusion: Our results suggest that abnormality of the HGF/MET pathway occurs during the course of progression from non-invasive to invasive pulmonary adenocarcinoma. An increased MET gene copy number is indicative of a poor outcome in patients with small pulmonary adenocarcinomas.

Proteomic surfaceome analysis of mesothelioma

2011-08-11

Abstract: Identification of new markers for malignant pleural mesothelioma (MPM) is a challenging clinical need. Here, we propose a quantitative proteomics primary screen of the cell surface exposed MPM N-glycoproteins, which provides the basis for the development of new protein-based diagnostic assays. Using the antibody-independent mass-spectrometry based cell surface capturing (CSC) technology, we specifically investigated the N-glycosylated surfaceome of MPM towards the identification of protein-marker candidates discriminatory between MPM and lung adenocarcinoma (ADCA). Relative quantitative CSC analysis of MPM cell line ZL55 in comparison with ADCA cell line Calu-3 revealed a bird's eye view of their respective surfaceomes. In a secondary screen of fifteen MPM and six ADCA, we used high throughput low density microarrays (LDAs) to verify specificity and sensitivity of nineteen N-glycoproteins overregulated in the surfaceome of MPM. This proteo-transcriptomic approach revealed thy-1/CD90 (THY1) and teneurin-2 (ODZ2) as protein-marker candidates for the discrimination of MPM from ADCA. Thy-1/CD90 was further validated by immunohistochemistry on frozen tissue sections of MPM and ADCA samples. Together, we present a combined proteomic and transcriptomic approach enabling the relative quantitative identification and pre-clinical selection of new MPM marker candidates.

Long-term prognosis of patients with lung cancer detected on low-dose chest computed tomography screening

2011-08-03

Abstract: The effectiveness of lung cancer screening using low-dose chest computed tomography (CT) remains elusive. The present study examined the prognosis of patients with lung cancer detected on CT screening in Japanese men and women. Subjects were 210 patients with primary lung cancer identified on CT screening at two medical facilities in Hitachi, Japan, where a total of 61,914 CT screenings were performed among 25,385 screenees between 1998 and 2006. Prognostic status of these patients was sought by examining medical records at local hospitals, supplemented by vital status information from local government. The 5-year survival rate was estimated according to the characteristics of patients and lung nodule. A total of 203 (97%) patients underwent surgery. During a 5.7-year mean follow-up period, 19 patients died from lung cancer and 6 died from other causes. The estimated 5-year survival rate for all patients and for those on stage IA was 90% and 97%, respectively. Besides cancer stage, smoking and nodule appearance were independent predictors of a poor survival; multivariable-adjusted hazard ratio (95% confidence interval) was 4.7 (1.3, 16.5) for current and past smokers versus nonsmokers and 4.6 (1.6, 13.9) for solid nodule versus others. Even patients with solid shadow had a 5-year survival of 82% if the lesion was 20mm or less in size. Results suggest that lung cancers detected on CT screening are mostly curative. The impact of CT screening on mortality at community level needs to be clarified by monitoring lung cancer deaths.

Safety and feasibility of a combined exercise intervention for inoperable lung cancer patients undergoing chemotherapy: A pilot study

2011-08-04

Abstract: Aim: To investigate the safety and feasibility of a six-week supervised structured exercise and relaxation training programme on estimated peak oxygen consumption, muscle strength and health related quality of life (HRHRQOL) in patients with inoperable lung cancer, undergoing chemotherapy.Methods: A prospective, single-arm intervention study of supervised, hospital based muscle and cardiovascular group training and individual home-based training. Peak oxygen consumption (VO2peak) was assessed using an incremental exercise test. Muscle strength was measured with one repetition maximum test (1RM). HRQOL was assessed using the Functional Assessment of Cancer Therapy-Lung (FACT-L) scale.Results: Twenty-five patients with non-small cell cancer (NSCLC) stage III–IV and four patients with extensive disease small cell lung cancer (SCLC-ED) were recruited. Six patients (20.7%) dropped out leaving 23 patients for analysis. Exercise adherence in the group training was 73.0% and 8.7% in the home-based training. There were improvements in estimated VO2peak and six-minute walk distance (6 MWD) as well as increased muscle strength measurements (p<0.05). There was significant improvement in the “emotional well-being” parameter (FACT-L) while there were no significant changes in HRQOL.Conclusion: Exercise training produces significant improvements in physiological indices and emotional HRQOL and is safe and feasible in patients with advanced stage lung cancer, undergoing chemotherapy. No analysis on home-based training was done because of low adherence.

Prediction of the prognosis and surgical indications for pulmonary metastectomy from colorectal carcinoma in patients with combined hepatic metastases

2011-08-08

Abstract: Background: The value of surgical treatment for patients with pulmonary and hepatic metastases from colorectal carcinoma is controversial. The purpose of this study was to analyze our initial experience with this aggressive strategy, and to define the prognosis and the surgical indications.Methods: The records of 35 patients who underwent surgical treatments for both hepatic and pulmonary metastases from colorectal carcinoma, from January 1997 to December 2008, were retrospectively analyzed.Results: There were 18 females and 17 males with a median age was 62.0 years. The primary colorectal neoplasm was located at the colon in 23 patients (65.7%) and in the rectum in 12 patients (34.3%). The overall 5-year and 10-year survival rates were 65.3% and 31.5% from the date of primary colorectal resection, respectively. For patients who underwent metachronous hepatic and pulmonary surgical treatment, the 10-year survival rate was 40.9%, which was significantly better than that of those undergoing synchronous hepatic and pulmonary surgical treatment (p=0.0265). Patients who have pulmonary less than ten of metastasis thus seemed to have a better prognosis than those with more than ten, but the difference was quite significant (p=0.0719). In a multivariate Cox proportional hazards model, synchronous hepatic and pulmonary metastases was identified as an independent predictor of adverse survival (p=0.0073).Conclusions: The results of our study suggest that hepatic and pulmonary surgical treatment can provide a better prognosis for patients with metachronous hepatic and pulmonary metastases from colorectal carcinoma. We believe that aggressive metastasectomy can be an option for selected patients, even if a patient has been previously treated for hepatic and pulmonary metastases from colorectal carcinoma.

Epirubicin and ifosfamide in relapsed or refractory small cell lung cancer patients

2011-08-10

Abstract: Introduction: In small cell lung cancer (SCLC), despite the high response rates induced by platinum-based first line chemotherapies, relapse happens in 85% of the first-line responding tumors. Since 1992 we used a combination of epirubicin and ifosfamide (EI) as a non-cross-resistant regimen in relapsed or refractory SCLC. With the topotecan approval in second line treatment, this combination has been moved from the second line to the third line setting.Methods: Patients presenting with a relapsed or refractory, histologically proven, SCLC were considered for this combination associating ifosfamide 3g/m2 day 1–2 with uroprotection using mesna, and epirubicin 90mg/m2 day 1 given every four weeks until progression or unacceptable toxicity.Results: Seventy patients were accrued between September 1992 and August 2010 (seven women). Median age was 56years. Performance Status was 0, 1, 2 and 3 for 16 (23%), 25 (35%), 20 (29%) and 9 (13%) patients respectively. Proportion of refractory, resistant and sensitive tumors was 20, 21 and 59% respectively. Median time from first line chemotherapy until progression was 90days (range 5–1720days). Forty-four patients were treated in second line setting whereas the 26 others have had received two lines at time of accrual. A total of 203 cycles were delivered (median 2 cycles, range: 1–6). Fifteen patients (21.4%) achieved an objective response (including one complete), and 10% had a stable disease. Median overall survival was 3.9months (95% confidence interval: 3.3–5.1). Overall NCI-CTC grade 3 and 4 toxicity was mainly hematological: neutropenia (71% of the patients, febrile neutropenia 9.4% of the cycles), thrombocytopenia (23%), and anemia (22%). In univariate analysis, previous anthracyclines treatment was associated with a trend towards shorter survival (median overall survival 3.9 versus 4.6months, p=0.12). In multivariate analysis, only a high serum NSE level and presence of brain metastases were independent prognostic variables.Conclusion: The EI combination is an active regimen in relapsed or refractory SCLC. The trend towards a greater activity of this regimen in patients not pretreated using anthracyclines suggests that class of agents should be tested in SCLC relapsing after the etoposide–platinum standard regimen.

Overexpression of the mammalian target of rapamycin (mTOR) and angioinvasion are poor prognostic factors in early stage NSCLC: A verification study

K. Gately, B. Al-Alao, T.Dhillon, F. Mauri, S. Cuffe, M. Seckl, K. O’Byrne — 2011-08-01

Abstract: Background: A recent study by Dhillon et al. , identified both angioinvasion and mTOR as prognostic biomarkers for poor survival in early stage NSCLC. The aim of this study was to verify the above study by examining the angioinvasion and mTOR expression profile in a cohort of early stage NSCLC patients and correlate the results to patient clinico-pathological data and survival.Methods: Angioinvasion was routinely recorded by the pathologist at the initial assessment of the tumor following resection. mTOR was evaluated in 141 early stage (IA-IIB) NSCLC patients (67 – squamous; 60 – adenocarcinoma; 14 – others) using immunohistochemistry (IHC) analysis with an immunohistochemical score (IHS) calculated (% positive cells×staining intensity). Intensity was scored as follows: 0 (negative); 1+ (weak); 2+ (moderate); 3+ (strong). The range of scores was 0–300. Based on the previous study a cut-off score of 30 was used to define positive versus negative patients. The impact of angioinvasion and mTOR expression on prognosis was then evaluated.Results: 101 of the 141 tumors studied expressed mTOR. There was no difference in mTOR expression between squamous cell carcinoma and adenocarcinoma. Angioinvasion (p=0.024) and mTOR staining (p=0.048) were significant univariate predictors of poor survival. Both remained significant after multivariate analysis (p=0.037 and p=0.020, respectively).Conclusions: Our findings verify angioinvasion and mTOR expression as new biomarkers for poor outcome in patients with early stage NSCLC. mTOR expressing patients may benefit from novel therapies targeting the mTOR survival pathway.

Preoperative lymphocyte count is an independent prognostic factor in node-negative non-small cell lung cancer

2011-07-18

Abstract: A number of prognostic factors have been reported in non-small cell lung cancer (NSCLC). Although lymph node metastasis is the most poorly predictive value in completely resected NSCLC, a significant number of patients have a fatal recurrence even in node-negative curative NSCLC. Recently inflammatory response has been shown as a predictive value in NSCLC. Neutrophils and lymphocytes play an important role in cancer immune response. In this study, we retrospectively examined the impact of preoperative peripheral neutrophil and lymphocyte counts on survival, and investigated the relationships of these factors to clinicopathological factors in node-negative NSCLC. A total 237 patients were evaluated. When the cut-off value of neutrophil count was 4500mm−3 with a maximum log-rank statistical value, overall 5-year survival rates were 79.7% for the low-neutrophil-count group and 69.5% for the high-neutrophil-count group (P=0.04). When the cut-off value of lymphocyte count was 1900mm−3 with a maximum log-rank statistical value, overall survival rates were 67.9% for the low-lymphocyte group and 87.7% for the high-lymphocyte group (P<0.001). High-neutrophil-counts were associated with tumor size (P=0.002) and pleural invasion (P<0.001). Low-lymphocyte-counts were correlated with vascular invasion (P=0.018) and recurrence of NSCLC (P=0.01). Multivariate analysis showed that the lymphocyte count was an independent prognostic factor (hazard ratio: 3.842; 95% confidence interval: 1.827–8.078; P<0.001), but the neutrophil count was not (P=0.185). We conclude that a peripheral lymphocyte count, which is associated with vascular invasion, is an independent prognostic factor in node-negative NCSLC.

Predictive and prognostic value of human copper transporter 1 (hCtr1) in patients with stage III non-small-cell lung cancer receiving first-line platinum-based doublet chemotherapy

2011-07-26

Abstract: Background: Recent studies have shown that human copper transporter 1 (hCtr1), the major copper influx transporter, is involved in the transport of platinum-based antitumor agents. We investigated the predictive and prognostic values of hCtr1, and copper efflux transporters ATP7A and ATP7B, in patients with locally advanced non-small cell lung cancer (NSCLC) receiving first-line platinum-based chemotherapy.Methods: From 2004 to 2009, we identified 54 consecutive stage III NSCLC patients who underwent first-line platinum-based doublet chemotherapy. Immunohistochemical studies of hCtr1, ATP7A and ATP7B on the paraffin-embedded pre-treatment tumor samples were performed and correlated with chemotherapy response and survival.Results: Overexpression of hCtr1, ATP7A and ATP7B were observed in 68%, 48% and 74% of the participants, respectively. hCtr1 overexpression was associated with better chemotherapy responses (P<0.01); whereas ATP7A and ATP7B were not. Patients with hCtr1 overexpressing tumors had better progression-free survival (PFS) and overall survival (OS) (P=0.01 and 0.047, respectively). In multivariate analyses for chemotherapy response and PFS, only hCtr1 overexpression emerged as a favorable independent predictive and prognostic factor (all P<0.01).Conclusion: This is the first report to state that hCtr1 is not only an independent predictor of platinum-based chemotherapy response but also a prognostic factor in stage III NSCLC.

Overexpression of matrix metalloproteinase-7 and -9 in NSCLC tumor and stromal cells: Correlation with a favorable clinical outcome

2011-07-18

Abstract: Background: Matrix metalloproteinases (MMPs) are considered important players in angiogenesis and cancer progression. Several drugs developed for targeting MMPs have until now been without clinical efficacy. As both malignant cells and cells of the surrounding stroma contribute to tumor growth, we have explored the impact of MMP-2, -7 and -9 expression in both the tumor and stromal compartment of non-small-cell lung cancers (NSCLC).Patients and methods: From 335 unselected stage I to IIIA NSCLC carcinomas, duplicate tumor and tumor-associated stromal cores were collected in tissue microarrays (TMAs). Immunohistochemistry was used to detect the expression of MMP-2, -7 and -9 in tumor and stromal cells.Results: In univariate analyses, high tumor cell MMP-7 expression (P=0.029) and high stromal MMP-9 expression (P=0.001) were positive prognostic factors. In the multivariate analysis, high tumor cell MMP-7 expression (HR 1.58, CI 1.08–2.32, P=0.020) and high stromal MMP-9 expression (HR 1.92, CI 1.25–2.96, P=0.003) were independent positive prognostic factors for disease-specific survival.Conclusion: High levels of MMP-7 in tumor cells and high levels of MMP-9 in tumor associated stroma were independent positive prognostic factors in NSCLC patients.

Circulating tumor cell detection in advanced non-small cell lung cancer patients by multi-marker QPCR analysis

2011-08-05

Abstract: Background: The aim of this study was to explore circulating tumor cell (CTC) detection in advanced non-small cell lung cancer (NSCLC). CTCs may not only serve as a prognostic marker in selected tumor types, but may also be useful as pharmacodynamic marker in drug development.Methods: Fourty-six advanced NSCLC patients and fourty-six healthy controls were included in the study and 8.0ml of peripheral blood was obtained from each of the participants. Immunomagnetic bead enrichment for cells expressing epithelial cell adhesion molecule (EpCAM) was performed, followed by multi-marker quantitative real-time PCR of a panel of marker genes: cytokeratin 7 (CK7), cytokeratin 19 (CK19), human epithelial glycoprotein (EGP) and fibronectin 1 (FN1). Using quadratic discriminant analysis (QDA), expression values were combined into a single score, which indicated CTC-positivity or -negativity. Test characteristics were assessed using receiver operating characteristic (ROC) curve analysis.Results: ROC curve analysis showed capability of discrimination between advanced NSCLC patients and healthy controls (area=0.712; 95% CI 0.606–0.819; P<0.001). A cut-off minimizing overall misclassification for QDA-positivity reached a sensitivity of 46% (95% CI 31–61) and a specificity of 93% (95% CI 82–99).Conclusions: In this exploratory study, an assay was developed for discriminating CTCs in peripheral blood samples of advanced NSCLC patients from healthy controls. The assay demonstrated an acceptable sensitivity in combination with good specificity. Further validation studies should take place in NSCLC patients and a matched control group.

The predictive role of serum VEGF in an advanced malignant mesothelioma patient cohort treated with thalidomide alone or combined with cisplatin/gemcitabine

2011-07-15

Abstract: There is a need for new treatment strategies and prognostic markers for the management of malignant mesothelioma (MM). The activity of thalidomide/cisplatin/gemcitabine (arm A) or thalidomide alone (arm B) was investigated in two parallel phase II studies in patients with advanced MM, using 6 month progression free survival (PFS) as the principal end-point. The predictive role of pre-treatment and 8 week follow-up serum C-reactive protein (CRP), interlukin-6 (IL-6), interlukin-6 soluble receptor (sIL-6R), mesothelin (SMRP) and vascular endothelial growth factor (VEGF) was also assessed. The proportion of patients with stable disease for >6 months was similar in both studies (arm A 35%, arm B 29%) and toxicity was mainly grade I/II. In univariate analyses only pre-treatment VEGF and CRP were correlated with survival. At 8 weeks post treatment, increased survival was found with low ( median) VEGF and CRP (P<0.05). Change in VEGF over the first 8 weeks of treatment was also predictive for survival (P<0.05). When pre-treatment VEGF was >median, decreasing VEGF was associated with increased survival (P<0.05). In conclusion, thalidomide alone, or in combination with cisplatin/gemcitabine, controlled disease for >6 months in ∼30% of patients. Patients with decreasing VEGF during treatment had longest survival. Pre-treatment VEGF or CRP and early change in VEGF on treatment may predict treatment benefit and should be examined in future studies.

Factors associated with adherence to chemotherapy guidelines in patients with non-small cell lung cancer

Ramzi G. Salloum, Thomas J. Smith, Gail A. Jensen, Jennifer Elston Lafata — 2011-08-04

Summary: Background: Evidence-based guidelines recommend chemotherapy for medically fit patients with stages II–IV non-small cell lung cancer (NSCLC). Adherence to chemotherapy guidelines has rarely been studied among large populations, mainly because performance status (PS), a key component in assessing chemotherapy appropriateness, is missing from claims-based datasets. Among a large cohort of patients with known PS, we describe first line chemotherapy use relative to guideline recommendations and identify patient factors associated with guideline concordant use.Patients and methods: Insured patients, ages 50+, with stages II–IV NSCLC between 2000 and 2007 were identified via tumor registry (n=406). Chart abstracted PS, automated medical claims, Census tract information, and travel distance were linked to tumor registry data. Chemotherapy was considered appropriate for patients with PS 0–2. Multivariate logit models were fit to evaluate patient characteristics associated with chemotherapy over- and under-use per guideline recommendations. Tests of statistical significance were two sided.Results: Overall compliance with first line chemotherapy guidelines was 71%. Significant (p<0.05) predictors of chemotherapy underuse (19%) included increasing age (odds ratio [OR], 1.09), higher income (OR, 1.02), diagnosed before 2003 (OR, 2.05), and vehicle access (OR, 6.96) in the patient's neighborhood. Significant predictors of chemotherapy overuse (10%) included decreasing age (OR, 0.92), diagnosed after 2003 (OR, 3.24), and higher income (OR, 1.05) in the patient's neighborhood.Among NSCLC patients 29% do not receive guideline recommended chemotherapy treatment missing opportunities for cure or beneficial palliation, or receiving chemotherapy with more risk of harm than benefit. Care concordant with guidelines is influenced by age, economic considerations such as income and transportation barriers.

Raltitrexed plus cisplatin is cost-effective compared with pemetrexed plus cisplatin in patients with malignant pleural mesothelioma

Beth Woods, Noman Paracha, David A. Scott, Nicholas Thatcher — 2011-09-21

Abstract: Introduction: The National Institute for Health and Clinical Excellence (NICE) has previously recommended pemetrexed plus cisplatin for the treatment of patients with advanced malignant pleural mesothelioma (MPM) and WHO performance status 0–1. Subsequent to this appraisal, randomised controlled trial (RCT) data for raltitrexed plus cisplatin and comparing chemotherapy to active symptom control (ASC) has become available, allowing a more complete analysis of the comparative efficacy and cost-effectiveness of first-line chemotherapy in MPM.Methods: An adjusted indirect comparison is used to estimate the relative efficacy of raltitrexed plus cisplatin and pemetrexed plus cisplatin. A cost-effectiveness model is used to assess the lifetime costs and health outcomes associated with these comparators and ASC. Patient level data from the EORTC 08983 trial are used to estimate baseline progression and survival rates. Relative treatment effects are taken from RCTs; cost and utility data from the literature.Results: Raltitrexed plus cisplatin and pemetrexed plus cisplatin were not found to be statistically significantly different with respect to overall response, progression free survival or overall survival. The cost-effectiveness analysis found raltitrexed plus cisplatin to be cost-effective at a cost per quality adjusted life year of £13,454 compared to cisplatin and £27,360 compared to ASC. Pemetrexed plus cisplatin is dominated by raltitrexed plus cisplatin as the raltitrexed combination offers marginally higher quality adjusted life years (QALYs) and life years (LYs) at a substantially lower total cost.Conclusion: Raltitrexed plus cisplatin is a cost-effective first-line treatment for MPM. This conclusion was maintained across a number of sensitivity analyses.

Lung Cancer

Editorial Board

Contents

PET scans in radiotherapy planning of lung cancer

Implementation of hypoxia measurement into lung cancer therapy

Cancer mortality among Chinese chrysotile asbestos textile workers

Smoking history and lung carcinoma: KRAS mutation is an early hit in lung adenocarcinoma development

The anti-proliferative effect of heat shock protein 90 inhibitor, 17-DMAG, on non-small-cell lung cancers being resistant to EGFR tyrosine kinase inhibitor

Mesenchymal stem cells enhance lung cancer initiation through activation of IL-6/JAK2/STAT3 pathway

Exhaled breath condensate pH in patients with lung cancer

Abnormality of the hepatocyte growth factor/MET pathway in pulmonary adenocarcinogenesis

Proteomic surfaceome analysis of mesothelioma

Long-term prognosis of patients with lung cancer detected on low-dose chest computed tomography screening

Safety and feasibility of a combined exercise intervention for inoperable lung cancer patients undergoing chemotherapy: A pilot study

Prediction of the prognosis and surgical indications for pulmonary metastectomy from colorectal carcinoma in patients with combined hepatic metastases

Epirubicin and ifosfamide in relapsed or refractory small cell lung cancer patients

Overexpression of the mammalian target of rapamycin (mTOR) and angioinvasion are poor prognostic factors in early stage NSCLC: A verification study

Preoperative lymphocyte count is an independent prognostic factor in node-negative non-small cell lung cancer

Predictive and prognostic value of human copper transporter 1 (hCtr1) in patients with stage III non-small-cell lung cancer receiving first-line platinum-based doublet chemotherapy

Overexpression of matrix metalloproteinase-7 and -9 in NSCLC tumor and stromal cells: Correlation with a favorable clinical outcome

Circulating tumor cell detection in advanced non-small cell lung cancer patients by multi-marker QPCR analysis

The predictive role of serum VEGF in an advanced malignant mesothelioma patient cohort treated with thalidomide alone or combined with cisplatin/gemcitabine

Factors associated with adherence to chemotherapy guidelines in patients with non-small cell lung cancer

Raltitrexed plus cisplatin is cost-effective compared with pemetrexed plus cisplatin in patients with malignant pleural mesothelioma