Lung Cancer - Articles in Press

Correlations between serial pro-gastrin-releasing peptide and neuron-specific enolase levels, and the radiological response to treatment and survival of patients with small-cell lung cancer - Corrected Proof

2012-02-02

Abstract: Introduction: To investigate whether decrease in the serum levels of pro-gastrin releasing peptide (ProGRP) and neuron-specific enolase (NSE) were correlated with the radiological response in patients with small-cell lung cancer (SCLC).Methods: Of the 196 patients, we retrospectively reviewed 118 patients elevated baseline levels of ProGRP and NSE prior to the initial therapy (IT) who survived for more than 1 month. The radiological response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST 1.1).Results: Decrease in the serum ProGRP was strongly correlated with the decrease of the sum of the tumor diameters (SOD) before the third course (ρ=0.50) and after the fourth course (ρ=0.42) of IT. Decrease in the serum NSE was weakly correlated with the decrease of the SOD after the fourth course (ρ=0.27), but not before the third courses (ρ=0.22). In the receiver operating characteristic (ROC) curves predicting 1-year survivors, the area under the curve (AUC) for percent changes in serum ProGRP before the third course were significantly larger than those for NSE (0.714 vs. 0.527, p=0.004).Conclusions: Percent changes in serum ProGRP showed better correlation to SOD and prognostic impact than that of NSE.

Prognostic impact of education level of patients with advanced non-small cell lung cancer enrolled in clinical trials - Corrected Proof

2012-02-02

Abstract: Background: Socioeconomic status can potentially affect prognosis of cancer patients. Our aim was to describe potential differences in demographic and clinical characteristics, treatment, and survival by education level in patients with advanced non-small cell lung cancer (NSCLC) enrolled in clinical trials of first-line treatment.Methods: Individual data of Italian patients with advanced NSCLC (stage IV, or IIIB with supraclavicular nodes or malignant pleural effusion), ECOG performance status (PS) 0–2, enrolled in four phase III randomized trials conducted between 1996 and 2005 were pooled. Information about education was available for 1680 of 1709 patients (98.3%). Patients were divided in two groups according to education level: high (patients with at least high school diploma) or low (those with less than high school diploma). Survival analyses were stratified by treatment arm within trial.Results: There were 312 (19%) and 1368 (81%) patients with high and low education, respectively. Education level was significantly different among birth cohorts, with a time-trend toward higher education level. Patients with high education were significantly younger (median age 65 vs. 70), were less frequently unfit at diagnosis (ECOG PS2 5% vs. 16%), and their tumor type was more frequently adenocarcinoma (47% vs. 37%). Number of treatment cycles received was not significantly different between education groups. Median survival was 9.4 and 7.6months in high and low education, respectively (p=0.012). At multivariable analysis, female sex, better PS and high education level (Hazard Ratio 0.85, 95%CI 0.73–0.99, p=0.03) were independently associated with longer survival.Conclusions: In Italian patients enrolled in four randomized trials of first-line chemotherapy for advanced NSCLC, high education was significantly more frequent among younger patients, and was associated with lower proportion of PS2 patients. Education level did not significantly affect number of chemotherapy cycles received. Overall survival was longer in patients with high education, after adjustment for PS and other prognostic factors. The exact underlying mechanisms of the independent prognostic role of education level are substantially unknown, but lead-time bias (anticipation in diagnosis and time to inclusion in the trial), differences in adherence to care outside the trial procedures, differences in comorbidities and life-style factors may all contribute.

Stromal CD4/CD25 positive T-cells are a strong and independent prognostic factor in non-small cell lung cancer patients, especially with adenocarcinomas - Corrected Proof

2012-02-02

Abstract: Within the concert of immune reactions against tumour cells cytotoxic and regulatory T-cells are of utmost importance. Several studies revealed contradictory results on this issue. We therefore focused on functional expression patterns and localization of tumour-infiltrating T-lymphocytes in non-small cell lung cancer (NSCLC) and their impact on patient's survival. 232 curatively operated NSCLC patients were included. After histological reevaluation and construction of tissue-multi-arrays immunohistochemical doublestains for CD3/CD8 and CD4/CD25 were performed to evaluate the total number of T-cells and their subsets of cytotoxic and activated T-cells. Additionally, the localization of the lymphocytes was included in the analysis. Hereby, T-cells within the tumour stroma were regarded as stromal, those among cancer cells as intraepithelial. The number of lymphocytes differed significantly between the histological subtypes being most prominent in large cell carcinomas. Survival analysis showed that high numbers of stromal T-lymphocytes are of beneficial prognostic influence in NSCLC patients. This also proved to be an independent prognostic factor in adenocarcinomas. Thus, in a large and well characterized cohort of NSCLC this is the first study to determine the prognostic value of stromal T-lymphocytes, as these are an independent prognosticator in NSCLC especially in adenocarcinomas whereas intraepithelial T-cells are not.

Stereotactic body radiotherapy (SBRT) for solitary pulmonary nodules clinically diagnosed as lung cancer with no pathological confirmation: Comparison with non-small-cell lung cancer - Corrected Proof

2012-02-02

Abstract: Introduction: In non-surgical candidates with solitary pulmonary nodules (SPNs) and no histological confirmation, optimal management remains uncertain.Methods: Between February 2005 and February 2011 we treated 298 lung cancers with stereotactic body radiotherapy (SBRT), including SPNs clinically diagnosed as lung cancer (CDLC). Among them, we extracted patients treated with a total dose of 40–50Gy per 5 fractions and followed up more than 6months. Patients who had a history of previously treated lung cancer, or were diagnosed pathologically, or suspected as having small-cell lung cancer or large cell neuroendcrine cancer were excluded from this study. The remaining patients were divided into two groups; CDLC and non-small-cell lung cancer (NSCLC) patients and their outcomes were assessed and compared.Results: Fifty-eight CDLC and 115 NSCLC patients were included in this study. The proportions of female and inoperable cases were significantly higher in the CDLC group. Other characteristics, including T stage and standard uptake value, were well balanced. Median follow-up durations were 20.2 (range, 6.0–58.8) and 21.2 (range, 6–63.7) months, respectively. The 3-year local control, regional-free, metastasis-free, progression-free, cause-specific survival, and overall survival rates were 80% and 87% (p=0.73), 88% and 91% (p=0.72), 70% and 74% (p=0.57), 64% and 67% (p=0.45), 74% and 71% (p=0.17), 54% and 57% (p=0.48), respectively.Conclusion: These results indicate that the treatment outcome of CDLC group was almost identical to that of NSCLC and that few benign lesions seemed to be included. We advocate that SBRT can be legitimately applied to CDLC, provided that they are carefully diagnosed by integrating various clinical findings.

Prognostic impact of the primary tumor location based on the hilar structures in non-small cell lung cancer with mediastinal lymph node metastasis - Corrected Proof

2012-01-30

Abstract: The status of mediastinal lymph node metastasis is one of the main factors determining the treatment strategy for non-small cell lung cancer (NSCLC), but the primary tumor location is not considered crucial in the tumor-node-metastasis (TMN) classification at present. The aim of this study was to estimate the prognostic value of the primary tumor location on the basis of the hilar structures in NSCLC with mediastinal lymph node metastasis. We retrospectively reviewed the cases of 337 consecutive patients who underwent surgical resection for NSCLC between 1995 and 2004, divided the pN2 NSCLC cases (n=40) into central- and peripheral-type tumors according to the distance of the primary tumor from the first branch of the extrapulmonary bronchus, and compared the surgical outcomes between these tumor groups. Eighteen and twenty-two cases were classified as central- and peripheral-type tumors, respectively. The 5-year survival rate was significantly better for patients with central-type tumors than peripheral-type tumors (51.5% vs. 21.2%, P=0.034). The location-specific prognostic tendency was noted irrespective of the presence (n=13) or absence of skip metastasis. In a multivariate Cox analysis of the N2 NSCLC cases, the primary tumor location was a significant (P=0.026) prognostic factor for overall survival. In conclusion, evaluation of the primary tumor location based on the hilar structures is useful to predict the prognosis in N2 NSCLC.

When will I get my breath back? Recovery time of exercise-induced breathlessness in patients with thoracic cancer - Corrected Proof

2012-01-30

Breathlessness is a common symptom in thoracic cancer. It impacts adversely on physical activity levels and the resultant deconditioning may exacerbate the decline in physical capacity . Therapeutic exercise can help counter this downward spiral and a rehabilitation approach is recommended . A prerequisite to encourage exercise is the provision of appropriate assurance that breathlessness per se is not dangerous, and that it will settle with rest . To our knowledge, the time taken for breathlessness to recover following exertion has not been formally studied in patients with thoracic cancer. To better inform patient and carer expectations and the advice given by professionals, we have collated recovery data from two studies in which the Incremental Shuttle Walk Test (ISWT) was used to assess exercise performance in this group.

EGFR–TKI resistant non-small cell lung cancer (NSCLC): New developments and implications for future treatment - Corrected Proof

Wolfram Brugger, Michael Thomas — 2012-01-27

Abstract: Treatment with receptor-tyrosine kinase inhibitors (TKIs) has improved progression-free and overall survival in patients with advanced non-small cell lung cancer (NSCLC). One major target for treatment with TKI is the epidermal growth factor receptor (EGFR), particularly in patients harboring activating mutations. However, despite initial responses and long lasting remissions, the development of secondary resistance inevitably leads to treatment failure. Analyzing recent data from various phase II/III trials it seems obvious that the single mode of action of gefitinib or erlotinib can provide temporary success only. Both preclinical and clinical evidence suggest that irreversible TKIs such as afatinib or PF00299804, or combined approaches using multiple kinase inhibition (e.g. EGFR and MET) and vertical inhibition by combination of small molecules and antibodies, seem to be more promising and will be the prevailing concepts to overcome secondary EGFR–TKI resistance for the near future.

Verification of beam delivery using fibrosis after proton beam irradiation to the lung tumor - Corrected Proof

2012-01-27

Abstract: Background and purpose: To investigate the geometrical accuracy in proton beam therapy (PBT) to the lung by comparing the location of the fibrosis after PBT and the tumor using less invasive method.Patients and methods: We examined 50 lung tumors that had been treated by respiratory-gated PBT (33–74 Gray equivalents). Image registration and re-slicing of computed tomography (CT) before and after PBT were performed using an image analysis software system. We investigated whether the location of fibrosis was accurate with the tumor site and which factor among the respiratory rhythm, tumor volume, location, fixation, beam direction and clinical outcome was affected with accuracy.Results: The area of fibrosis was accurate with the tumor in 45 tumors (Group A) and not accurate in 5 tumors (Group B). All lesions with a small irregularity of respiratory rhythm showed fibrosis in an area accurate with the tumor. This percentage (100%) was higher than that of the lesions with a large irregularity of respiratory rhythm (67%, p=0.037). Radiation pneumonitis was found for 1 lesion in group A and 2 lesions in Group B (p=0.0009).Conclusion: The geometrical accuracy of beam delivery to the lung was higher in the patients with a regular respiratory rhythm in PBT. The patients of Group B had greater risk of pneumonitis.

Benefits and risks of using erythropoiesis-stimulating agents (ESAs) in lung cancer patients: Study-level and patient-level meta-analyses - Corrected Proof

2012-01-25

Abstract: In anemic patients receiving myelosuppressive chemotherapy, erythropoiesis-stimulating agents (ESAs) raise hemoglobin levels and reduce transfusion requirements, but ESA-related safety concerns exist. To evaluate ESA benefits and risks in lung cancer, we conducted meta-analyses of data from controlled ESA trials conducted in lung cancer patients. Study-level analyses included controlled ESA trials reporting lung cancer mortality, identified from the 2006 Cochrane ESA report and from a systematic search for studies published through December 2010. Patient-level analyses included data from lung cancer patients receiving chemotherapy in Amgen studies evaluating darbepoetin alfa (DA) vs placebo. Study-level and patient-level analyses examined deaths, progression, and transfusion incidence. Patient-level analyses also examined adverse events (AEs) and fatigue.In a study-level meta-analysis of nine ESA studies of 2342 patients receiving chemotherapy, the ESA odds ratio (OR) was 0.87 (95% confidence interval [CI] 0.69–1.09) for mortality; the overall random-effects risk difference (95% CI) for mortality was −0.02 (−0.06, 0.02). The ESA OR (95% CI) for disease progression in five chemotherapy studies reporting progression was 0.84 (0.65–1.09). The ESA odds ratio (95% CI) was 0.34 (0.28–0.41) for transfusion incidence.In a patient-level meta-analysis of four studies evaluating 1009 patients through follow-up, the median survival time was 41 weeks with DA and 38 weeks with placebo. During the combined study and follow-up periods, 80% of placebo-group patients and 74% of DA patients died (mortality hazard ratio [HR] 0.90 [95% CI, 0.78–1.03] for DA); results were similar for small cell lung cancer and non-small cell lung cancer. Overall, 87% of placebo patients and 84% of DA patients progressed or died. Fewer DA patients had transfusions (week 5 through end-of-study, DA 19%, placebo 43%). AEs included thrombotic/embolic events (DA 10.5%, placebo 7.2%), cerebrovascular disorders (DA 3.7%, placebo 4.2%), pulmonary edema (DA 0.4%, placebo 1.0%) and pulmonary embolism (DA 1.8%, placebo 0.6%).These meta-analyses suggest that ESAs reduce transfusions without increasing mortality or disease progression in lung cancer patients undergoing chemotherapy.

Differential effect of age on survival in advanced NSCLC in women versus men: Analysis of recent Eastern Cooperative Oncology Group (ECOG) studies, with and without bevacizumab - Corrected Proof

2012-01-24

Abstract: Background: The impact of age on prognosis in advanced stage non-small cell lung cancer (NSCLC) may differ by sex.Patients and methods: Eligible patients (N=1590) from E1594, a 4-arm platinum-based chemotherapy trial, and E4599 (carboplatin/paclitaxel±bevacizumab) chemotherapy arm were divided into male and female cohorts and separated into age groups of <60 or ≥60 years old. Eligible E4599 patients (N=850) were similarly separated by age and sex and by treatment (±bevacizumab). Survival was calculated separately for each cohort.Results: The median survival time (MST) for women ≥60 years old treated with chemotherapy alone on E1594 and E4599 was 11.6 months versus 9.0 months for women <60 (p=0.03). MST was 7.4 and 8.3 months for men ≥60 and <60 years old respectively (NS). In E4599 the age <60 by bevacizumab treatment interaction was statistically significant (p=0.03) for women (younger had greater benefit), with no age effect in men.Conclusions: In this unplanned, exploratory subgroup analysis of advanced stage NSCLC ECOG trials, women ≥60 years old treated with chemotherapy live longer than men and younger women. In contrast, bevacizumab survival benefit was more pronounced in men of any age and in younger women on E4599.

Maintenance treatment of advanced non-small-cell lung cancer: Results of an International Expert Panel Meeting of the Italian Association of Thoracic Oncology - Corrected Proof

2012-01-24

Abstract: Several randomized trials have recently investigated the role of maintenance treatment for patients with advanced non-small-cell lung cancer (NSCLC) with responding or stable disease after completion of first-line chemotherapy. Maintenance strategy has relevant implications in terms of potential toxicity, logistics and costs, and all of these aspects should be taken into account, together with the magnitude of benefit for the patient. In order to assess the strengths and limitations of available evidence, to help clinical practice, and to suggest priorities for future clinical research, the Italian Association of Thoracic Oncology (AIOT) organized an International Experts Panel Meeting on maintenance treatment of advanced NSCLC, which took place in Sperlonga (Italy) in May 2011. Based on the available evidence, panelists agreed that maintenance therapy represents a treatment option in advanced NSCLC. Maintenance should be discussed with patients not progressed after 4–6 cycles of first-line chemotherapy, who are fit (performance status 0–1) and without persistent chemotherapy-induced toxicity. Patients need to be well informed about potential advantages and disadvantages of accepting additional therapy without a “treatment-free period”. Two different strategies, switch or continuation maintenance, are supported by available evidence. At the moment, there is no direct comparison between switch maintenance and continuation maintenance. For future trials, the panel recommends the use of overall survival as the primary endpoint, with pre-defined second-line treatment. Translational research is essential to identify predictive factors, and should be performed, whenever feasible, in order to achieve treatment optimization with proper patient selection.

In situ detection of lung cancer volatile fingerprints using bronchoscopic air-sampling - Corrected Proof

2012-01-20

Abstract: Lung cancer diagnosis via breath analysis has to overcome some issues that can be summarized by two crucial points: (1) further developments for more performant breath sampling technologies; (2) discovering more differentiated volatile fingerprints to be ascribed to specific altered biological mechanisms. The present work merges these two aspects in a pilot study, where a breath volume, sampled via endoscopic probe, is analyzed by an array of non-selective gas sensors. Even if the original non-invasive methods of breath analysis has been laid in favour of the endoscopic means, the innovative technique here proposed allows the analysis of the volatile mixtures directly sampled near the tumor mass. This strategy could open the way for a better understanding of the already obtained discrimination among positive and negative cancer cases. The results obtained so far confirm the established discrimination capacity. This allows to discriminate the different subtypes of lung cancer with 75% of correct classification between adenocarcinoma and squamous cell carcinoma. This result suggests that a ‘zoom-in’ on the cancer settled inside the human body can increase the resolution power of key-volatiles detection, allowing the discrimination among different cancer fingerprints. We report this novel technique as a robust support for a better comprehension of the promising results obtained so far and present in literature; it is not to be intended as a replacement for non-invasive breath sampling procedure with the endoscope.

Inhibitory effect of riccardin D on growth of human non-small cell lung cancer: In vitro and in vivo studies - Corrected Proof

2012-01-19

Abstract: Riccardin D is a macrocyclic bisbibenzyl compound extracted from liverwort plant Dumortiera hirsuta. Our previous study showed that riccardin D induced apoptosis of human leukemia cells by targeting DNA topoisomerase II (topo II). Riccardin D has been considered as a novel DNA topo II inhibitor and potential chemotherapeutic agent for treatment of cancers. In this study, we evaluated the inhibitory effects of riccardin D on growth of human non-small cell lung cancer (NSCLC) both in vitro and in vivo. Riccardin D effectively inhibited the proliferation of NSCLC cells as estimated by the MTT assay. Further examination showed that the ability of invasion and migration of NSCLC cells was suppressed on exposure to riccardin D as estimated by the assays of scratch and transwell chamber. The anticancer activity of riccardin D was verified in mice bearing human NSCLC H460 xenografts. Riccardin D injection produced a 44.5% inhibition of cancer growth without apparent signs of toxicity to animals. Further, riccardin D induced apoptosis of NSCLC cells as evidenced by the increases of cells with externalization of phosphatidylserine and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive in H460 xenografts. The analysis of apoptotic proteins showed that riccardin D activated the caspases cascade signaling pathway as demonstrated by the increases of cleaved caspase-3 and cleaved PARP in NSCLC cells in vitro and in H460 xenografts in mice. The pBR322 DNA relaxation assay indicated that riccardin D inhibited the activity of DNA topo II in H460 and A549 cells, suggesting the mechanism of riccardin D in induction of NSCLC apoptosis. In addition, we studied the activity and expression of matrix metalloproteinases (MMPs) in NSCLC cells. The activities of MMP-2 and MMP-9 in supernatants of NSCLC cells were suppressed on exposure to riccardin D as estimated by gelatin zymography assay. The inhibitory effects of riccardin D on expressions of MMP-2 and MMP-9 were verified in H460 xenografts in mice and the decreases of vascular endothelial growth factor (VEGF) and Erk1/2 might associate with the inhibition of MMPs and NSCLC growth. Together, our results suggest that riccardin D has a high inhibitory effect on human NSCLC growth through induction of apoptosis.

An ectopic ACTH-producing small cell lung carcinoma associated with enhanced corticosteroid biosynthesis in the peritumoral areas of adrenal metastasis - Corrected Proof

2012-01-17

Abstract: A 60-year-old Japanese male presented with swelling of bilateral cervical lymph nodes was subsequently diagnosed as the late stage of primary small cell lung carcinoma (SCLC). He was then treated with cisplatin and irinotecan as first-line chemotherapy, but hypokalemia with muscle weakness of the bilateral legs became gradually noticeable following two months of effective chemotherapy. A computed tomography (CT) scan revealed enlargement of bilateral adrenal glands and abdominal and mediastinal lymph nodes, though primary lung tumor remained the same in size. An ectopic ACTH-producing syndrome (EAS) was subsequently revealed by the following endocrinological studies. Hypokalemia was clinically improved by the treatment with metyrapone and the second-line chemotherapy with amrubicin for SCLC was started, but the patient died 12 days after the second-line chemotherapy. Post-mortem examination revealed ACTH immunoreactivity in tumor cells of all the metastatic lesions. Non-neoplastic adrenal cortex demonstrated hyperplasia associated with lipid depletion and marked expression of steroidogenic enzymes, especially in cortical cells around tumor infiltration, suggestive of paracrine ACTH stimulation of cortisol production. This is the first report evaluating expression of steroidogenic enzymes in adrenal cortex especially adjacent to the adrenal metastasis in the patients with EAS due to SCLC. These findings suggest that ACTH producing adrenal metastasis can induce EAS more frequently and severely, and that the symptoms and examination of EAS should be monitored carefully in the patients with adrenal metastasis of SCLC.

Randomized phase II study of first-line carboplatin-paclitaxel with or without bevacizumab in Japanese patients with advanced non-squamous non-small-cell lung cancer - Corrected Proof

2012-01-16

Abstract: Purpose: This multicenter, randomized, open-label, phase II study (JO19907) compared the efficacy and safety of first-line carboplatin-paclitaxel (CP) alone with bevacizumab-CP in Japanese patients with advanced non-squamous non-small-cell lung cancer (NSCLC).Methods: Chemonaïve patients with stage IIIB, IV or recurrent non-squamous NSCLC were eligible for participation. Patients were randomly assigned in a 2:1 ratio to receive bevacizumab-CP or CP alone. Chemotherapy was repeated for up to 6 cycles or until disease progression or unacceptable toxicity. Bevacizumab recipients who completed ≥3 cycles of chemotherapy could continue bevacizumab as monotherapy until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS).Results: After confirming the tolerability of bevacizumab-CP in a small number of patients, 180 patients were recruited, of whom 121 were assigned to bevacizumab-CP and 59 to CP alone. Hazard ratio (HR) for PFS was 0.61 with bevacizumab-CP versus CP alone (p=0.0090; median 6.9 versus 5.9 months). Objective response rate was significantly higher with bevacizumab-CP than with CP alone (60.7% versus 31.0%; p=0.0013). Median overall survival was >22 months in both treatment groups (HR 0.99; p=0.9526). No new safety signals were detected.Conclusion: Study JO19907 met its primary endpoint, demonstrating that the addition of bevacizumab to first-line CP significantly improves PFS in Japanese patients with advanced non-squamous NSCLC. This prolonged PFS by bevacizumab did not translate into OS benefit with the extremely longer underlying survival compared to historical data. No new safety signals were identified in this population. (Japan Pharmaceutical Information Center [JAPIC] registration number: CTI-060338).

Extrapleural pneumonectomy for early stage malignant pleural mesothelioma: An harmful procedure - Corrected Proof

Ottavio Rena, Caterina Casadio — 2012-01-13

Abstract: The effects on long-term post-operative quality of life (QoL) and disease-control in malignant pleural mesothelioma (MPM) of extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D) are compared. Seventy-seven patients affected by early-stage MPM received EPP (40) or P/D (37) associated with multimodal treatment between 1998 and 2009 at our institution. The last consecutive 39 (19 EPP and 20 P/D) were asked to answer the EORTC-QLQ-C30 questionnaire at baseline and at 6- and 12-months after treatment completion to evaluate the impact on QoL of both procedures. QoL evaluation was stopped at recurrence demonstration. Twenty-five (62%) EPP vs 9 (24%) P/D patients (p=0.002) had in-hospital major complications, and 2/40 (5%) EPP vs no one P/D patients died after surgery. Both procedures caused a significant impairment of all the considered variables of the EORTC-QLQ-C30 questionnaire after treatment completion; only P/D patients returned at baseline levels after12 months. EPP patients had a worse long-term post-operative QoL when compared with P/D. Median post-operative disease-free period was longer for EPP patients (14 vs 11 months) whereas the residual life to death period after recurrence detection was significantly longer for P/D patients (13 vs 9 months) (p=0.01). Median long-term survival was longer, even not significant, for P/D patients (25 vs 20 months). MPM patients submitted to EPP had a higher post-operative complication rate, a worse long-term QoL, a shorter residual life time after recurrent disease, despite a similar long-term survival when compared to P/D.

MO19390 (SAiL): Bleeding events in a phase IV study of first-line bevacizumab with chemotherapy in patients with advanced non-squamous NSCLC - Corrected Proof

2012-01-12

Abstract: Introduction: The clinical benefit and safety profile associated with first-line bevacizumab with doublet chemotherapy in patients with advanced non-squamous non-small cell lung cancer (NSCLC) was established in two large phase III studies, E4599 and AVAiL. SAiL, a single-arm phase IV study, was conducted to evaluate bevacizumab with a range of first-line chemotherapy regimens in a routine oncology practice setting.Methods: This analysis of the SAiL data was undertaken to specifically evaluate bleeding adverse events (AEs) in this study, and to explore potential associations between bleeding and baseline patient and disease characteristics.Results: In total, 2212 patients were evaluated. Bleeding AEs (any grade) occurred in 38.2% of patients (grade ≥3 bleeding AEs: 3.6%). Grade ≥3 pulmonary hemorrhage and central nervous system bleeding events were observed in 0.7% and 0.1% of patients, respectively. The incidence of grade ≥3 bleeding AEs was comparable across patient subgroups defined by central tumor location, tumor cavitation, histology, concomitant anticoagulation therapy and age. The majority (88.6%) of bleeding events resolved or improved, 10.2% persisted and 1.3% led to death; 10.2% of bleeding events required bevacizumab interruption or discontinuation.Conclusions: This analysis from the SAiL trial reaffirms a comparable incidence of clinically significant bleeding associated with first-line bevacizumab and chemotherapy as previous phase III studies in NSCLC patients despite less stringent first-line selection criteria. Grade ≥3 bleeding appears to be comparable when analyzed for patient and tumor characteristics, including tumor cavitation and concomitant anticoagulation therapy. Most bleeding events resolved or improved, and interruption/discontinuation of bevacizumab was infrequent in a standard oncology practice setting.

Higher expression of EphA2 and ephrin-A1 is related to favorable clinicopathological features in pathological stage I non-small cell lung carcinoma - Corrected Proof

2012-01-11

Abstract: Background: The overexpression of receptor tyrosine kinase EphA2 has been reported in various cancers. In non-small cell lung cancer (NSCLC), a positive correlation has been reported between high EphA2 immunohistochemical staining level and poor prognosis. However, its ligand, ephrin-A1, is supposed to act as a tumor suppressor via the kinase activity of EphA2. Thus, the biphasic roles of this system are not fully elucidated. We retrospectively evaluated the expression levels of EphA2 and ephrin-A1 in surgically treated pathological (p-) stage I NSCLC tumor samples, and their relation to clinicopathologic features or postoperative prognoses.Methods: The levels of EphA2 and ephrin-A1 mRNA expression were quantified by real-time reverse-transcription polymerase chain reaction in tissue samples from p-stage I NSCLC patients who had undergone complete resection in our facility (n=195). They were divided into two (EphA2/ephrin-A1-Low and -High) groups based on the median expression level, and their respective clinicopathologic features and prognoses were analyzed. Furthermore, samples were stained immunohistochemically and classified into four groups according to their staining levels, and their prognoses analyzed.Results: Marked demographic differences were found between EphA2/ephrin-A1-Low and -High groups. Both EphA2-High and ephrin-A1-High groups had more females, no smoking history, adenocarcinoma histology, well-differentiated carcinomas, p-stage IA patients, and patients with EGFR gene mutations. Five-year overall survival rates of the EphA2-Low and the EphA2-High patient groups were 68.9% and 86.1%, respectively (P=0.017), and five-year disease-free survival rates were 69.9% and 83.2%, respectively (P=0.035). There were no statistical differences between ephrin-A1-Low and ephrin-A1-High groups concerning postoperative survival. Although showing smaller differences, the findings from the immunohistochemical analyses supported the above results.Conclusions: Higher expression of EphA2 and ephrin-A1 was more related to the female sex, reduced smoking status, adenocarcinoma, well differentiated carcinomas, p-stage IA, and EGFR gene mutations. Higher EphA2 mRNA expression in p-stage I NSCLC patients was positively related to improved prognoses. These results may reflect a tumor suppressive role for the EphA2/ephrin-A1 system in a population of patients restricted to p-stage I NSCLC.

A meta-analysis of paclitaxel-based chemotherapies administered once every week compared with once every 3 weeks first-line treatment of advanced non-small-cell lung cancer - Corrected Proof

Guanghui Gao, Haiqing Chu, Lan Zhao, Tao Gui, Qinghua Xu, Jianping Shi — 2012-01-09

Abstract: Objective: The published data on the curative effects of comparing the once weekly paclitaxel-based chemotherapies (W-paclitaxel) with the standard every 3 weeks paclitaxel-based chemotherapies (S-paclitaxel) in the first-line treatment of advanced non-small-cell lung cancer (NSCLC) were still controversial. To derive a more precise estimation of the two regimens, a meta-analysis was performed.Methods: Medical databases and conference proceedings were searched for randomized controlled trials which compared W-paclitaxel with S-paclitaxel in patients with first-line treatment of advanced NSCLC. The following keywords were used: “paclitaxel”, “weekly schedule” and “non-small cell lung cancer”. Reference lists of original articles and review articles were also examined. The published languages and years were not limited. Endpoints were overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and adverse events. Statistical tests for heterogeneity were one-sided; statistical tests for effect estimates were two-sided.Results: Five eligible trials involved 940 patients were identified. They were all published as full-text articles. The intention to treatment (ITT) analysis demonstrated that the ORR of W-paclitaxel regimens patients was 30.89% (143/463), whereas the ORR of S-paclitaxel regimens patients was 27.09% (123/454). The overall pooled relative ratio (RR) for ORR was 1.24 (95% confidence intervals (CI)=0.93–1.66; P=0.14) when W-paclitaxel regimens patients were compared with S-paclitaxel regimens patients. Although the patients with W-paclitaxel regimens had an similar OS and PFS in comparison with S-paclitaxel regimens (median OS was 9.8 versus 10.7 months; hazard ratio (HR)=1.00; 95%CI=0.86–1.17; P=0.99; median PFS was 5.2 versus 4.7 months; HR=0.90; 95%CI=0.79–1.03; P=0.13, respectively), the W-paclitaxel regimens led to significantly less frequent adverse events of hematological toxicities and nonhematological toxicities.Conclusion: These results suggest that the W-paclitaxel is not superior than S-paclitaxel regimens. The paclitaxel-based chemotherapies given by every 3 weeks are still standard regimens. For patients, especially for the elder or the people with poor conditions who cannot tolerate the standard regimen, the weekly schedule can be considered.

Erlotinib or best supportive care for third-line treatment of advanced non-small-cell lung cancer: A real-world cost-effectiveness analysis - Corrected Proof

2012-01-09

Abstract: Erlotinib has been approved as a third-line treatment for advanced non-small-cell lung cancer (NSCLC) in British Columbia (BC). A cost-effectiveness analysis was conducted to compare costs and effectiveness in patients who received third-line erlotinib to those in a historical patient cohort that would have been eligible had erlotinib been available.Methods: In a population of patients who have been treated with drugs for advanced NSCLC, overall survival (OS), progression-to-death survival (PTD) and probability of survival one year after end of second-line (1YS) were determined using a Kaplan–Meier survival analysis. Costs were collected retrospectively from the perspective of the BC health care system.Results: Incremental mean OS was 90 days (0.25 LYG), and incremental mean cost was $11,102 (CDN 2009), resulting in a mean ICER of $36,838/LYG. Univariate sensitivity analysis yielded ICERs ranging from $21,300 to $51,700/LYG.Conclusion: Our analysis suggests that erlotinib may be an effective and cost-effective third-line treatment for advanced NSCLC compared to best supportive care.

Challenges scoring radiation pneumonitis in patients irradiated for lung cancer - Corrected Proof

2012-01-09

Abstract: Background and purpose: To quantify uncertainties in scoring radiation pneumonitis.Materials and methods: Records of 434 patients irradiated for lung cancer from 2000 to 2010 were retrospectively reviewed; IRB-approved study. From these, 121 received ≥60Gy for non-small cell lung cancer (NSCLC) with ≥6 months follow-up. Patients where the physicians were uncertain of the diagnosis due to confounding factors were deemed “hard to score”. Subgroups were defined based on lung dosimetric parameters, and frequencies in different subgroups were compared via Fisher's exact test.Results: 21/121 of patients were considered to have pneumonitis; median follow 17 months. Of these, 10/21 were “hard to score”; reasons including acute COPD exacerbation, infection, and tumor progression. “Hard to score” pneumonitis was slightly more common in patients with a COPD history (15%) vs. without COPD (4%) (p=0.05); and with a pre-RT FEV1<1.7L (16%) vs. ≥1.7L (4%) (p=0.09). Rates of “unambiguous” pneumonitis trended to be non-significantly slightly higher in patients higher mean lung doses, V5, and V30.Conclusion: Radiation pneumonitis occurred in 17% of patients undergoing RT for NSCLC; with diagnostic uncertainty in 48% of these. Poor pre-RT pulmonary function increases the rate of “hard to score” pneumonitis. Dosimetric parameters are slightly better related to “unambiguous” than “hard to score” pneumonitis, as expected.

History of tuberculosis as an independent prognostic factor for lung cancer survival - Corrected Proof

2012-01-09

Abstract: Introduction: It is well known that pulmonary tuberculosis is associated with an increased risk of lung cancer. We investigated whether a history of pulmonary tuberculosis is an independent risk factor for lung cancer survival in Caucasian patients.Methods: The data of the prospective population-based cohort of The Rotterdam Study were used. During a mean follow-up time of 18 years, there were 214 incident cases of pathology-proven lung cancer in a source population of 7983 study participants. History of tuberculosis was assessed at baseline by interviewers using standardized questionnaires. Associations of lung cancer survival with the occurrence of pulmonary tuberculosis were assessed using Cox's proportional hazard regression analysis adjusted for age, gender, pack-years, educational level and tumor stage.Results: A history of tuberculosis was reported in 13 of the 214 subjects with lung cancer. The survival of patients with lung cancer was significantly shorter in subjects with a history of pulmonary tuberculosis (HR=2.36, CI95%: 1.1–4.9), than in subjects without a history of pulmonary tuberculosis with a mean difference of 311 days.Conclusion: The presence of a history of pulmonary tuberculosis may be an important prognostic factor in the survival of lung cancer.

Circulating tumour cells, their role in metastasis and their clinical utility in lung cancer - Corrected Proof

2012-01-03

Abstract: Circulating tumour cells (CTCs) have attracted much recent interest in cancer research as a potential biomarker and as a means of studying the process of metastasis. It has long been understood that metastasis is a hallmark of malignancy, and conceptual theories on the basis of metastasis from the nineteenth century foretold the existence of a tumour “seed” which is capable of establishing discrete tumours in the “soil” of distant organs. This prescient “seed and soil” hypothesis accurately predicted the existence of CTCs; microscopic tumour fragments in the blood, at least some of which are capable of forming metastases. However, it is only in recent years that reliable, reproducible methods of CTC detection and analysis have been developed. To date, the majority of studies have employed the CellSearch™ system (Veridex LLC), which is an immunomagnetic purification method. Other promising techniques include microfluidic filters, isolation of tumour cells by size using microporous polycarbonate filters and flow cytometry-based approaches. While many challenges still exist, the detection of CTCs in blood is becoming increasingly feasible, giving rise to some tantalizing questions about the use of CTCs as a potential biomarker. CTC enumeration has been used to guide prognosis in patients with metastatic disease, and to act as a surrogate marker for disease response during therapy. Other possible uses for CTC detection include prognostication in early stage patients, identifying patients requiring adjuvant therapy, or in surveillance, for the detection of relapsing disease. Another exciting possible use for CTC detection assays is the molecular and genetic characterization of CTCs to act as a “liquid biopsy” representative of the primary tumour. Indeed it has already been demonstrated that it is possible to detect HER2, KRAS and EGFR mutation status in breast, colon and lung cancer CTCs respectively. In the course of this review, we shall discuss the biology of CTCs and their role in metastagenesis, the most commonly used techniques for their detection and the evidence to date of their clinical utility, with particular reference to lung cancer.

Clonality status of multifocal lung adenocarcinomas based on the mutation patterns of EGFR and K-ras - Corrected Proof

Kazuya Takamochi, Shiaki Oh, Joe Matsuoka, Kenji Suzuki — 2011-12-30

Abstract: Purpose: The purpose of this study is to clarify the clonality status of multifocal lung adenocarcinomas based on the mutation patterns of epidermal growth factor receptor (EGFR) and K-ras.Methods: We analyzed 82 multifocal lung adenocarcinomas from 36 patients who underwent surgical resection. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissue and analyzed for EGFR and K-ras mutations. We determined the clonality status of multifocal lung adenocarcinomas based on the mutation patterns of EGFR and K-ras. The actuarial survival time was estimated and the prognostic factors were evaluated for 31 patients with synchronous multifocal lung adenocarcinomas.Results: EGFR and K-ras mutations were detected in 36 (44%) and 19 (23%) of the 82 tumors, respectively. EGFR mutations had occurred randomly in 20 (91%) of the 22 patients with at least one EGFR mutated tumor. K-ras mutations had occurred randomly in 14 (93%) of the 15 patients with at least one K-ras mutated tumor. Combining the results for the EGFR and K-ras mutation patterns, the clonality status of multifocal lung adenocarcinomas could be determined in 30 (83%) of the 36 patients. No statistically significant difference in the actuarial survival of the patient subgroups stratified according to the clonality status, which was based on the presence of EGFR and K-ras mutations, was observed.Conclusions: Both EGFR and K-ras mutations frequently occur randomly in multifocal lung adenocarcinomas. Combined mutation pattern analyses of EGFR and K-ras may be useful for making decisions regarding treatment strategies for patients with multifocal lung adenocarcinomas.

The management impact of clinically significant incidental lesions detected on staging FDG PET-CT in patients with non-small cell lung cancer (NSCLC): An analysis of 649 cases - Corrected Proof

Michael Lin, Chaitanya Ambati — 2011-12-29

Abstract: To evaluate FDG PET-CT in the detection of unexpected pre-malignancy or second malignancy at the initial staging of patients with histologically proven non-small cell lung cancer (NSCLC) and its impact on management.Methods: Staging FDG PET-CT scans acquired between February 2006 and July 2010 in 649 patients (M=389; F=260) with NSCLC were reviewed for the presence of unexpected pre-malignancy or second primary. A “True-Positive” lesion represented a second primary or pre-malignant lesion. A “False-Positive” lesion was due to benign causes or an atypical site of metastasis from NSCLC.Results: 77 (12%) patients were identified on PET-CT as having a potential pre-malignancy or second primary. 39 out of 77 (51%) patients had diagnostic verification where histopathology served as reference standard in 33 patients (85%) and the rest had endoscopy and progress PET-CT scans. 20 patients (3.1%) had a second primary (n=11) or pre-malignant lesions comprising dysplastic colorectal polyps (n=9), and additional therapy and/or management change for the index tumour was instigated in 17 patients (85%). In patients with a second primary, 3 (27%) patients had a high impact change in management from an initial curative intent to palliative.Conclusion: Staging FDG PET-CT is highly valuable in identifying second primary cancers or pre-malignant lesions in patients with NSCLC. When a second primary is detected on PET-CT, there is a high impact change in management in 27% of patients.

Vatalanib in malignant mesothelioma: A phase II trial by the Cancer and Leukemia Group B (CALGB 30107) - Corrected Proof

2011-12-26

Abstract: Introduction: The Cancer and Leukemia Group B (CALGB) conducted a multi-center phase II trial to evaluate the efficacy and safety of vatalanib in previously untreated patients with malignant mesothelioma and to evaluate potential biomarkers of disease response (CALGB 30107).Methods: Treatment consisted of vatalanib 1250mg given orally once daily. CT scans were obtained at baseline and every 6 weeks thereafter. Baseline serum levels of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), thrombospondin-1 (TSP-1), and mesothelin were obtained. The primary endpoint was 3-month progression-free survival (PFS).Results: Forty-seven patients enrolled at 19 centers. The median age was 75 years, and the majority of patients (79%) had an ECOG performance status of 1. Tumors were classified as epithelial (77%), sarcomatoid (10%), or mixed (9%) histology. Toxicity was mild; the most common grade 3/4 adverse events were neutropenia (2%), nausea (15%), elevated alanine aminotransferase (11%), hypertension (2%), and gastrointestinal bleeding (2%). Partial responses were observed in 6% of patients and stable disease in 72% of patients. The 3-month PFS rate was 55% (95% CI: 40%, 68%). The median PFS was 4.1 months. Median overall survival was 10.0 months. There was no correlation between serum levels of VEGF, PDGF, TSP-1, or mesothelin and treatment response, PFS, or survival.Conclusions: Vatalanib as a single agent with this dose and schedule does not warrant further study in this disease.

Characteristics of lung cancer in women: Importance of hormonal and growth factors - Corrected Proof

2011-12-26

Abstract: Based on epidemiological, clinical, and preclinical data, lung carcinogenesis can be distinctive in women, suggesting that women should be treated differently depending on the expression of various specific biomarkers. We aimed to describe the hormonal and genetic profile of lung cancer in both men and women to identify gender specificities. Primary lung-tumor tissues from surgically treated patients, (50 men, 50 women) were analyzed and compared for expression of estrogen receptors (ER) α and β, progesterone receptors (PR), epidermal growth-factor receptor (EGFR), and HER2 (for EGFR and K-Ras mutations). These data were combined with clinical and outcome data. Fewer women with lung cancer were smokers (p=0.001) and they smoked fewer cigarettes (p=0.001). We observed a higher rate of EGFR mutations (p=0.02) and ERα expression (p=0.006) in women. ERβ and EGFR were also expressed more frequently in women (p=0.29 and p=0.16). HER2 was overexpressed regardless of gender in three men and two women. K-Ras was mutated in 16% of both men and women. Interestingly, there was a positive link between EGFR expression and expression of ERα (p=0.028) and ERβ (p=0.047) in both men and women. Expression of ERα was associated with improved disease-free survival (p=0.007). Our findings provide further evidence on the specificities of lung cancer in women. The differential expression of specific biomarkers, which could be targeted by therapy, favors the development of gender-based treatment guided by biomarker expression.

Trabectedin in patients with advanced non-small-cell lung cancer (NSCLC) with XPG and/or ERCC1 overexpression and BRCA1 underexpression and pretreated with platinum - Corrected Proof

2011-12-26

Abstract: Background: Previous studies in sarcoma found that a composite gene signature, including high expression of nucleotide excision repair (NER) genes (XPG and/or ERCC1) and low expression of homologous recombination repair (HR) genes (BRCA1), identifies a highly sensitive population of patients with significantly improved outcome to trabectedin. This exploratory phase II trial evaluated a customized trabectedin treatment according to this gene signature in patients with non-small cell lung cancer (NSCLC) after the failure of standard platinum-based treatment.Methods: Patients were selected according to their mRNA expression (elevated XPG and/or ERCC1, with low BRCA1) using the following values as cutoff: XPG=0.99, ERCC1=3.47 and BRCA1=12.00. Trabectedin was administered as a 1.3mg/m2 3-hour intravenous infusion every 3 weeks (q3wk). The primary efficacy endpoint was the progression-free survival rate at 3 months. Objective response according to the Response Evaluation Criteria in Solid Tumors (RECIST) was a secondary efficacy endpoint.Results: Two of 18 evaluable patients (11.1%; 95% CI, 1.38–34.7%) achieved progression-free survival rate at 3 months. The primary efficacy objective (at least 3 of 18 patients being progression-free at 3 months) was not met, and therefore the trial was early finalized. No objective responses per RECIST were achieved. Four patients had stable disease. Median PFS was 1.3 months, and median overall survival was 5.9 months. Trabectedin was usually well tolerated, with a safety profile similar to that described in patients with other tumor types.Conclusions: Customized treatment with trabectedin 1.3mg/m2 3-h q3wk according to composite gene signature (XPG and/or ERCC1 overexpression, and BRCA1 underexpression) was well tolerated, but had modest activity in NSCLC patients pretreated with platinum. Therefore, further clinical trials with trabectedin as single agent in this indication are not warranted.

Small-cell carcinoma of the lung detected by CT screening: Stage distribution and curability - Corrected Proof

2011-12-22

Abstract: Background: Prognosis is incompletely known for small-cell lung carcinoma (SCLC) detected by CT screening of at-risk subjects.Methods: A multinational study of baseline and annual repeat CT screening for lung cancer of 48,037 at-risk subjects yielded 48 persons (median age 68 years) with SCLC. Stage (tumor, node, metastasis system) distribution and death rates were compared with those of 7960 usual-care SCLC subjects (chi-square or Fisher exact testing, as appropriate), as reported by the International Association for the Study of Lung Cancer. Cure was estimated by Kaplan–Meier analysis.Results: Forty-four (92%) of the patients were asymptomatic at screening CT detection of their SCLC; four (8%) presented with cancer-related symptoms before the next scheduled repeat screening. SCLC was diagnosed in clinical stages IA and IV in 16 (33%) and 7 (15%), respectively, of 48 patients, compared to 211 (3%) and 4530 (57%), respectively, of the 7960 patients in the usual-care study (P<0.0001). Tumor diameter was ≤3.0cm for each of the 16 subjects in clinical stage I. The percentage of clinical stage I SCLC-related deaths within 5 years was lower in the screening study than in the usual-care study (44% vs. 71%, P=0.03), as was also the percentage of advanced stage (IIIB plus IV) SCLC-related deaths (62% vs. 94%, P<0.0001).Conclusions: Compared to usual-care detection of SCLC, CT screening identified a shift toward early stage and away from late stage disease, and was associated with a decrease in deaths from the disease.

Prospective phase II trial of a combination of gemcitabine and UFT as first-line treatment in elderly patients with advanced non-small cell lung cancer - Corrected Proof

2011-12-22

Abstract: Background: The standard regimen in elderly patients with non-small-cell lung cancer (NSCLC) is still uncertain. Gemcitabine is one of the most widely used drugs for the treatment of NSCLC, and several phase II trials specifically designed for elderly patients with advanced NSCLC have confirmed the role of gemcitabine in this setting. In addition, oral uracil-tegafur (UFT) was associated with a survival advantage in the adjuvant setting. Therefore, we performed a phase II study using the combination of gemcitabine and UFT as first-line therapy in elderly patients with advanced NSCLC.Methods: Chemotherapy-naïve, elderly (≥70 years) patients who had histologically or cytologically confirmed with stage IIIB or IV NSCLC with a performance status of 1–2 were enrolled. Patients received gemcitabine (1250mg/m2 on days 1 and 8, respectively) and UFT (400mg/day on days 1–14) every 3 weeks for up to four cycles. Patients who had not progressed after four cycles continued UFT monotherapy until progression. Primary endpoint was overall response rate and secondary endpoints were overall survival, time to progression and safety profiles.Results: Between March 2008 and November 2010, 48 patients were enrolled. The median age was 74.5 years (range: 70–84 years), and there were 29 males. The performance status was 1 in 41 and 2 in 7 patients. Thirty-one (64.6%) patients were stage IV and seventeen (35.4%) patients were stage IIIB. Thirty patients (62.5%) completed four cycles of chemotherapy. Response was evaluated in 44 patients. Partial response was achieved in twelve (25.0%) patients and stable disease in 23 (47.9%) patients. Disease control rate was 72.9%. The median survival time was 6.1 months (95% confidence interval [CI]; 5.1–7.0 months), the 1-year survival rate was 29.1% and the median time to progression was 4.6 months (95% CI; 3.7–5.5 months). Toxicities were mild and mostly hematological adverse events. Grade 3/4 neutropenia occurred in 8.3% of patients and one patients experienced febrile neutropenia. Grade 3/4 anemia and thrombocytopenia occurred in 2.1% and 2.1% of patients, respectively. Non-hematological toxicities were tolerable.Conclusions: The combination of gemcitabine and UFT was effective in disease control and well tolerated first-line regimen in elderly patients with advanced NSCLC.

Phase 2 study of frontline bortezomib in patients with advanced non-small cell lung cancer - Corrected Proof

2011-12-20

Abstract: Background: Preliminary results indicated that bortezomib (B) (Velcade*) as a single agent may have activity in pretreated NSCLC patients with similar or lesser toxicity compared to chemotherapy. This phase II study was initiated to determine the efficacy of single-agent B in chemonaïve patients with advanced NSCLC. An early tumor assessment (after 6 weeks of therapy) was performed to allow for rapid and appropriate management of non-responding patients.Methods: Patients received B (1.5mg/m2) twice a week for 2 consecutive weeks (days 1, 4, 8, and 11) followed by a 10-day rest period. The primary endpoint was non-progression rate (NPR) after 6 weeks of treatment. Secondary endpoints included response rate, progression-free survival (PFS), overall survival (OS), and safety. Exploratory analyses included FDG-PET response at 6 weeks and circulating tumors cell (CTC) assessment at day 1 of each cycle in a subset of patients.Results: 18 patients were enrolled from 06/06 to 02/07 from 3 French institutions. Demographics: male/female 15/3; median age 66 (54–79); PS 0/1/2, 3/12/3; pathology: adenocarcinoma 11, squamous cell carcinoma 5, large-cell carcinoma 2; smoking status never/former/current 1/10/7; stage IIIB/IV 2/16. Seventeen patients received B and 16 were assessable (1 early withdrawal and 1 progression at D26). The most frequent toxicity was fatigue (17 patients). Twelve patients (71%) had at least one grade 3 toxicity: 4 haematological, 1 infection, 5 gastro-intestinal toxicity, 9 fatigue, 1 neuropathy. The non-progression rate was 59% [33–82%] at 6 weeks (10/17 patients). No objective response was seen. With a median follow-up of 12.3 months, the median PFS and OS were 2.4 and 9.8 months respectively. Eleven deaths occurred. No PET response was observed, and CTC were detected only in 1 out of 8 patients evaluated.Conclusions: Although according to the protocol rules the trial should not be stopped, the lack of any objective response either by CT-scan or PET-CT, along with substantial toxicity, did not argue in favor of the current strategy of B as a single agent in the front-line setting of NSCLC.

CHD5, a tumor suppressor that is epigenetically silenced in lung cancer - Corrected Proof

Rui Zhao, Qitao Yan, Jingye Lv, Haili Huang, Wenling Zheng, Bao Zhang, Wenli Ma — 2011-12-20

Abstract: Chromodomain helicase DNA binding protein 5 (CHD5) is a potent tumor suppressor that serves as a master regulator of a tumor-suppressive network. Examination of the role played by CHD5 in a wide range of human cancers is warranted. In this study, we focused on the epigenetic modification and tumor-suppressive role of CHD5 in lung cancer. We measured CHD5 mRNA and protein expression in lung cancer cells, lung cancer tissues, and their corresponding noncancerous lung tissues using real-time PCR and Western blot analysis. We then determined the methylation status of the CHD5 promoter in these samples using methylation-specific sequencing and analyzed CHD5 re-expression in lung cancer cells treated with or without 5-aza-2-deoxycytidine, an inhibitor of DNA methylation. Next, the lung cancer cell clones stably expressing EGFP-CHD5 protein or EGFP protein, respectively, were obtained and the effects of restored CHD5 expression on cell proliferation, colony formation, and tumorigenicity were assessed. CHD5 expression ranged from low to absent in the lung cancer cell lines and tissues examined; the CHD5 promoter was hyperethylated in these samples. Treatment with 5-aza-dC resulted in a localized decrease in methylation density and an increase in CHD5 expression. Clonogenicity and tumor growth were abrogated in A549 and H1299 cells upon restoration of CHD5 expression. A significant reduction in clonogenicity was observed; an average of 47.83±4.6% reduction for A549-EGFP-CHD5 was observed compared to A549-EGFP, and an average of 56.39±5.3% reduction for H1299-EGFP-CHD5 was observed compared to H1299-EGFP. A549-EGFP exhibited an average tumor size of 452.3±36.5mm3, whereas A549-EGFP-CHD5 exhibited an average tumor size of only 57.7±18.5mm3. Thus, our findings indicate that CHD5 is a potential tumor suppressor gene that is inactivated via an epigenetic mechanism in lung cancer.

Clinical outcomes of leptomeningeal metastasis in patients with non-small cell lung cancer in the modern chemotherapy era - Corrected Proof

2011-12-20

Abstract: Background: We analyzed the patterns of treatment and clinical outcomes of leptomeningeal metastasis (LM) in patients with non-small cell lung cancer (NSCLC) in the modern chemotherapy era.Methods: We retrospectively reviewed the data of NSCLC patients who were diagnosed with LM between 2003 and 2009 at Seoul National University Bundang Hospital.Results: Of the 50 patients with cytologically proven LM, 25 were male (50%), 14 (28%) had an ECOG performance status (PS) ≥3, and the median age was 62.5years (range, 34–81years). The patients were diagnosed with LM after a median of 10.4 months (range, 0–86.8 months) from the initial diagnosis of metastatic NSCLC. LM was present in 11 patients at the time of initial diagnosis. The median overall survival (OS) after the diagnosis of LM was 4.3 months (95% CI, 1.5–6.7 months). Forty-eight patients (96%) received intrathecal chemotherapy and the cytological response rate was 52%. The median survival was 5.5 months in cytological responders and 1.4 months in non-responders (p=0.075). The median OS in patients with an ECOG PS of 1–2 was longer than patients with an ECOG PS of 3–4 (5.5 vs. 0.7 months, p<0.001). Twenty-two patients (44%) received systemic cytotoxic chemotherapy or an EGFR tyrosine kinase inhibitor (TKI) after being diagnosed with LM. These patients had prolonged survival (11.5 vs. 1.4 months, p<0.001), and in 14 patients (28%) who received an EGFR TKI, the median OS was 19.2 months. In subgroup of patients with an ECOG PS of 1–2, those who received further systemic chemotherapy had improved survival compared to patients who did not receive further chemotherapy (11.5 vs. 2.1 months, p<0.001).Conclusion: NSCLC patients with LM exhibited diverse clinical outcomes rather than a uniformly poor prognosis. Systemic chemotherapy, especially EGFR TKIs in addition to intrathecal chemotherapy, might confer a survival benefit.

Biomarkers for small cell lung cancer: Neuroendocrine, epithelial and circulating tumour cells - Corrected Proof

2011-12-19

Abstract: Small cell lung cancer (SCLC) is characterised by an aggressive clinical course with invariable resistance to chemotherapy despite initially high response rates. There has been little improvement in outcome over the past few decades, with no breakthrough yet in targeted therapies. Recent preclinical data and studies of circulating tumour cells (CTCs) highlight distinct cellular heterogeneity within SCLC. Better understanding of how these phenotypes contribute to metastasis and tumour progression might pave the way for development of more successful targeted therapies. Here we review these studies, their implications for future research and for the incorporation of biomarkers reflecting neuroendocrine, epithelial and mesenchymal phenotypes in clinical studies.

Estimation of renal function in lung cancer patients - Corrected Proof

Katja Trobec, Lea Knez, Pika Meško Brguljan, Tanja Cufer, Mitja Lainščak — 2011-12-19

Abstract: Introduction: In lung cancer patients treated with chemotherapy, renal function is an important parameter to be monitored. Since measurement of renal function with either isotope or creatinine clearance is time consuming and expensive, we evaluated which of the following equations: Cockcroft–Gault (CG), Wright, modification of diet in renal disease equation (MDRD), MDRD adjusted for body surface area (BSA) and chronic kidney disease epidemiology collaboration (CKD-EPI) best resembles endogenous creatinine clearance (ECC) and could therefore replace its measurement in clinical practice.Methods: 218 lung cancer patients, who had their 24-h creatinine secretion in urine measured prior to the start of any chemotherapy, were included. Estimation of renal function was calculated and compared to ECC.Results: There were no major differences in the performance of the tested equations. Mean percentage error of more than 20% and general underestimation was common to all equations. Wright equation performed best although it describes only 43% of ECC variability. Mean measured ECC was 94mL/min (95% confidence interval [CI]: 90–98mL/min) and 90mL/min for Wright equation (95% CI: 87–93mL/min) (). MDRD and CKD-EPI equation performed poorest since they do not include any body size descriptor. Large deviations of differences were observed, with a median standard deviation of more than 20% and deviations from ECC exceeding 100%. Wright equation performed best, whereas, despite their leading role in the detection of renal diseases, the MDRD and CKD-EPI equation performed poorest since they do not include any body size descriptor. In the range of ECC<50mL/(min×1.73m2), the CG equation most often detected a contraindication for cisplatin use. Differences between ECC and calculated values correlated with patients’ weight, BSA and body mass index when these were not included in the equation itself.Conclusions: In evaluating the renal function of lung cancer patients, equations adjusted for body size descriptors should be preferred. Estimated renal function should be interpreted against the characteristics of patient's body size and special attention is needed when these are reaching the extremes.

Soluble epidermal growth factor receptor isoforms in non-small cell lung cancer tissue and in blood - Corrected Proof

2011-12-19

Abstract: Epidermal growth factor receptor (EGFR) is implicated in tumor development and is highly expressed in many human tumors. EGFR overexpression has been observed in both premalignant lesions and in malignant lung tumors, as well as in 40–80% of patients with non-small cell lung cancer (NSCLC). EGFR is a 170-kDa transmembrane glycoprotein with an extracellular ligand-binding domain and a cytoplasmic domain with intrinsic tyrosine kinase activity. Soluble forms of EGFR (sEGFR) containing the extracellular domain have been described both in conditioned media from EGFR overexpressing cells as well as in peripheral blood. However, very little is known regarding the molecular function and the biochemical properties of these circulating EGFR isoforms.This study investigates the expression of sEGFR in lung cancer cultured cells and NSCLC patients with the aim of identifying clinically relevant isoforms specifically produced by tumor cells.Proteomic approaches including OFFGEL electrophoresis and Western blotting analysis were used to assess the sEGFR expression pattern in primary lung tumor samples, normal counterparts and matched plasma.We discover that the isoelectric points of sEGFR isoforms in NSCLC biopsy tissue differ from those of the isoforms present in healthy tissue and detected in the plasma of all subjects.These results demonstrate, for the first time, the existence of sEGFR isoforms specifically produced by NSCLC tumor cells which could represent a new potential biomarker for diagnosis and therapy of lung tumors. However, our observations indicate that more highly sensitive and specific quantitative assays are needed in order to reliably detect the tumor-associated sEGFR isoforms in plasma samples.

The role of molecular analyses in the era of personalized therapy for advanced NSCLC - Corrected Proof

2011-12-16

Abstract: Platinum-based doublet chemotherapy is the traditional treatment of choice for advanced non-small cell lung cancer (NSCLC); however, the efficacy of these regimens has reached a plateau. Increasing evidence demonstrates that patients with sensitizing mutations in the epidermal growth factor receptor (EGFR) experience improved progression-free survival and response rates with first-line gefitinib or erlotinib therapy relative to traditional platinum-based chemotherapy, while patients with EGFR-mutation negative tumors gain greater benefit from platinum-based chemotherapy. These results highlight the importance of molecular testing prior to the initiation of first-line therapy for advanced NSCLC. Routine molecular testing of tumor samples represents an important paradigm shift in NSCLC therapy and would allow for individualized therapy in specific subsets of patients. As these and other advances in personalized treatment are integrated into everyday clinical practice, pulmonologists will play a vital role in ensuring that tumor samples of adequate quality and quantity are collected in order to perform appropriate molecular analyses to guide treatment decisions. This article provides an overview of clinical trial data supporting molecular analysis of NSCLC, describes specimen acquisition and testing methods currently in use, and discusses future directions of personalized therapy for patients with NSCLC.

Parity and risk of lung cancer in women: Systematic review and meta-analysis of epidemiological studies - Corrected Proof

Issa J. Dahabreh, Thomas A. Trikalinos, Jessica K. Paulus — 2011-12-12

Abstract: Multiple studies have assessed parity as a risk factor for lung cancer but results have been inconclusive. We searched MEDLINE (through August 2010) and the Institute of Scientific Information Web of Knowledge database (through April 2011) to identify studies investigating the association of parity with lung cancer and allowing the calculation of dose–response trends using a linear model. Between-study heterogeneity was assessed using Cochran's Q statistic and the I2 index. Summary per-child relative risks (RRs) with their 95% confidence interval (CI) were estimated using random effects meta-analysis. Sixteen eligible studies (8077 lung cancer patients; 350,295 unaffected individuals) provided data for meta-analysis. There was significant between-study heterogeneity (p<0.001; I2=73%). The summary per livebirth RR was 0.98 (95% CI, 0.95–1.02), indicating no effect of parity on lung cancer risk. Results were consistent in case–control (n=11), RR=0.99 (95% CI, 0.94–1.04), and cohort studies (n=5), RR=0.97 (95% CI, 0.92–1.03). Studies not including small-cell lung cancer patients found a borderline protective effect of parity, RR=0.94 (95% CI, 0.88–1.00). In contrast, no effect was observed in studies including small-cell lung cancer patients, RR=1.00 (95% CI, 0.98–1.03); p for difference=0.05. Overall, there was little evidence of a dose–response relationship between increasing number of livebirths and lung cancer; however, studies have produced heterogeneous results. Future studies should include analyses in well-defined histological disease subgroups.

Histologic subtypes, immunohistochemistry, FISH or molecular screening for the accurate diagnosis of ALK-rearrangement in lung cancer: A comprehensive study of Caucasian non-smokers - Corrected Proof

2011-12-08

Abstract: EML4-ALK adenocarcinomas constitute a new molecular subgroup of lung tumours that respond very well to crizotinib, an ALK inhibitor. However, the diagnosis of ALK rearrangement in lung cancer is challenging. The aim of this study was to compare the diagnostic accuracy of five different methods in a series of 20 EGFRwt/wt lung adenocarcinomas from non- or light- smokers. Multiplex RT-PCR was considered as gold standard and identified four ALK-rearranged tumours among the 20 tested tumours. qRT-PCR got an interpretability rate of 100% and accurately typed all 20 tumours. qRT-PCR from corresponding formalin-fixed paraffin-embedded (FFPE) specimens got an interpretability rate of 65%. Out of the four previously identified ALK-rearranged cases, three were interpretable and two were retrieved using FFPE qRT-PCR. ALK break-apart FISH got an interpretability rate of 60% and accurately typed all of the twelve remaining cases. Anti-ALK immunohistochemistry (IHC) accurately typed all twenty tumours using a cut-off value of strong staining of 100% tumour cells. The 16 non ALK-rearranged tumours got no/light staining in 13 cases, and a moderate staining of 80–100% tumour cells in 3 cases. We then analysed four solid signet-ring lung adenocarcinomas. FFPE qRT-PCR, FISH and immunohistochemistry were concordant in three cases, with positive and negative results in respectively one and two cases. The fourth case, which was positive by FISH and immunohistochemistry but negative by RT-PCR, was shown to have a non-EML4-ALK ALK-rearrangement. As various factors such as RNA quality, fixation quality and type of ALK rearrangement may impede ALK screening, we propose a combined FISH/molecular biology diagnostic algorithm in which anti-ALK immunohistochemistry is used as a pre-screening step.

Differences in metabolism between adeno- and squamous cell non-small cell lung carcinomas: Spatial distribution and prognostic value of GLUT1 and MCT4 - Corrected Proof

2011-12-08

Abstract: Background: Hypoxia leads to changes in tumor cell metabolism such as increased glycolysis. In this study, we examined the spatial distribution of the glycolysis and hypoxia related markers glucose transporter 1 (GLUT1) and monocarboxylate transporter 4 (MCT4) expression in relation to the vasculature in stage I, II and resectable stage IIIA NSCLC. Furthermore, associations of these markers with survival were investigated.Methods: GLUT1 and MCT4 expression were determined in 90 NSCLC fresh frozen biopsies using immunohistochemical techniques and a computerized image analysis system. Markers were analyzed for adenocarcinomas (n=41) and squamous cell carcinomas (n=34) separately. Eighty-four patients were retrospectively evaluated for relapse and survival.Results: Squamous cell carcinomas demonstrated higher GLUT1 expression, relative to adenocarcinomas. Also, in squamous cell carcinomas, GLUT1 and MCT4 expression increased with increasing distance from the vasculature, whereas in adenocarcinomas upregulation of MCT4 was already found at closer distance from vessels. In adenocarcinomas, high GLUT1 expression correlated with a poor differentiation grade and positive lymph nodes at diagnosis. High GLUT1 plus high MCT4 expression was associated with a poor disease-specific survival in only adenocarcinomas (p=0.032).Conclusion: Analysis of GLUT1 and MCT4 expression on the histological level suggested a different metabolism for adenocarcinomas and squamous cell carcinomas. Likely, adenocarcinomas rely mainly on aerobic glycolysis for ATP production, whereas the behavior of squamous cell carcinomas is more physiologically, i.e. mitochondrial oxidation with anaerobic glycolysis under hypoxic conditions. High GLUT1 plus high MCT4 expression indicated an aggressive tumor behavior in adenocarcinomas. This subgroup of tumors may benefit from new treatment approaches, such as MCT4 inhibitors. Since this study has an exploratory character, our results warrant further investigation and need independent validation.

Characterization of the immunophenotype of the tumor budding and its prognostic implications in squamous cell carcinoma of the lung - Corrected Proof

2011-12-08

Abstract: Tumor budding is morphologically defined as infiltration by small clusters of cancer cells. While the biological properties of budding cells in adenocarcinoma (decreased expression of adhesion molecules and of differentiation markers) have been elucidated, those of the cells in squamous cell carcinoma (SqCC) of the lung still remain to be clarified. We examined the clinicopathological data of 217 patients with SqCC of the lung. Furthermore we evaluated the immunohistochemical properties of the budding cells. Tumor budding was observed in 83 (38.2%) patients. A statistically significant difference was observed in overall 5-year survival rates between the cases showing tumor budding and the cases not showing budding (45.6% vs. 64.0%, p<0.001). As compared with cancer cells forming solid nests, budding cells (BCs) exhibited reduced expression levels of the cellular adhesion molecules (E-cadherin; p=0.004, β-catenin; p=0.002) and increased expression levels of laminin-5γ2 (p=0.001). On the other hand, no significant differences in the staining scores for differentiation markers (p63 and podoplanin) were found between BCs and cancer cells forming nests. Multivariate analysis revealed that tumor budding was a significant independent prognostic factor in patients with SqCC of the lung (p=0.022). Tumor budding is an independent adverse prognostic factor in patients with SqCC of the lung. Although budding cells in SqCC exhibited reduced expression levels of the cellular adhesion molecules, the expression levels of specific differentiation markers were retained, suggesting that the budding mechanism in SqCC may differ, at least in part, from that in adenocarcinoma.

Carcinoembryonic antigen (CEA) as tumor marker in lung cancer - Corrected Proof

M. Grunnet, J.B. Sorensen — 2011-12-08

Abstract: The use of CEA as a prognostic and predictive marker in patients with lung cancer is widely debated. The aim of this review was to evaluate the results from studies made on this subject.Using the search words “CEA”, “tumor markers in lung cancer”, “prognostic significance”, “diagnostic significance” and “predictive significance”, a search was carried out on PubMed. Exclusion criteria was articles never published in English, articles before 1981 and articles evaluating tumor markers in lung cancer not involving CEA.Initially 217 articles were found, and 34 were left after selecting those relevant for the present study. Four of these included both Non-Small Cell Lung Cancer (NSCLC) and Small Cell Lung Cancer (SCLC) patients, and 31 dealt solely with NSCLC patients.Regarding SCLC no studies showed that serum level of CEA was a prognostic marker for overall survival (OS).The use of CEA serum level as a prognostic marker in NSCLC was investigated in 23 studies and the use of CEA plasma level in two. In 18 (17 serum, 1 plasma) of these studies CEA was found to be a useful prognostic marker for either OS, recurrence after surgery or/and progression free survival (PFS) in NSCLC patients. Interestingly, an overweight of low stage (stage I-II) disease and adenocarcinoma (AC) patients were observed in this group. The remaining 7 studies (6 serum, 1 plasma) contained an overweight of patients with squamous carcinoma (SQ). One study found evidence for that a tumor marker index (TMI), based on preoperative CEA and CYFRA21-1 serum levels, is useful as a prognostic marker for OS in NSCLC.Six studies evaluated the use of CEA as a predictive marker for risk of recurrence and risk of death in NSCLC patients. Four of these studies found, that CEA was useful as a predictive marker for risk of recurrence and risk of death measured over time. No studies found CEA levels useful as a diagnostic marker for lung cancer.With regard to NSCLC the level of CEA measured in tumor tissue in NSCLC patients, were not of prognostic, diagnostic or predictive significance for OS or recurrence after treatment.In one study CEA level was measured in Pleural Lavage Fluid (PLF) it was here found to be useful as prognostic markers for overall survival (OS) after surgery.In conclusion serum level of CEA carries prognostic and predictive information of risk of recurrence and of death in NSCLC independent of treatment or study design. The observation that TMI index could be a potential prognostic marker for OS in NSCLC is interesting. Future studies may benefit from evaluating more than one marker at a time, which may possibly create a more precise index for prognosis and recurrence in lung cancer, than is possible by the use of single biomarkers.

A cross-market cost comparison of erlotinib versus pemetrexed for first-line maintenance treatment of patients with locally advanced or metastatic non-small-cell lung cancer - Corrected Proof

2011-12-07

Abstract: Erlotinib and pemetrexed were approved by the European Medicines Agency for first-line maintenance treatment of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) to prolong overall survival after first-line therapy. An adjusted, matched, indirect comparison of erlotinib and pemetrexed suggested that survival benefits were not statistically significantly different between treatments. We conducted a cost-comparison analysis of erlotinib versus pemetrexed in first-line maintenance treatment of locally advanced or metastatic, non-squamous NSCLC in France, Germany, Italy and Spain, performed from the perspective of national health-care decision-makers or purchasers. The analysis was limited to direct costs and comprised drug-acquisition costs, administration costs and costs of treating adverse events (AEs). A one-way sensitivity analysis on administration, acquisition and AE costs was also performed. Total monthly per-patient treatment costs for erlotinib in France, Germany, Italy and Spain were €2140, €2732, €1518 and €2048, respectively, and for pemetrexed €3453, €5534, €2921 and €3164, respectively. AE cost was greater for pemetrexed in all countries, as was administration cost. As an oral treatment, erlotinib is not associated with any administration costs, except in Germany, where the cost is lower than for pemetrexed. The sensitivity analysis showed acquisition costs to be the main driver of total monthly per-patient costs. Erlotinib appears to be a cost-saving treatment alternative to pemetrexed, producing comparable survival benefits, based on an indirect comparison, at a lower cost.

The challenge of NSCLC diagnosis and predictive analysis on small samples. Practical approach of a working group - Corrected Proof

2011-12-06

Highlights: ► The diagnosis of lung cancer involves the identification and complete classification of malignancy. ► New therapeutic options require specific subtyping of NSCLCs and, increasingly, the identification of therapeutically predictive molecular markers, to determine the safest and most effective choice of drugs. ► Small diagnostic sample size and tumour complexity often prevent specific subtyping on morphological grounds alone (NSCLC-NOS). ► Immunohistochemistry can predict the likely NSCLC subtype (squamous cell vs. adenocarcinoma) in most NSCLC-NOS cases. ► Tissue sampling should be maximized whenever feasible and deemed clinically safe, reducing the need for re-biopsy for additional studies. ► Tissue handling, processing and sectioning should minimize wastage and optimize use of tissue for diagnosis.Abstract: Until recently, the division of pulmonary carcinomas into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) was adequate for therapy selection. Due to the emergence of new treatment options subtyping of NSCLC and predictive testing have become mandatory. A practical approach to the new requirements involving interaction between pulmonologist, oncologist and molecular pathology to optimize patient care is described. The diagnosis of lung cancer involves (i) the identification and complete classification of malignancy, (ii) immunohistochemistry is used to predict the likely NSCLC subtype (squamous cell vs. adenocarcinoma), as in small diagnostic samples specific subtyping is frequently on morphological grounds alone not feasible (NSCLC-NOS), (iii) molecular testing. To allow the extended diagnostic and predictive examination (i) tissue sampling should be maximized whenever feasible and deemed clinically safe, reducing the need for re-biopsy for additional studies and (ii) tissue handling, processing and sectioning should be optimized.Complex diagnostic algorithms are emerging, which will require close dialogue and understanding between pulmonologists and others who are closely involved in tissue acquisition, pathologists and oncologists who will ultimately, with the patient, make treatment decisions. Personalized medicine not only means the choice of treatment tailored to the individual patient, but also reflects the need to consider how investigative and diagnostic strategies must also be planned according to individual tumour characteristics.

FATS expression is associated with cisplatin sensitivity in non small cell lung cancer - Corrected Proof

Yin Tian, Jun Zhang, Shuangshuang Yan, Li Qiu, Zheng Li — 2011-12-05

Abstract: Background: Although the survival benefit of cisplatin-based adjuvant chemotherapy has been proven for patients with non small cell lung cancer (NSCLC), the resistance to cisplatin and its dose-dependent side effects remain a challenge. Improvement in survival and reduction of side effects require a biomarker capable of defining the response to cisplatin treatments in patients with NSCLC. FATS is a newly identified tumor suppressor involved in DNA damage-induced carcinogenesis. In this study, we investigated whether the quantified mRNA expression of FATS can predict cisplatin sensitivity in NSCLC.Methods: The expression level of FATS mRNA in tumor samples from patients receiving an initial diagnosis of NSCLC (n=89) was determined by quantitative real-time reverse transcription PCR. The histological characteristics of patients were retrospectively reviewed. Cisplatin-induced apoptosis in NSCLC cells was evaluated by flow cytometry after Annexin V staining.Results: The mRNA level of FATS was significantly downregulated in NSCLC samples compared with normal tissues from the same patient (P=0.001). Low level of FATS mRNA expression was correlated with poor overall survival in NSCLC (P=0.030). For those NSCLC patients receiving cisplatin-based chemotherapy, the overall survival was significantly longer in FATS-high subgroup than that in FATS-low subgroup (P=0.038). Multivariate analysis revealed the independent value of FATS mRNA in predicting the overall survival for NSCLC patients receiving cisplatin-based chemotherapy. Furthermore, enhanced expression of FATS significantly sensitized NSCLC cells to cisplatin-induced apoptosis.Conclusion: The relatively high expression of FATS mRNA provides a new biomarker for a good outcome in patients receiving cisplatin-based chemotherapy.

Mesothelioma and lung cancer mortality: A historical cohort study among asbestosis workers in Hong Kong - Corrected Proof

2011-12-02

Abstract: Objectives: To investigate the mortality pattern among a cohort of workers with asbestosis in Hong Kong, with special emphases on mesothelioma and lung cancer.Methods: All 124 male workers with confirmed asbestosis in Hong Kong during 1981–2008 were followed up to December 31, 2008 to ascertain the vital status and causes of death. Standardized mortality ratio (SMR) for each underlying cause of death was calculated by using person-year method. Axelson's indirect method was applied to adjust for the potential confounding effect of cigarette smoking.Results: A total of 86 deaths were observed after 432.8 person-years of observations. The SMR for overall mortality (6.06, 95% CI: 4.90–7.51) increased significantly. The elevated risk of deaths from all cancers (7.53, 95% CI: 5.38–10.25) was mainly resulted from a significantly excess risk from lung cancer (SMR=7.91, 95% CI: 4.32–13.29, 14 deaths) and mesothelioma (SMR=6013.63, 95% CI: 3505.95–9621.81, 17 deaths). The SMR for lung cancer retained statistically significant after adjustment of smoking. An increased smoking adjusted SMR was also suggested for all heart diseases (2.32, 95% CI: 0.93–4.79, 7 deaths) and acute myocardial infarction (3.10, 95% CI: 0.84–7.94, 4 deaths), though the statistical significance was borderline. We found a positive association with net years of exposure to asbestos for mesothelioma and lung cancer.Conclusions: Our study provided further evidence on the carcinogenesis of asbestos/asbestosis with the risk of deaths from lung cancer and mesothelioma. This study also provided a preliminary support for a possible link between asbestosis and heart disease, but power is limited.

Conversion from the “oncogene addiction” to “drug addiction” by intensive inhibition of the EGFR and MET in lung cancer with activating EGFR mutation - Corrected Proof

2011-12-02

Abstract: Emergence of acquired resistance is virtually inevitable in patients with a mutation in the epidermal growth factor receptor gene (EGFR) treated with EGFR tyrosine kinase inhibitors (TKIs). Several novel TKIs that may prevent or overcome the resistance mechanisms are now under clinical development. However, it is unknown how tumor cells will respond to intensive treatment using these novel TKIs. We previously established HCC827EPR cells, which are T790M positive, through combined treatment with erlotinib and a MET-TKI from erlotinib-hypersensitive HCC827 cells. In this study, we treated HCC827EPR cells sequentially with an irreversible EGFR-TKI, CL-387,785, to establish resistant cells (HCC827CLR), and we analyzed the mechanisms responsible for resistance. In HCC827CLR cells, PTEN expression was downregulated and Akt phosphorylation persisted in the presence of CL-387,785. Akt inhibition restored CL-387,785 sensitivity. In addition, withdrawal of CL-387,785 reduced cell viability in HCC827CLR cells, indicating that these cells were “addicted” to CL-387,785. HCC827CLR cells overexpressed the EGFR, and inhibition of the EGFR or MEK–ERK was needed to maintain cell proliferation. Increased senescence was observed in HCC827CLR cells in the drug-free condition. Through long-term culture of HCC827CLR cells without CL-387,785, we established HCC827-CL-387,785-independent cells, which exhibited decreased EGFR expression and a mesenchymal phenotype. In conclusion, PTEN downregulation is a newly identified mechanism underlying the acquired resistance to irreversible EGFR-TKIs after acquisition of T790M against erlotinib. This series of experiments highlights the flexibility of cancer cells that have adapted to environmental stresses induced by intensive treatment with TKIs.

Clinicopathologic implication of ALK rearrangement in surgically resected lung cancer: A proposal of diagnostic algorithm for ALK-rearranged adenocarcinoma - Corrected Proof

2011-12-02

Abstract: Background: To characterize the clinicopathologic features of ALK-rearranged lung cancer, and suggest a molecular test protocol for lung adenocarcinoma in the small biopsy specimen.Methods: In 735 NSCLC surgical specimens, clinicopathologic features, ALK protein over-expression by immunohistochemistry (IHC), and ALK rearrangement by fluorescence in situ hybridization (FISH) as well as EGFR and KRAS mutation studies were analyzed.Results: Of the 735 NSCLC cases, 28 (3.8%) were ALK FISH-positive. ALK rearrangement, EGFR and KRAS mutation were mutually exclusive. ALK rearrangement was significantly higher in adenocarcinomas (6.8%, p<0.001), younger age (p<0.0007), women (7.6%, p<0.001), and never-smokers (8.9%, p<0.001) with no gender difference in the adenocarcinoma or never-smoker subgroup. ALK FISH-positivity was not associated with disease recurrence (HR, 0.79; 95% CI, 0.42–1.49) or overall survival (HR, 0.61; 95% CI, 0.24–1.55). However, ALK-rearranged lung cancer tended to show more frequent lymph node metastasis despite its lower T stage. Similar to EGFR-mutated lung cancer, ALK-rearranged lung cancer was enriched in adenocarcinoma, women, and never-smokers. The results of ALK IHC and FISH obtained from tissue microarray (TMA)/biopsy specimens and whole sections after resection were concordant.Conclusion: ALK rearrangement was not a significant prognostic factor in surgically resectable NSCLC. The clinical profiles of ALK-rearranged lung cancer patients overlapped with those of EGFR-mutated patients. Therefore, we suggest that simultaneous tests for ALK IHC and EGFR mutation (Chung's SNUBH molecular test protocol), which has important implications for the storage and use of small biopsy or cytology samples for genetic analysis.

Hedgehog signaling pathway molecules and ALDH1A1 expression in early-stage non-small cell lung cancer - Corrected Proof

2011-11-24

Abstract: Introduction: The Hedgehog Signaling Pathway (HHSP) has been implicated in the development of multiple cancers. HHSP activation may primarily be hedgehog ligand-dependent in non-small cell lung cancer (NSCLC); while a subset may be ligand-independent. In this study NSCLC primary tumors were used to identify correlations between multiple biomarkers thought to be involved in the HHSP and the clinical outcomes of patients with NSCLC. Identification of such correlations could be used to aid in NSCLC treatment and predicting patient prognosis.Methods: A tissue microarray representing 248 clinically annotated stage I–II NSCLC cases was stained using immunohistochemistry (IHC) and scored for HHSP proteins namely, SHH, PTCH1, SMO, GLI1, and GLI2; as well as, ALDH1A1, a putative cancer stem cell marker. Data was analyzed for correlation between IHC staining, EGFR and KRAS mutations, and clinical characteristics including relapse-free survival (RFS) and overall survival (OS).Results: In adenocarcinoma, there were significant correlations of IHC expression between SHH and downstream HHSP receptor SMO (p=0.017) and transcription factor GLI1 (p=0.001), while SMO correlated with GLI1 (p=0.007). In squamous cell carcinoma, SHH significantly correlated with GLI2 protein expression (p=0.003). After multiple testing correction, there was no significant correlation between any of the six markers and RFS or OS.Conclusions: Key downstream components of the HHSP show correlation with sonic hedgehog ligand (SHH) expression, suggesting that ligand-dependent signaling is more prevalent in primary NSCLC tumors. Surprisingly, in early-stage NSCLC, there were no significant correlations between HHSP proteins or ALDH1A1 and RFS or OS.

Comparison of pemetrexed plus cisplatin with other first-line doublets in advanced non-small cell lung cancer (NSCLC): A combined analysis of three phase 3 trials - Corrected Proof

2011-11-24

Abstract: Introduction: In a first-line study of advanced NSCLC, pemetrexed–cisplatin was more effective among patients with adenocarcinoma and large-cell carcinoma compared with gemcitabine–cisplatin (median survival of 11.8 versus 10.4 months, P=.005), while survival with pemetrexed–cisplatin was shorter than with gemcitabine–cisplatin in patients with squamous cell carcinoma. The comparability of pemetrexed–cisplatin to other commonly used regimens within histology subgroups needs to be explored.Methods: This retrospective analysis combined the patient-level data from three phase 3 randomized controlled trials that compared the efficacy of different third generation platinum- and non-platinum based doublets. Unadjusted median survival times and Cox covariate-adjusted treatment hazard ratio (HR) estimates were calculated. Overall results and subgroups by histological type were reported.Results: This combined analysis consisted of 3467 patients. In the overall analysis, adjusted HRs favored pemetrexed (HR <1.0) to each of the other 5 regimens, though none of these HRs were statistically significant. Among patients with non-squamous histology, pemetrexed–cisplatin produced favorable HRs to each of the other regimens, achieving statistical significance when compared with vinorelbine–cisplatin (HR=0.67; 95% confidence intervals [CI]: 0.50, 0.91) and gemcitabine–cisplatin (HR=0.85; 95% CI: 0.75, 0.97). Among patients with squamous histology, 4 of the 5 comparison regimens produced favorable HRs (HR >1.0) when compared with pemetrexed–cisplatin, with only the comparison with gemcitabine–cisplatin achieving statistical significance (HR=1.23; 95% CI: 1.00, 1.51).Conclusion: In the absence of randomized clinical trial data comparing pemetrexed–cisplatin to commonly used doublets in advanced NSCLC other than gemcitabine–cisplatin, this combined analysis of multiple trials provides estimates for such comparisons.