Lung Cancer

Editorial Board

2012-06-01

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

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.

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

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.

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

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.

A specific diplotype defined by PPP1R13L rs1970764, CD3EAP rs967591 and ERCC1 rs11615 and lung cancer risk in a Chinese population

2012-02-15

Abstract: Haplotypes defined by multiple loci may be more precise and useful than genotypes in providing risk estimates for particular cancers. Diplotype is defined as a specific combination of two haplotypes. A Chinese case–control analysis comprising 370 cases and 388 controls was conducted to evaluate the effects of the high-risk diplotype predefined as PPP1R13L rs1970764AA-CD3EAP rs967591GG-ERCC1 rs11615AA among Caucasians and three SNPs alone or other haplotypes combined for lung cancer risk. Both the variant G-allele of PPP1R13L rs1970764 and the variant A-allele of CD3EAP rs967591 were significantly over-represented among cases (P=0.03 and P=0.002, respectively). The variant GG-homozygotes of PPP1R13L rs1970764 had increased risk [GG versus AA: adjusted OR (95% CI)=1.30 (1.04–1.62), P=0.02]. The carriers of variant A-allele of CD3EAP rs967591 also presented increased risk [AA versus GG: adjusted OR (95% CI)=1.40 (1.12–1.75), P=0.004; AG versus GG: adjusted OR (95% CI)=1.47 (1.05–2.07), P=0.03 and AG+AA versus GG: adjusted OR (95% CI)=1.26 (1.07–1.48), P=0.005]. Interaction between CD3EAP rs967591 and smoking duration was observed (P=0.003). Only haplotype 1 (the common haplotype) defined as PPP1R13L rs1970764G-CD3EAP rs967591A-ERCC1 rs11615G showed marginally increased risk [OR (95% CI)=1.38 (1.09–1.75), P=0.009] after Bonferroni correction. The frequency of the high-risk diplotype predefined among Caucasians was 1% in controls and no significant evidence of the diplotype distribution between cases and controls was detected in present study. In conclusion, we found that variant alleles of PPP1R13L rs1970764 and CD3EAP rs967591 may contribute to risk factors of lung cancer, but the high-risk diplotype predefined among Caucasians was rare and the diplotype is unlikely to confer lung cancer risk in a Chinese population.

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

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.

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

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.

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

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

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.

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

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.

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

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.

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

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.

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

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.

Challenges scoring radiation pneumonitis in patients irradiated for lung cancer

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.

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

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.

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

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).

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

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.

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

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.

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

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.

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

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.

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

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.

Estimation of renal function in lung cancer patients

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

Pemetrexed as a possible cause of severe rhabdomyolysis in the treatment of lung cancer

Ming-Shyan Huang, Jong-Rung Tsai, Mei-Chiou Shen, Shah-Hwa Chou, Chih-Jen Yang — 2012-03-09

Abstract: According to many published clinical trials, both haematological and non-haematological toxicities resulting from pemetrexed were relatively mild and therefore this drug is considered to be well tolerated. We came across a 60 y/o woman patient with stage IV adenocarcinoma, suffered from unexpected life threatening complication, rhabdomyolysis. Severe lower leg weakness and respiratory failure occurred on the day 3 after pemetrexed administration. To the best of our knowledge, this is the first report that addresses severe and life-threatening rhabdomyolysis which occur during chemotherapy for the treatment of lung cancer.We believed pemetrexed is a safe drug but we should pay attention to possible complications related to pemetrexed-based treatment and to also treat the life-threatening disorder of rhabdomyolysis immediately to prevent further damage.

Hypereosinophilia driven by GM-CSF in large-cell carcinoma of the lung

2012-03-15

Abstract: In contrast to leukocytosis, paraneoplastic hypereosinophilia is uncommon in lung cancer. We present a patient with large-cell carcinoma of the lung, in which cancer cells generate large amounts of GM-CSF leading to a leukemoid reaction with prominent hypereosinophilia and potentially involved in autocrine tumor stimulation.

Intravitreal administration of bevacizumab in the treatment of choroidal metastasis in a patient with erlotinib-failed pulmonary adenocarcinoma

Chun-Liang Lai, Kuo-Sheng Fan, Yen-Hsien Lee, Hsing-Chun Chen, Wen-Hsiung Fan — 2012-04-09

Abstract: Choroidal metastasis is uncommon and usually identified in a relatively advanced cancer status. The median survival after diagnosing choroid metastasis in lung cancer patients was only 1.9months. Once failed to systemic treatment, there was no effective local treatment for saving visual acuity. The off-label use of intravitreal bevacizumab was popular in treating VEGF-mediated chorioretinal diseases worldwide. We here demonstrate a dramatic and durable response to intravitreal bevacizumab. Unlike the previous similar reports, our patient had failed both first- and second-line therapies.

3rd line Erlotinib for lung cancer in Asia may be as cost-effective as in the Western world

Ching-Chan Lin, Te-Chun Hsia, Chun-Ru Chien — 2012-04-16

We wish to add some comments regarding the recent article written by Cromwell et al. entitled “Erlotinib or best supportive care for third-line treatment of advanced non-small-cell lung cancer: A real-world cost–effectiveness analysis”. It is already well known that there might be population-based differences in treatment outcome following anticancer drug therapies, such as in the case of epidermal growth factor receptor kinase inhibitors for lung cancer . However, it is not known this is a general rule or not.

Lung Cancer

Editorial Board

Contents

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

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

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

A specific diplotype defined by PPP1R13L rs1970764, CD3EAP rs967591 and ERCC1 rs11615 and lung cancer risk in a Chinese population

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

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

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

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

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

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

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

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

Challenges scoring radiation pneumonitis in patients irradiated for lung cancer

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

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

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

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

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

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

Estimation of renal function in lung cancer patients

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

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

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

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

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

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

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

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

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

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

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

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

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

Pemetrexed as a possible cause of severe rhabdomyolysis in the treatment of lung cancer

Hypereosinophilia driven by GM-CSF in large-cell carcinoma of the lung

Intravitreal administration of bevacizumab in the treatment of choroidal metastasis in a patient with erlotinib-failed pulmonary adenocarcinoma

3rd line Erlotinib for lung cancer in Asia may be as cost-effective as in the Western world