Treatment Of Small Cell Lung Carcinoma Research Articles

Small Cell Lung Carcinoma Cells Depend on KIF11 for Survival.

Few efficacious treatment options are available for patients with small cell lung carcinoma (SCLC), indicating the need to develop novel therapeutic approaches. In this study, we explored kinesin family member 11 (KIF11), a potential therapeutic target in SCLC. An analysis of publicly available data suggested that KIF11 mRNA expression levels are significantly higher in SCLC tissues than in normal lung tissues. When KIF11 was targeted by RNA interference or a small-molecule inhibitor (SB743921) in two SCLC cell lines, Lu-135 and NCI-H69, cell cycle progression was arrested at the G2/M phase with complete growth suppression. Further work suggested that the two cell lines were more significantly affected when both KIF11 and BCL2L1, an anti-apoptotic BCL2 family member, were inhibited. This dual inhibition resulted in markedly decreased cell viability. These findings collectively indicate that SCLC cells are critically dependent on KIF11 activity for survival and/or proliferation, as well as that KIF11 inhibition could be a new strategy for SCLC treatment.

NDRG2 acts as a negative regulator of the progression of small-cell lung cancer through the modulation of the PTEN-AKT-mTOR signalling cascade

N-myc downstream-regulated gene 2 (NDRG2) has been recognised as a negative regulator of the progression of numerous tumours, yet its specific role in small-cell lung carcinoma (SCLC) is not fully understood. The purpose of the current study was to investigate the biological role and mechanism of NDRG2 in SCLC. Initial investigation using the Gene Expression Omnibus (GEO) dataset revealed marked downregulation of NDRG2 transcripts in SCLC. The decreased abundance of NDRG2 in SCLC was verified by examining clinical specimens. Increasing NDRG2 expression in SCLC cell lines caused significant changes in cell proliferation, cell cycle progression, colony formation, and chemosensitivity. NDRG2 overexpression decreased the levels of phosphorylated PTEN, AKT and mTOR. In PTEN-depleted SCLC cells, the upregulation of NDRG2 did not result in any noticeable impact on AKT or mTOR activation. Additionally, the reactivation of AKT reversed the antitumour effects of NDRG2 in SCLC cells. Notably, increasing NDRG2 expression retarded the growth of SCLC cell-derived xenografts in vivo. In conclusion, NDRG2 serves as an inhibitor of SCLC, and its cancer-inhibiting effects are achieved through the suppression of AKT/mTOR via the activation of PTEN. This work suggests that NDRG2 is a potential druggable target for SCLC treatment.

Proteomics analysis of meclofenamic acid-treated small cell lung carcinoma cells revealed changes in cellular energy metabolism for cancer cell survival.

Small cell lung carcinoma (SCLC) is a highly aggressive cancer with low survival rate. Although initial response to chemotherapy in SCLC patients is well-rated, the treatments applied after the disease relapses are not successful. Drug resistance is accepted to be one of the main reasons for this failure. Therefore, there is an urgent need for new treatment strategies for SCLC. Meclofenamic acid, a nonsteroidal anti-inflammatory drug, has been shown to have anticancer effects on various types of cancers via different mechanisms. The aim of this study was to investigate the alterations that meclofenamic acid caused on a SCLC cell line, DMS114 using the tools of proteomics namely two-dimensional gel electrophoresis coupled to MALDI-TOF/TOF and nHPLC coupled to LC-MS/MS. Among the proteins identified by both methods, those showing significantly altered expression levels were evaluated using bioinformatics databases, PANTHER and STRING. The key altered metabolism upon meclofenamic acid treatment appeared to the cellular energy metabolism. Glycolysis was suppressed, whereas mitochondrial activity and oxidative phosphorylation were boosted. The cells underwent metabolic reprogramming to adapt into their new environment for survival. Metabolic reprogramming is known to cause drug resistance in several cancer types including SCLC. The identified differentially regulated proteins in here associated with energy metabolism hold value as the potential targets to overcome drug resistance in SCLC treatment.

Insulinoma-Associated Protein 1 (INSM1): Diagnostic, Prognostic, and Therapeutic Use in Small Cell Lung Cancer

Small cell lung carcinoma (SCLC) is an aggressive and difficult to treat cancer. Although immunohistochemistry is not mandatory for a SCLC diagnosis, it might be required, especially in small samples. Insulinoma-associated protein 1 (INSM1) is expressed in endocrine and nervous tissues during embryogenesis, generally absent in adults and re-expressed in SCLC and other neuroendocrine neoplasms. Its high specificity propelled its use as diagnostic biomarker and an attractive therapeutic target. Herein, we aim to provide a systematic and critical review on the use of INSM1 for diagnosis, prognostication and the treatment of SCLC. An extensive bibliographic search was conducted in PubMed® focusing on articles published since 2015. According to the literature, INSM1 is a highly sensitive (75–100%) and specific (82–100%) neuroendocrine immunohistochemical marker for SCLC diagnosis. It can be used in histological and cytological samples. Although advantageous, its standalone use is currently not recommended. Studies correlating INSM1 expression and prognosis have disclosed contrasting results, although the expression seemed to entail a worse survival. Targeting INSM1 effectively suppressed SCLC growth either as a suicide gene therapy regulator or as an indirect target of molecular-targeted therapy. INSM1 represents a valuable biomarker for a SCLC diagnosis that additionally offers vast opportunities for the development of new prognostic and therapeutic strategies.

Antagonist G-targeted liposomes for improved delivery of anticancer drugs in small cell lung carcinoma

Ligand-mediated targeted liposomes have the potential to increase therapeutic efficacy of anticancer drugs. This work aimed to evaluate the ability of antagonist G, a peptide targeting agent capable of blocking the action of multiple neuropeptides, to selectivity improve targeting and internalization of liposomal formulations (long circulating liposomes, LCL, and stabilized antisense lipid particles containing ionizable amino lipid, SALP) to H69 and H82 small cell lung carcinoma (SCLC) cell lines. Antagonist G-targeted LCL and SALP were prepared by two different methods (either by direct covalent linkage at activated PEG grafted onto the liposomal surface or by post-insertion of DSPE-PEG-antagonist-G-conjugates into pre-formed liposomes). Association of the liposomal formulations with target SCLC cells was studied by fluorescence microscopy using fluorescence-labelled liposomes and confirmed quantitatively with [3H]-CHE-labelled liposomes. An antisense oligodeoxynucleotide against the overexpressed oncogene c-myc(as(c-myc)) was efficiently loaded into SALP formulations, the encapsulation efficiency decreased due to the inclusion of the targeting ligand. Also, liposome size was affected by as(c-myc) physical chemical properties. The amount of antagonist G linked to the surface of the liposomal formulations was dependent on the coupling method and lipid composition used. Covalent attachment of antagonist G increased liposomes cellular association and internalization via receptor-mediated and clathrin-dependent endocytosis, as assessed in SCLC cell lines. Biodistribution studies in healthy mice revealed a preferential lung accumulation of antagonist G–targeted SALP as compared to the non-targeted counterpart. Lung levels of the former were up to 3-fold higher 24 h after administration, highlighting their potential to be used as delivery vectors for SCLC treatment.

Kdm1a promotes SCLC progression by transcriptionally silencing the tumor suppressor Rest

Small cell lung carcinoma (SCLC) is one of the deadliest cancer types, with a 5-year survival rate less than 10%. Kdm1a/Lsd1 has recently been implicated as a potential therapeutic target for SCLC. However, the underlying molecular mechanism by which Kdm1a promotes the oncogenesis of SCLC has not been fully understood. Kdm1a is significantly elevated in most human SCLC specimens, whereas Rest, a tumor suppressor and neuronal repressive transcriptional factor, is typically inactivated. Knock-out of Kdm1a (Kdm1a-KO) in mouse SCLC cell lines resulted in the suppression of cell growth and soft agar colony formation. RNA-Seq analysis of the Kdm1a-KO cells revealed significant repression of a program of neuroendocrine signature genes, and conversely, a significant upregulation of a network of genes capable of inhibiting tumor cell growth. Rest was identified among the top 10 upregulated genes in Kdm1a-KO cells. The treatment of the SCLC cells with Kdm1a demethylase inhibitors resulted in a dramatic up-regulation of Rest similar to the extent of that in Kdm1a-KO cells. Importantly, accompanying the restored expression of the SCLC signature genes, knock-out of Rest in Kdm1a-KO cells rescued the restricted cell growth and soft agar colony formation. Taken together, these novel findings show that Kdm1a is a key transcriptional repressor of Rest, and that suppression of SCLC progression by the targeted inhibition of Kdm1a depends on the reactivation of Rest, suggesting a new strategy for effective SCLC treatment by targeting the Kdm1a/Rest molecular pathway.

Small-cell lung carcinoma with ovarian metastasis 4\xa0years after the first-line treatment

Small-cell lung carcinoma rarely metastasizes to the ovary. Only few cases of this condition have been reported to date. A 42-year-old female nonsmoker was an outpatient after receiving treatment for small-cell lung carcinoma. Approximately 45 months after the first-line treatment, the pro-gastrin-releasing peptide level exhibited a gradual increase. Positron emission tomography-computed tomography revealed abnormal accumulation in the left ovary. Accordingly, we performed laparoscopic salpingo-oophorectomy. Both pathological and immunohistochemical examinations (thyroid transcription factor-1, synaptophysin, and chromogranin A staining) led to the diagnosis of ovarian metastasis of small-cell lung carcinoma. The pro-gastrin-releasing peptide level declined postoperatively, and no recurrence has been reported thus far. Here we reported an extremely rare case of small-cell lung carcinoma metastatic to the ovary after several years of receiving the initial treatment for small-cell lung carcinoma, which, however, exhibited an excellent course postoperatively.

Abstract 3932: Metabolic biomarkers predict the sensitivity to phosphatidylinositol 3-kinase pathway inhibitor in small-cell lung carcinoma

Abstract Comprehensive genomic analysis has revealed that the PI3K/AKT/mTOR pathway is a feasible therapeutic target in small-cell lung carcinoma (SCLC). However, biomarkers to identify patients likely to benefit from inhibitors of this pathway have not been identified. Here we show that metabolic features determine sensitivity to the PI3K/mTOR dual inhibitor gedatolisib in SCLC cells. We analyzed the phosphatidyl lipid profile including the acyl groups of 11 SCLC cell lines using electrospray ionization mass spectrometry. We found that a specific phosphatidylinositol (3,4,5)-triphosphate (PIP3) subspecies lipid product, PIP3 (38:4), is predictive in assessing sensitivity to gedatolisib. We generated a large-scale metabolomic dataset for 28 SCLC cell lines. Notably, we found that higher amounts of purine-related aqueous metabolites such as hypoxanthine led to resistance to PI3K pathway inhibition. The levels of the mRNA encoding hypoxanthine phosphoribosyl transferase 1 (HPRT1), a key component of the purine salvage pathway, differed significantly between SCLC cells sensitive or resistant to gedatolisib. Loss of HPRT1 in SCLC cells decreased cellular proliferation in the presence of gedatolisib compared with a control. Further, complementation with purine metabolites could reverse the vulnerability to targeting of the PI3K pathway in SCLC cells normally sensitive to gedatolisib. These results indicate that the mechanism of resistance to PI3K pathway inhibitors is mediated by activation of the purine salvage pathway, which supplies purine resources for nucleotide biosynthesis. Metabolic profiles of clinical samples of SCLC revealed that purine-related metabolites were higher in SCLC tumor tissues, suggesting that higher amounts of purine-related aqueous metabolites might be characteristic of SCLC biology. Metabolomics is a powerful approach for identifying novel therapeutic biomarkers applicable to SCLC treatment. Citation Format: Shigeki Umemura, Hideki Makinoshima, Genichiro Ishii, Takehiko Sasaki, Hiroyasu Esumi, Koichi Goto, Katsuya Tsuchihara. Metabolic biomarkers predict the sensitivity to phosphatidylinositol 3-kinase pathway inhibitor in small-cell lung carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3932.

Inhibitory effects of XAV939 on the proliferation of small-cell lung cancer H446 cells and Wnt/β-catenin signaling pathway in vitro.

Lung cancer, including small-cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC), are the most common tumor types, which represent 13% of newly diagnosed cancer cases worldwide. SCLC represents 15% of all lung cancer cases. Although an increasing number of novel targeted drugs are employed for the treatment of NSCLC, including Iressa, Tarceva and Conmana, there have been almost no major breakthroughs in SCLC over the last 30 years. Therefore, new drug targets are required to treat or prevent SCLC. Aberrant Wnt signaling is associated with numerous types of tumors, and it plays a key role in cell proliferation and survival. Recent preclinical studies suggested that XAV939 is a small-molecule inhibitor of the Wnt signaling pathway. In the present study, whether XAV939 is able to inhibit the proliferation of SCLC cells and the underlying mechanism were investigated. The inhibition of cell proliferation was detected by Cell Counting Kit-8 (CCK-8) assay. The mRNA expression of β-catenin and cyclin D1 were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and the protein expression of β-catenin and cyclin D1 was determined by western blotting. The results from the CCK-8 cell viability assay confirmed that XAV939 is able to inhibit the proliferation of SCLC cells in a dose-dependent manner. However, the effects of XAV939 were not time-dependent. By contrast, the effect of DDP treatment was time- and dose-dependent. Furthermore, the effect of combination treatment with XAV939 and DDP was antagonistic at low doses and synergistic at high doses. It was also observed that the mRNA and protein expression of β-catenin and cyclin D1 was significantly in SCLC cells following XAV939 treatment compared with the control group. These findings suggested that XAV939 is able to inhibit the proliferation of H446 cells, at least partially, through downregulating the Wnt/β-catenin signaling pathway. All of these results may provide potential therapeutic approaches for the treatment of SCLC.

Metabolic Determinants of Sensitivity to Phosphatidylinositol 3-Kinase Pathway Inhibitor in Small-Cell Lung Carcinoma.

Comprehensive genomic analysis has revealed that the PI3K/AKT/mTOR pathway is a feasible therapeutic target in small-cell lung carcinoma (SCLC). However, biomarkers to identify patients likely to benefit from inhibitors of this pathway have not been identified. Here, we show that metabolic features determine sensitivity to the PI3K/mTOR dual inhibitor gedatolisib in SCLC cells. Substantial phosphatidyl lipid analysis revealed that a specific phosphatidylinositol (3,4,5)-trisphosphate (PIP3) subspecies lipid product PIP3 (38:4) is predictive in assessing sensitivity to PI3K/mTOR dual inhibitor. Notably, we found that higher amounts of purine-related aqueous metabolites such as hypoxanthine, which are characteristic of SCLC biology, lead to resistance to PI3K pathway inhibition. In addition, the levels of the mRNA encoding hypoxanthine phosphoribosyl transferase 1, a key component of the purine salvage pathway, differed significantly between SCLC cells sensitive or resistant to gedatolisib. Moreover, complementation with purine metabolites could reverse the vulnerability to targeting of the PI3K pathway in SCLC cells normally sensitive to gedatolisib. These results indicate that the resistance mechanism of PI3K pathway inhibitors is mediated by the activation of the purine salvage pathway, supplying purine resource to nucleotide biosynthesis. Metabolomics is a powerful approach for finding novel therapeutic biomarkers in SCLC treatment.Significance: These findings identify features that determine sensitivity of SCLC to PI3K pathway inhibition and support metabolomics as a tool for finding novel therapeutic biomarkers. Cancer Res; 78(9); 2179-90. ©2018 AACR.

Carboplatin and etoposide followed by once-daily thoracic radiotherapy in limited disease small-cell lung cancer: unsatisfactory results.

There has been a trend to replace cisplatin with carboplatin in the treatment of small-cell lung carcinoma. The goal of the present study was to determine the efficacy of carboplatin and etoposide followed by thoracic radiotherapy in patients with previously untreated limited disease small-cell lung carcinoma. From February 2001 to March 2007, 47 patients with limited disease small-cell lung cancer were enrolled in the study. Etoposide, 100 mg/m2, was administrated intravenously on days 1-3 in combination with carboplatin, AUC 6, on day 1 every 21 days for 6 cycles. In cases considered to have non-progressive disease following induction chemotherapy, thoracic radiotherapy was given with in a once daily fraction of 2.0 Gy, 5/wk, up to 50-60 Gy. Forty-one patients were evaluated. Median age was 62 (range, 40-78), 88% of patients were male. ECOG PS was 0-1 in 38 patients. Seven of the 41 patients (17.5%) had pleural effusion (one malignant) and 7 patients (17.5%) had involved supraclavicular lymph nodes. Ninety percent of patients had elevated serum lactate dehydrogenase levels. Median follow-up was 13.5 mo. A total of 209 cycles of chemotherapy was administered (median, 6; range, 1-6). Thoracic irradiation was given to 33 patients. The overall response rate to combined modality on an intention-to-treat basis was 73%. Median survival time was 13.7 months (95% CI, 10.3-17.1), and median progression-free survival was 9.5 months (95% CI, 8.6-10.4). Two- and four-year overall survival was 23% and 7%, respectively. Grade 3-4 neutropenia and leukopenia were the most common adverse events and occurred in 46.0% and 24.0% of the patients, respectively. Six (14%) patients experienced febrile neutropenia. Three patients (7%) died of sepsis and neutropenic fever. Non-hematological toxicities were mild. Carboplatin and etoposide chemotherapy followed by thoracic radiotherapy in LD-SCLC appears to be unsatisfactory.

Lung cancer drug therapy in Hungary - 3-year experience.

Hungary is a world leader in lung cancer deaths, so it is of crucial importance that patients have access to modern treatments. The aim of our analysis was to explore how drug treatments are used in Hungary and how they are compatible with international practice. The inpatient and prescription database of the National Health Insurance Fund Administration of Hungary was used to study the frequency of certain chemotherapy protocols and duration of therapies during a 3-year period (2008–2010). During the study period, 12,326 lung cancer patients received first-line chemotherapy, a third of those (n=3,791) received second-line treatment, and a third of the latter (n=1,174) received third-line treatment. The average treatment duration was between 3 and 4 months. The first-line treatment of non-small-cell lung carcinoma mainly consisted of platinum treatment in combination with third-generation cytotoxic agents. A downward trend of gemcitabine, still the most common combination compound, was observed, in parallel with a significantly increased use of paclitaxel, and as a consequence carboplatin replaced cisplatin. Among the new agents, the use of pemetrexed and bevacizumab increased. Pemetrexed appeared mainly in second-line treatment, while erlotinib appeared also in second-line but mostly in third-line treatments. The first-line treatment of small-cell lung carcinoma consisted of a platinum–etoposide combination, while in the second-line setting topotecan was the most commonly used drug. According to our results, the chemotherapeutic combinations and sequencing are in accordance with international and national recommendations. Further detailed analysis of the available data may help to obtain a more accurate picture of the efficacy of lung cancer treatments as well.

Pentraxin-3 as a prognostic marker in patients with small-cell lung cancer.

The aim of this study was to determine the incidence and role of pentraxin-3 (PTX-3) overexpression as a predictive/prognostic marker in small-cell lung carcinoma (SCLC). We performed a retrospective study on subjects with a biopsy-proven diagnosis of SCLC. A chart review for demographic and clinical data was performed on patients with SCLC diagnosed between 2005 and 2008. PTX-3 overexpression was evaluated using immunohistochemistry performed on archival paraffin-embedded specimens. 125 patients with SCLC were identified (23 females, 102 males; median age 62.91±8.55 years, range 37-82) all of whom had adequate tissue specimens available for PTX-3 testing. High PTX-3 expression was detected in 25.6% SCLCs and was significantly associated with male gender and smokers. Moreover, elevated PTX-3 levels were correlated with reduced overall (OS) and disease-free survival, and were an independent negative prognostic factor for OS in SCLC. Our findings suggest that high PTX-3 expression appeared to correlate with aggressive behavior in SCLC, and it may be a useful prognostic marker for SCLC patients and a potential molecular target for SCLC treatment.

Silibinin reverses drug resistance in human small-cell lung carcinoma cells

Small-cell lung carcinoma (SCLC) has a dismal prognosis in part because of multidrug resistance (MDR). Silibinin is a flavonolignan extracted from milk thistle (Silybum marianum), extracts of which are used in traditional medicine. We tested the effects of silibinin on drug-sensitive (H69) and multi-drug resistant (VPA17) SCLC cells. VPA17 cells did not show resistance to silibinin (IC50=60μM for H69 and VPA17). Flow cytometry analysis after incubation in 30μM silibinin showed no changes in cell cycle phases in VPA17 or H69 cells compared with untreated cells. Silibinin (30μM) incubation was pro-apoptotic in VPA17 cells after >3days, as measured by ELISA of BUdR labeled DNA fragments. Apoptosis was also indicated by an increase in caspase-3 specific activity and decrease in survivin in VPA17 MDR cells. VPA17 cells had increased Pgp-mediated efflux of calcein acetoxymethyl ester (calcein AM); however, this was inhibited in cells pre-incubated in silibinin for 5days. Pre-incubation of VPA17 cells in 30μM silibinin for 5days also reversed resistance to etoposide (IC50=5.50 to 0.65μM) and doxorubicin (IC50=0.625 to 0.035μM). The possible synergistic relationship between silibinin and chemotherapy drugs was determined by exposure of VPA17 cells to 1:1 ratios of their respective IC50 values, with serial dilutions at 0.25 to 2.0×IC50 and calculation of the combination index (CI). Silibinin and etoposide showed synergism (CI=0.46 at ED50), as did silibinin and doxorubicin (CI=0.24 at ED50). These data indicate that in SCLC, silibinin is pro-apoptotic, reverses MDR and acts synergistically with chemotherapy drugs. Silibinin, a non-toxic natural product may be useful in the treatment of drug-resistant SCLC.

Carboplatin and etoposide followed by once-daily thoracic radiotherapy in limited-disease small-cell lung cancer.

e18540 Background: There has been a trend to replace cisplatin with carboplatin in the treatment of small-cell lung carcinoma. The goal of the present study was to determine the efficacy of carboplatin and etoposide followed by thoracic radiotherapy in patients with previously untreated limited disease small-cell lung carcinoma. Methods: From February 2001 to March 2007, 47 patients with limited disease small-cell lung cancer were enrolled in the study. Etoposide, 100 mg/m2, was administrated intravenously on days 1-3 in combination with carboplatin, AUC 6, on day 1 every 21 days for 6 cycles. In cases considered to have non-progressive disease following induction chemotherapy, thoracic radiotherapy was given with in a once daily fraction of 2.0 Gy, 5/wk, up to 50-60 Gy. Results: Forty-one patients were evaluated. Median age was 62 (range, 40-78), 88% of patients were male. ECOG PS was 0-1 in 38 patients. Seven of the 41 patients (17.5%) had pleural effusion (one malignant) and 7 patients (17.5%) had involved supraclavicular lymph nodes. Ninety percent of patients had elevated serum lactate dehydrogenase levels. Median follow-up was 13.5 mo. A total of 209 cycles of chemotherapy was administered (median, 6; range, 1-6). Thoracic irradiation was given to 33 patients. The overall response rate to combined modality on an intention-to-treat basis was 73%. Median survival time was 13.7 months (95% CI, 10.3-17.1), and median progression-free survival was 9.5 months (95% CI, 8.6-10.4). Two- and four-year overall survival was 23% and 7%, respectively. Grade 3-4 neutropenia and leukopenia were the most common adverse events and occurred in 46.0% and 24.0% of the patients, respectively. Six (14%) patients experienced febrile neutropenia. Three patients (7%) died of sepsis and neutropenic fever. Non-hematological toxicities were mild. Conclusions: Carboplatin and etoposide chemotherapy followed by thoracic radiotherapy in LD-SCLC appears to be unsatisfactory.

A Rare Case of Tarceva Resulting in Tympanic Membrane Necrosis

Objective: To report a novel case of Tarceva? treatment for small cell lung carcinoma resulting in tympanic membrane necrosis. Patient: A 49-year-old male with tympanic membrane necrosis and presumed resistant acute otitis externa and chronic inflammation of the left ear. Patient is status post chemotherapy and radiation diagnosed with non-small cell lung cancer in December 2008 with on-going therapy with Tarceva? for residual disease. Intervention: Tympanoplasty of left ear. Results: Improvement of symptoms of irritation and improvement of hearing and speech reception thresholds. All acid fast bacilli, fungal and bacterial cultures of the intra-op specimen were negative. Conclusions: The possibility that long term Tarceva? therapy could have caused the tympanic membrane necrosis and acute otitis media like symptoms is feasible since Tarceva? is an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase. Upon activation of EGFRs it undergoes a transition from inactive monomeric form to active homodimer or hertodimer with another member of the ErbB receptor family. This then initiates several signal transduction cascades, leading to DNA synthesis and cell proliferation. Activation of the receptor is important in the innate immune response in human skin. Some of the common side effects include an aceiform skin rash but this is the first reported link between tympanic membrane necrosis and Tarceva?.

Étude post-autorisation de mise sur le marché sur le topotécan dans le cancer bronchique à petites cellules. Utilisation du topotécan dans un service de pneumologie universitaire

Lung cancer is the leading cause of cancer related death in France and Europe. Small-cell lung carcinoma (SCLC) represents 15-20% of cases. International standards of care recommend the use of first-line chemotherapy, which has a high response rate. However, tumour recurrence occurs after a variable disease-free period. If the first-line treatment cannot be repeated during the relapse, intravenous topotecan may be used according to its market authorization (MA). We report the first French postmarketing surveillance study on the use of topotecan in the SCLC. Between August 2005 to December 2009, 26 SCLC patients received at least one cycle of intravenous topotecan in our department. All patients were treated in accordance with MA. Seventeen patients received this treatment as second line, as in the MA study, while nine patients where treated beyond the second line. In the first group, we showed that the anti-tumour efficiency of topotecan is similar to that observed in the MA study (24% response) while grade 3 to 4 haematological toxicities were less frequent. In the second group of patients, who could not have been included in the MA study, the tumour response rate was equal to 11% without an increase in severe toxicity compared to the first group. Specific or overall survival was not different between the two groups. Our study provides original public health data on the target population, the anti-tumor efficiency and the toxicity of topotecan in the treatment of SCLC.

Novel strategies for the treatment of small-cell lung carcinoma

Small-cell lung cancer (SCLC) is a disease with a poor prognosis and limited treatment options. Over the past 30 years, basic and clinical research have translated to little innovation in the treatment of this disease. The Study of Picoplatin Efficacy After Relapse (SPEAR) evaluated best supportive care with or without picoplatin for second-line SCLC treatment and failed to meet its primary end point of overall survival. As the largest second-line, randomized study in patients with SCLC, SPEAR provides an opportunity to critically examine the drug development model in this disease. In this Review, we discuss the current standard approach for the management of SCLC that progresses after first-line therapy, analyze the preliminary data that supported the evaluation of picoplatin in this setting, and critically evaluate the SPEAR trial design and results. Lastly, we present advances in the understanding of the molecular biology of SCLC that could potentially inform future clinical trials and hopefully lead to the successful development of molecular targeted agents for the treatment of this disease.

Carboplatin and Etoposide Followed by Once-Daily Thoracic Radiotherapy in Limited Disease Small-Cell Lung Cancer: Unsatisfactory Results

There has been a trend to replace cisplatin with carboplatin in the treatment of small-cell lung carcinoma. The goal of the present study was to determine the efficacy of carboplatin and etoposide followed by thoracic radiotherapy in patients with previously untreated limited disease small-cell lung carcinoma. From February 2001 to March 2007, 47 patients with limited disease small-cell lung cancer were enrolled in the study. Etoposide, 100 mg/m2, was administrated intravenously on days 1-3 in combination with carboplatin, AUC 6, on day 1 every 21 days for 6 cycles. In cases considered to have non-progressive disease following induction chemotherapy, thoracic radiotherapy was given with in a once daily fraction of 2.0 Gy, 5/wk, up to 50-60 Gy. Forty-one patients were evaluated. Median age was 62 (range, 40-78), 88% of patients were male. ECOG PS was 0-1 in 38 patients. Seven of the 41 patients (17.5%) had pleural effusion (one malignant) and 7 patients (17.5%) had involved supraclavicular lymph nodes. Ninety percent of patients had elevated serum lactate dehydrogenase levels. Median follow-up was 13.5 mo. A total of 209 cycles of chemotherapy was administered (median, 6; range, 1-6). Thoracic irradiation was given to 33 patients. The overall response rate to combined modality on an intention-to-treat basis was 73%. Median survival time was 13.7 months (95% CI, 10.3-17.1), and median progression-free survival was 9.5 months (95% CI, 8.6-10.4). Two- and four-year overall survival was 23% and 7%, respectively. Grade 3-4 neutropenia and leukopenia were the most common adverse events and occurred in 46.0% and 24.0% of the patients, respectively. Six (14%) patients experienced febrile neutropenia. Three patients (7%) died of sepsis and neutropenic fever. Non-hematological toxicities were mild. Carboplatin and etoposide chemotherapy followed by thoracic radiotherapy in LD-SCLC appears to be unsatisfactory.

Dosimetric and Clinical Parameters Contributing to Esophagitis and Radiation Pneumonitis following Treatment for Small-cell Lung Carcinoma

Conclusions: The analysis did not find definite dose response relationships for cardiac or pulmonary AEs. We found that patients who had a Grade $2 cardiac (general) AE had significantly lower heart V40 and V30 than those with Grade\2 AE. However, the number of events was small and further investigation as part of larger prospective studies of concurrent chemo-irradiation with or without biologic agents is likely warranted.