Survival Of Small Cell Lung Cancer Patients Research Articles

A microRNA-related single nucleotide polymorphism of the XPO5 gene is associated with survival of small cell lung cancer patients.

MicroRNA (miRNA)-related single nucleotide polymorphisms (miR-SNPs) in miRNA processing machinery genes affect cancer risk, treatment efficacy and patient prognosis. A miR-SNP of rs11077 located in the 3'UTR of miRNA processing machinery gene XPO5 was examined in small cell lung cancer (SCLC) patients to evaluate its association with cancer survival. A total of 42 patients were enrolled in the present study and genotyped for rs11077 and survival was assessed using the Kaplan-Meier method, as well as univariate and multivariate analyses. The AA genotype of rs11077 was identified for its significant association with better survival time (P=0.023). In addition, rs11077 was found to associate independently with overall survival in SCLC patients by multivariate analysis (relative risk 2.469; 95% CI, 1.088-5.603; P=0.031). The findings of this study suggest that although miR-SNP studies for miRNA processing machinery genes are still at an early age, miR-SNPs have an impact on cancer survival. In conclusion, a miR-SNP in the 3'UTR region of the XPO5 gene was identified as an independent prognostic marker for survival of advanced SCLC patients.

Prognostic factors and trends in outcome for small cell lung cancer over 20 years.

e17518 Background: There has been little change in the chemotherapeutic treatment of small cell lung cancer (SCLC) over the last 30 years but changes in radiotherapy have demonstrated a survival benefit in clinical trails. There is substantial disagreement in the literature on whether or not there has been an improvement in survival for SCLC patients and which patient characteristics serve as important prognostic factors. The majority of the data comes from the selective population of patients included in clinical trials, which do not necessarily reflect real world therapeutic effectiveness. Methods: Using the Manitoba Cancer Registry and Manitoba’s physician billing database, we extracted information on all patients receiving a pathologic diagnosis of SCLC in the Canadian province of Manitoba between Jan 1, 1985 and Dec 31, 2004. Linear regression and Cox proportional hazard regression were then used to determine trends in SCLC incidence, survival, sex distribution, treatment, and prognostic factors. Results: Over the course of the study, the number of cases of SCLC diagnosed each year decreased by 1.41 cases/year (p=0.007), due entirely to a decrease in male cases. The proportion of females increased by 1%/year (p<0.001, 95% CI [0.007, 0.013]). In the whole study population, the proportion of patients receiving no antineoplastic treatment increased dramatically with age, from 11.7% in those ≤50 to 50.6% in patients >80 years old (p<0.001). There has been no change in 2 or 5-year survival (p>0.05 at both time points), which is true for both males and females. Two-year survival was 12.7% for females vs 8% for males (p<0.001), and at 5 years 5.3% of females vs 2.6% of males survive (p=0.002). Male sex was a negative prognostic factor with an adjusted hazard ratio of 1.27 (95% CI [1.16, 1.39]). Conclusions: Female sex is a positive prognostic factor in SCLC. In this population based trial, evolution of therapy over 20 years did not translate into improved survival. A further decline solely in the number of male cases may independently improve survival in the future.

Investigation of PARP1 as a therapeutic target in small cell lung cancer.

7096 Background: Small cell lung cancer (SCLC) is an aggressive malignancy that differs from non-small cell lung cancer (NSCLC) in its metastatic potential and response to treatment. To date, no molecularly-targeted agent has prolonged survival of SCLC patients. Using a proteomic approach, we previously identified high expression of the DNA repair protein poly (ADP-ribose) polymerase 1 (PARP1) in SCLC cell lines and tumors. Here we test in vitro sensitivity of SCLC to PARP inhibition or knockdown. Methods: Cell lines were treated with PARP inhibitor olaparib or AG014699 for 14d +/- chemotherapy. Relative cell viability was assessed by cell count. siRNA against PARP1 was compared with scrambled siRNA and mock transfected cells. To assess DNA repair, RAD51 foci were counted after 1µM or 5µM olaparib and after 8Gy irradiation (RT). Results: SCLC cell lines were highly sensitive to PARP inhibition by olaparib (IC50s <0.5 µM for H69; ≤2µM in H524, H82, and H526) and AG014699 (IC50s <0.5 µM for H82, H69, and H524; 2.2 µM for H526 and H841). In contrast, A549 (NSCLC) was resistant to both drugs (IC50s >8µM). Because BRCA1/2 and PTEN mutations are associated with greater sensitivity to PARP inhibitors, we compared SCLC sensitivity with that of BRCA1-mutated (HCC1395) and PTEN-mutated (MDA-MB-468) breast lines. As expected, HCC1395 and MDA-MB-468 were sensitive to both PARP inhibitors. Remarkably, however, SCLC cell lines were as sensitive or more so. Combination of olaparib with topotecan or irinotecan (commonly used in SCLC) decreased tumor cell viability more than either agent alone (p <0.03). Consistent with the drug studies, knockdown of PARP1 by siRNA decreased growth of SCLC compared with that of controls. RAD51 foci increased in SCLC after olaparib treatment (>4-fold) and RT (>18-fold). Conclusions: SCLC lines were as sensitive to PARP inhibition as BRCA1- or PTEN-mutated breast cancer lines. Moreover, PARP inhibition enhanced the effect of chemotherapy on SCLC lines. Increased formation of RAD51 foci in SCLC cells after olaparib or RT suggests a deficiency in homologous recombination that may account for the sensitivity to PARP inhibitors. These results support the investigation of PARP inhibition as a novel therapeutic approach in SCLC lung cancer.

Tumor Cell Expression of Heat Shock Protein (HSP) 72 is Influenced by HSP72 [HSPA1B A(1267)G] Polymorphism and Predicts Survival in Small Cell Lung Cancer (SCLC) Patients

The inducible heat shock protein (HSP)72 plays a central role in antitumor immunomodulation. HSP72 expression was assessed on tumor samples of 43 patients with advanced and metastatic small cell lung cancer (SCLC) by immunohistochemistry and HSP72 [HSPA1B A(1267)G] polymorphism was determined. HSP72 expression of SCLC cells was significantly decreased in GG as compared to cells of AA or AG genotype patients, and was associated with significantly shorter survival in GG patients as compared to carriers of the A allele. Decreased HSP72 expression of SCLC cells associated with HSP72 GG genotype is a negative prognostic factor for survival in SCLC patients.

A polymorphism at the miR-502 binding site in the 3' untranslated region of the SET8 gene is associated with the outcome of small-cell lung cancer.

microRNAs (miRNAs) bind to the 3' untranslated regions (UTRs) of messenger RNAs, where they interfere with translation of genes that regulate cell differentiation, apoptosis and tumourigenesis. The histone methyltransferase SET8 has been reported to methylate TP53 and regulate genomic stability. We analysed a single nucleotide polymorphism (rs16917496) within the miR-502 miRNA seed region at the 3' UTR of SET8 in small-cell lung cancer (SCLC) patients. The SET8 CC+CT genotype was identified to be independently associated with longer survival in SCLC patients by multivariate analysis (relative risk, 0.453; 95% CI 0.217-0.944; p=0.035). The analysis of genetic polymorphisms in miRNA binding sites may help to identify patient subgroups at high risk of poor outcome.

Abstract 5411: Development of SCLC specific nanoparticle-mediated therapeutic gene delivery

Abstract Lung cancer is the most common cause of cancer-related deaths worldwide. Small cell lung cancer (SCLC) is a particularly aggressive form of lung cancer characterized by early metastatic behavior. Even with currently recommended therapy, the average survival of SCLC patients is less than 1 year. There is an urgent need for novel treatments. The majority (70-90%) of SCLC cases possess alterations in p53 and Rb. This relative genetic homogeneity makes SCLC an attractive context in which to develop and test novel gene therapy approaches. We have initiated studies using non-viral, poly-β amino acid ester (PBAE) nanoparticle delivery of gene therapy in SCLC. PBAE polymers possess numerous advantages over viral delivery systems such as structural diversity, cost effectiveness, low immunogenicity and higher stability. PBAEs encapsulate DNA to form biodegradable cationic nanoparticles and have been studied in a variety of cancer cell types and in primary endothelial cells. This is the first study of PBAEs in SCLC. A PBAE polymer library was screened in two SCLC lines using a luciferase-based high-throughput screen (HTS). Thirty-two of 112 polymers were further characterized in the H446 SCLC cell line using a CMV-GFP reporter construct and analyzed by qualitative (microscopy) and quantitative (flow cytometry) methods. This secondary screen revealed that the polymers had variable transfection efficiencies ranging from 8-55%. Four polymers, 446LG, 447LG, 456LG and 457 exhibited high transfection efficiencies (42-55%) in two SCLC cell lines, including one suspension line. Using PBAEs complexed with Cy5-labeled DNA, we were able to demonstrate that >90% cells bind and internalize the nanoparticles. We have initiated studies to better elucidate bottlenecks between nanoparticle uptake and gene expression. Additionally, preliminary studies in tumor-bearing athymic nude mice demonstrated gene uptake and expression via intratumoral injection of 457 and 446LG polymer/DNA complexes. Ongoing studies include further optimization of PBAEs for in vitro gene expression and systemic in vivo delivery. In parallel, we are performing genetic characterization of patient-derived primary SCLC xenografts to verify relevant gene targets. Taken together, our data supports further development of a non-viral PBAE-based gene delivery approach in SCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5411. doi:10.1158/1538-7445.AM2011-5411

Organic Anion Transporting Polypeptide 5A1 (OATP5A1) in Small Cell Lung Cancer (SCLC) Cells: Possible Involvement in Chemoresistance to Satraplatin

BackgroundThe role of organic anion transporting polypeptide 5A1 (OATP5A1) a member of a family of drug transporters that mediate cellular uptake of drugs has not been characterized so far.MethodsGene expression levels of OATP5A1 in small cell lung cancer (SCLC) cell lines were determined by real-time qPCR and chemosensitivity of HEK-293-SLCO5A1-transfected cells to satraplatin in MTT assays.ResultsSignificant expression of this transporter was found at the mRNA level, primarily in drug-resistant SCLC cells, and SLCO5A1-transfected HEK-293 cells showed higher resistance to satraplatin. OATP5A1 is found preferentially in cytoplasmic membranes of tumor cells, including SCLC.ConclusionsOATP5A1 seems to effect intracellular transport of drugs and may participate in chemoresistance of SCLC by sequestration, rather than mediating cellular uptake. Since satraplatin failed to improve survival in SCLC patients, the relation of OATP5A1 expression to clinical drug resistance and its use as marker of chemoresistance should be further investigated.

S93 Is Bcl-2 important in small cell lung cancer?

IntroductionBcl-2 is an anti-apoptotic protein that has previously been associated with increased cell survival in Small Cell Lung Cancer (SCLC) in vitro. However, several immunohistochemical studies of Bcl-2 expression and...

Phase III Double-Blind, Placebo-Controlled Study of Thalidomide in Extensive-Disease Small-Cell Lung Cancer After Response to Chemotherapy: An Intergroup Study FNCLCC cleo04–IFCT 00-01

This randomized, double-blind, placebo-controlled phase III study aimed to determine whether thalidomide prolongs survival of patients with extensive-disease small-cell lung cancer (SCLC). One hundred nineteen patients received two courses of etoposide, cisplatin, cyclophosphamide, and 4'-epidoxorubicin (PCDE). Responder patients who had recovered from chemotherapy toxicity were randomly assigned to receive four additional PCDE cycles plus thalidomide (400 mg daily) or placebo. After the first two PCDE cycles, objective response rate was 81.5%, and 92 patients were randomly assigned to placebo (n = 43) or thalidomide (n = 49). Median exposure duration to placebo was 4.5 months, and median exposure to thalidomide was 4.9 months. Patients treated with thalidomide had a longer survival compared with patients who received placebo, although the difference was not statistically significant (minimal follow-up, 3 years; median survival time, 11.7 v 8.7 months, respectively; log-rank test: hazard ratio [HR] = 0.74; 95% CI, 0.49 to 1.12; P = .16). Patients with a performance status (PS) of 1 or 2 who received thalidomide had a significantly longer survival (HR = 0.59; 95% CI, 0.37 to 0.92; P = .02). The disease also progressed slower in patients with PS of 1 or 2 receiving thalidomide (HR = 0.54; 95% CI, 0.36 to 0.87; P = .02), whereas the difference did not reach statistical significance for the whole population (HR = 0.74; 95% CI, 0.49 to 1.12; P = .15). Neuropathy occurred more frequently in the thalidomide group compared with the placebo group (33% v 12%, respectively). Treatment with thalidomide was not associated with a significant improvement in survival of SCLC patients. There was pronounced heterogeneity in survival outcomes between groups of patients. Some benefit was observed among patients with a PS of 1 or 2 (exploratory analyses), deserving further studies targeting angiogenesis in this disease.

Survival in small cell lung cancer in India: Prognostic utility of clinical features, laboratory parameters and response to treatment

Predictors of survival and response to treatment in patients with small cell lung cancer (SCLC) are ill-defined and unclear. In an attempt to assess the impact of common presenting symptoms and laboratory values on survival, we undertook this retrospective review of patients with SCLC. To our knowledge, there is no study on survival in SCLC patients from the Indian subcontinent. Retrospective Cohort study. All newly diagnosed small cell lung cancer cases from December 2001 through December 2004, were identified and clinical data on presenting symptoms and laboratory findings from their hospital records, noted. The influence of various pretreatment factors on survival was investigated using Kaplan-Meier plots and Cox multivariate regression model. 76 subjects were included (84% males, 91% smokers). 57% patients had five or more symptoms at presentation. Cumulative symptom burden was strongly associated with survival (P =0.02). Survival was also significantly related with Karnofsky performance status (KPS) (P =0.04), disease extent (P =0.03) and symptomatic response to treatment (P< 0.001). Patients with higher hemoglobin (P =0.02), serum sodium (P =0.04) and serum globulin (P =0.02), survived significantly longer. By multivariate regression analysis, hemoglobin, KPS and brain metastases, were significant predictors of survival (P =0.01, P =0.02, P< 0.01 respectively). Cumulative symptom burden, KPS, disease extent and symptomatic assessment of improvement after treatment, are useful predictors of survival. This has important clinical implications, keeping in view, the infrastructure and cost involved in more objective tests like CT scan, for evaluation of disease extent and prognosis. These findings can provide a simple basis for predicting prognosis in small cell lung cancer, especially in developing countries like ours.

Serum Vascular Endothelial Growth Factor (VEGF) and Interleukin-8 (IL-8) Levels in Small Cell Lung Cancer

This study was conducted to determine the value of the angiogenic serum factors, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), in patients with small cell lung cancer (SCLC). These serum angiogenic factors were measured of 34 SCLC patients on the before and after chemotherapy in comparison with 20 healthy controls using ELISA method. Serum levels of VEGF and IL-8 were significantly increased in SCLC patients compared with healthy controls (p < 0.001). No statistically significant relationships was found between investigated elevated serum angiogenic parameters and various characteristics of patients and disease such as disease stage and tumor burden. Likewise, we also found no correlation between serum angiogenic factors. Cytotoxic therapy of patients was accompanied by unchanged serum levels of angiogenic factors. Contrary to serum IL-8, elevated serum levels of VEGF was determined as a prognostic factor for survival by univariate analysis (p = 0.05). Multivariate analysis revealed that independent prognostic factors of overall survival included only response to chemotherapy and weight loss (p < 0.001 for both). In conclusion, our data suggest that the angiogenic serum factors, VEGF and IL-8, are useful diagnostic factors, but not predictive and prognostic markers for overall survival in SCLC patients.

Irinotecan in small-cell lung cancer: current data and the status of ongoing trials.

Small-cell lung cancer (SCLC) is a particularly aggressive form of lung cancer and is associated with a poor prognosis, rapid tumor growth, and early metastasis. Currently, the cornerstone of treatment in SCLC consists of combination therapy, with platinum/etoposide being the regimen of choice. Unfortunately, even with these advances in treatment, the median survival for patients with limited-stage disease is 10-15 months and 7-11 months for patients with extensive-stage disease. New treatment mechanisms need to be explored in order to extend the survival of SCLC patients. One such new treatment is the topoisomerase I inhibitor, irinotecan. This drug represents a promising advancement in the treatment of SCLC.

Expression of carcinoembryonic antigen in peripheral- or central-located small cell lung cancer: its clinical significance.

Small cell lung cancer (SCLC) has a higher percentage of hilar masses than other histological types of lung cancer. The primary site is usually adjacent to the hilum, but we often observe primary sites in the peripheral lung field. In this study, our objectives were to elucidate whether peripheral-located small cell lung cancer (PSCLC) is an independent entity and whether it differs clinically from central-located small cell lung cancer (CSCLC). We reviewed the clinical and pathological features of 52 patients treated at Kagawa Medical University Hospital between 1987 and 1996 with a diagnosis of SCLC. We defined CSCLC as a tumor whose primary site is located in the segmental bronchi or more proximally and PSCLC as a tumor located distal to the subsegmental bronchi. Twenty-one PSCLC patients and 31 CSCLC patients were identified. Kaplan-Meier survival curves were constructed and comparisons were made between PSCLC and CSCLC by the log-rank test. The carcinoembryonic antigen (CEA) level was also evaluated in each group. Although the percentage of limited disease (LD) in the patients with PSCLC was higher than that in the patients with CSCLC, the 3-year survival rate of PSCLC tended to be worse than that of CSCLC (9% for patients with PSCLC and 29% for those with CSCLC). Survival curves of patients with PSCLC also tended to be worse than those of patients with CSCLC, not only in the limited disease group but also in the extensive disease (ED) group. In addition, the mean CEA value in patients with PSCLC was higher than that in patients with CSCLC (p < 0.001), whereas the neuron specific enolase (NSE) level was not significantly different between PSCLC and CSCLC. The median survival of patients with pretherapeutic CEA titers of > or =5 ng/ml was significantly shorter than that in patients with CEA levels <5 ng/ml. These findings suggest that the survival of SCLC patients with a high CEA level was significantly shorter than that of patients with a low CEA level. In addition, CEA levels in PSCLC patients were significantly higher than those in CSCLC patients. However, the survivals of LD or ED patients with PSCLC and CSCLC were not statistically different.

Complementary roles of pro-gastrin-releasing peptide (ProGRP) and neuron specific enolase (NSE) in diagnosis and prognosis of small-cell lung cancer (SCLC)

In this study, we evaluated the clinical usefulness of ProGRP and NSE for diagnosis and prognosis of small-cell lung cancer (SCLC). Serum levels of ProGRP and NSE were determined in 108 healthy subjects, 103 patients with benign pulmonary diseases, 142 with non-small cell lung cancer (NSCLC), and 114 with SCLC. Sensitivity of ProGRP in diagnosis of SCLC was significantly higher than that of NSE (64.9 vs. 43.0%, P<0.001). The difference was substantial in patients with limited disease (56.5 vs. 20.3%, P<0.001). However, 11 of 40 SCLC patients with normal levels of serum ProGRP (27.5%) showed elevated levels of serum NSE. In the SCLC patients receiving chemotherapy, the CR rate in patients with elevated NSE levels was significantly lower than in patients with normal levels of NSE (18.5 vs. 61.7%, P<0.001). Elevation of both ProGRP and NSE was a poor prognostic factor, and patients with elevated levels of either ProGRP or NSE showed shorter survival than those without. From multivariate analysis, NSE was found to have a greater effect on survival of SCLC patients than ProGRP. These findings indicate that ProGRP is more sensitive than NSE for diagnosis of SCLC, while NSE is superior to ProGRP as a prognostic factor. In conclusion, both ProGRP and NSE are useful tumor markers and they have a complementary role for each other in diagnosis and prognosis of SCLC.

Serum p53 antibodies in small cell lung cancer: the lack of prognostic relevance

Prognostic relevance of serum p53 antibodies was assessed in 96 patients with microscopically proven small cell lung cancer (SCLC). The study group included 67 males and 29 females; mean age 58 years; range 35–86 years; 60 with limited disease (LD), and 36 with extensive disease (ED). The control group consisted of 41 patients with non-malignant diseases. The presence of p53 antibodies was assayed by the immunoenzymatic method (P53 ELISA kit, PharmaCell, France). Antibodies were present in 26 SCLC cases (27%); 15 (25%) in LD and 11 (31%) in ED. Antibodies were also found in one out of 41 control subjects (2%). There was no correlation between the level of antibodies and clinical characteristics of SCLC patients including age, gender and extent of disease. The median follow-up for the entire group was 30 months (range: 11–39 months). By the time of analysis, 78 patients (82%) had deceased. Median survival in SCLC patients with and without antibodies was 42 and 39 weeks, respectively (log rank, P=0.81). These results indicate the lack of clinical relevance of serum p53 antibodies in SCLC.

Superior vena cava obstruction in small-cell lung cancer

To identify prognostic or treatment factors influencing the response of superior vena cava obstruction (SVCO), time to SVCO recurrence, and overall survival of SCLC patients with SVCO at presentation; and to assess the role of retreatment in patients with SVCO at recurrent or persistent disease. Between January 1983 and November 1993, 76 consecutive patients who had small-cell lung cancer (SCLC) with SVCO were treated in our institution. Analysis was done according to the disease status at diagnosis of SVCO. The first analysis concerned a group of 50 patients who had SVCO at initial presentation. The second analysis concerned a group who had SVCO as a manifestation of persistent or recurrent disease. In the first analysis, 93% had significant improvement in symptoms of SVCO after chemotherapy and 94% after mediastinal radiation. Response is almost universal despite a wide range of radiation fractionation and total dose used. Seventy percent remained SVCO-free before death. Thirty percent developed recurrence of SVCO symptoms 1-16 months (median 8) after the start of initial treatment. Those who received combined chemotherapy and radiation had a longer time to SVCO recurrence (p = 0.018) compared to those who received chemotherapy alone. This effect is mainly seen in limited-stage patients. The presence of SVCO recurrence tends to have an adverse effect on the overall survival (p = 0.077) irrespective of the time when the recurrences occurred (p = 0.296). The median survival of this whole group of 50 patients in the first analysis was 9.5 months, and the 2-year survival was 10%. Stage was strongly predictive of survival (p < 0.001). Sixteen percent (3 of 19) of the patients with limited-stage diseases were long-term survivors (two patients survived 35 months and one survived 70 months). The early mortality from SVCO was 2%. In the second analysis, 85% had previously been treated with chemotherapy alone. The response rate of SVCO in the analysable patients (n = 39) was 77%. There was no significant difference in the response rate of SVCO to treatment comparing patients treated by chemotherapy first or mediastinal radiation first (p = 0.653), but most patients [82% (32 of 39)] received radiation as the initially treatment of SVCO. Ninety-three percent (38 of 41) received mediastinal radiation as a part of their ultimate retreatment regimen, and 68% (28 of 41) received mediastinal radiation as their sole retreatment regimen. Thirty-two percent (13 of 41) received chemotherapy as a part of their ultimate retreatment regimen, and only 7% received chemotherapy alone as their sole retreatment regimen. Eighty-three percent (25 of 30) of those whose SVCO responded remained free of SVCO before death, with a median survival of 3 months after recurrent or persistent disease documented. Chemotherapy or mediastinal radiation is very effective as an initial treatment in SCLC patients with SVCO at presentation and at recurrent or persistent disease. There is no obvious need to use big radiation fraction sizes for the first few radiation treatment as was previously believed. In patients with recurrent or persistent SCLC with SVCO, especially in those who previously received chemotherapy only, we have more experience in incorporating mediastinal radiation as a major component of the palliative regimen with highly effective and durable palliation achieved.