Small Cell Lung Carcinoma Patients Research Articles

High‐grade neuroendocrine carcinoma of the lung: Comparative clinicopathological study of large cell neuroendocrine carcinoma and small cell lung carcinoma

Large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC) are high-grade neuroendocrine carcinomas. In order to clarify the similarities and differences between these cancers, 22 cases each of LCNEC and SCLC were collected and a comparative pathological study was carried out. First, their clinicopathological characteristics were confirmed, which were very similar to those previously reported. The 5 year survival rate of LCNEC and SCLC patients was 38.3% and 29.7%, respectively. The morphological characteristics of LCNEC and SCLC were then reviewed with regard to the morphology previously used to differentiate these cancers. As a result, many morphological indicators, such as tumor cell size, nuclear/cytoplasmic ratio, nuclear molding, rosette formation, prominent nucleoli and karyolysis were confirmed to be significant indicators for distinguishing LCNEC from SCLC. On comparative immunohistochemistry, LCNEC had significantly high staining scores for the expression of keratin 7 and 18, E- and P-cadherins, beta-catenin, villin 1, retinoblastoma protein (pRB), c-met and alpha-enolase. These results might reflect the differentiation or deviation of LCNEC toward an epithelial nature irrespective of neuroendocrine tumor lineage. In conclusion, the present comparative study of LCNEC and SCLC defined the similarities and differences between these cancers, and showed the biologically and clinicopathologically overlapping spectrum of the tumor lineage.

MET in small cell lung carcinoma (SCLC): Effects of a MET inhibitor in SCLC cell lines and prognostic role of MET status in patients

e14617 Purpose: HGF/MET pathway is aberrantly activated by receptor overexpression and mutations in SCLC preclinical models, enhancing their oncogenicity. The significance of MET expression in SCLC remains unclear. Our aim was to analyze the effects of MET inhibition in chemosensitive/refractory SCLC models and to study the expression pattern and prognostic impact of total and phosphorylated (p) MET in SCLC patients. Methods: Total and p-MET expression (Western Blot), gene copy number (FISH), and exon 14 activating mutations (sequencing) were evaluated in H69 and H69AR SCLC cell lines. PHA-665752 (PHA), alone or combined with doxorubicin, was used to study the effects of pathway inhibition on viability, colony formation and invasion assays in basal/stimulated conditions (HGF). Fifty-eight SCLC cases were evaluated for MET and p-MET expression by immunohistochemistry. Survival analyses were performed. Results: H69 and H69AR (both R988C mutated) expressed MET at basal conditions, but not p-MET. HGF induced MET phosphorylation, increased proliferation (20%) and protected cells from doxorubicin cytotoxicity. PHA 0.5μM blocked MET phosphorylation, decreased colony formation by 50% in H69, counteracted the cytoprotective effect of HGF and inhibited invasion in H69AR. MET expression was found in 98% normal bronchial epithelia, and 78% tumor samples (overexpression 38%). Activated MET was focally detected in normal and metaplastic mucosa and expressed in 22% tumors. MET expression was associated with improved overall and disease free survival (p: 0.06 and 0.051, respectively). All p-MET positive cases within MET expressing tumors, showed relapsed disease (83% in negative p-MET samples, p=0.065), suggesting MET activation may revert the good prognosis linked to total MET expression. Conclusions: MET activation, results in a more aggressive phenotype in SCLC cells. PHA at MET inhibiting concentrations reverses this phenotype. In SCLC specimens, MET expression was more prevalent than p-MET and associated with raised prognosis. All these data suggest that studies with MET inhibitors should focus on p-MET positive SCLC. [Table: see text]

Analysis of GD2/GM2 synthase mRNA as a biomarker for small cell lung cancer

BackgroundGD2/GM2 synthase is a key enzyme in the synthesis of GD2 and GM2 gangliosides found on the surface of neuroblastoma and small cell lung carcinoma (SCLC) cells. In neuroblastoma, persistent levels of GD2/GM2 synthase RNA in bone marrow (BM) following therapy portend poorer progression-free and overall survival. We conducted this study to determine if GD2/GM2 synthase RNA could be detected in SCLC cell lines and human tissues, and whether mRNA transcript levels corresponded with disease status. Experimental designInitially, a pilot study enrolled patients with SCLC to determine the rate of GD2 expression at various points in the patients’ disease course. Peripheral blood (PB), bone marrow and tumor tissues were used to measure GD2/GM2 synthase levels. In addition, SCLC cell lines were analyzed for GD2/GM2 synthase expression. Based on data from that initial analysis, a prospective trial was developed enrolling patients with newly diagnosed SCLC and following them serially. GD2/GM2 synthase transcript was determined by a sensitive quantitative reverse transcription-PCR (qRT-PCR) assay and normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). ResultsSix SCLC cell lines were assayed for expression of GD2/GM2 synthase, and high expression was detected in all. GD2/GM2 synthase transcript levels were obtained from tumor tissue, BM, or PB of 29 patients in the pilot study. 6/10 (60%) tumor tissues or BM samples were positive (median 332.7 units; range 13–2323 units); 8/19 (42%) untreated patients were GD2/GM2 synthase positive in their PB prior to beginning therapy (median 10.2; range 5.1–32.2); 3/4 (75%) patients who were first tested when they developed recurrent disease were positive in their PB (median 16.1; range 8.5–19.9). The fourth patient had an initial value of 2.0 (negative), which increased to 8.4 (positive) within 1 month without treatment. Seven of 12 patients with baseline positive GD2/GM2 synthase values had post-treatment levels measured, all of which were ≤5 or showed a >50% decrease following successful treatment. Patients in the prospective trial demonstrated lower rates of positivity, with only 3/26 (12%) patients exhibiting detectable transcript levels in the peripheral blood prior to treatment. All 3 of these patients had their transcript levels fall below 5 after treatment. 11/26 patients had baseline levels of zero. Bone marrow was drawn at baseline on 7 patients in the prospective trial and 3 (43%) had transcript levels above 5 (range 0.65–27.43 units). There was no correlation between elevated levels in the BM and elevated levels in the PB. ConclusionsAlthough initial studies demonstrated that GD2/GM2 synthase transcripts were measurable in the peripheral blood of SCLC patients at diagnosis and declined with successful treatment, in a separate prospective study, these results could not be confirmed. Thus, GD2/GM2 is not a reliable biomarker in SCLC.

Prognostic factors in patients with small cell lung carcinoma

The current prognosis in patients with small cell lung cancer (SCLC) is unsatisfactory, even though there have been considerable improvements in diagnosis and treatment. We retrospectively analyzed all consecutive patients with small cell lung carcinoma between 1995 and 2007 in a Turkish chest hospital. A total of 116 SCLC patients initially presented with limited disease, while 92 small cell lung carcinoma patients were found to be extensive. The mean age of the patients (18 women and 190 men) was 56 years. The median survival was 74 weeks. Performance status, superior vena cava syndrome (SVCS), stage, elevated white blood cell count, elevated lactate dehidrogenase levels, short symptom duration (<or=4 weeks) response to chemotherapy and bone metastasis were significant prognostic factors in univariate analysis. It was necessary for patients to receive at least three cycles of chemotherapy for a survival benefit. Cox proportional hazards model identified only stage, performance status and SVCS as independent prognostic factors. Stage, performance status and SVCS were determined to be the most important prognostic factors for SCLC patients.

Differences in Practice Patterns and Costs between Small Cell and Non-Small Cell Lung Cancer Patients in Japan

Many reports exist regarding the economic evaluation of evolving chemotherapeutic regimens or diagnostic images for lung cancer (LC) patients. However, it is not clear whether clinical information, such as pathological diagnosis or cancer stage, should be considered as a risk adjustment in lung cancer. This study compared the cost and practice patterns between small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) patients. 6,060 LC patients treated at 58 academic hospitals and 14,507 at 257 community hospitals were analyzed. Study variables included demographic variables, comorbid status, cancer stage, use of imaging and surgical procedures, type of adjuvant therapy (chemotherapy, radiation or chemo-radiation), use of ten chemotherapeutic agents, length of stay (LOS), and total charges (TC; US$1 = 100 yen) in SCLC and NSCLC patients. The impact of pathological diagnosis on LOS and TC was investigated using multivariate analysis. We identified 3,571 SCLC and 16,996 NSCLC patients. The proportion of demographic and practice-process variables differed significantly between SCLC and NSCLC patients, including diagnostic imaging, adjuvant therapy and surgical procedures. Median LOS and TC were 20 days and US$6,015 for SCLC and 18 days and US$6,993 for NSCLC patients, respectively (p < 0.001 for each variable). Regression analysis revealed that pathological diagnosis was not correlated with TC. Physicians should acknowledge that pathological diagnosis dose not accounts for any variation in cost of LC patients but that should remain as an indicator of appropriate care like selection of chemotherapeutic agents.

Interleukin-18 promoter polymorphism is associated with lung cancer: A case-control study

Background. Interleukin-18 (IL-18) is a multifunctional cytokine that augments IFN-γ production and affects tumor immune response. In the present case-control study, we tested whether IL-18 promoter polymorphism contributes to lung cancer susceptibility in Iranian patients. Material and methods. The study groups were 73 patients with lung cancer, including 53 with squamous carcinoma (SC) and 20 with small cell lung carcinoma (SCLC), and 97 healthy regional aged-matched individuals. The frequency of IL-18 promoter single nucleotide polymorphisms (SNPs) at positions -656 (G/T), -607 (C/A), and -137 (G/C) was determined by polymerase chain reaction analyses. Results. There were significant differences in the IL-18 -607 allele and genotype distributions between the 73 lung cancer patients and controls. A significantly higher A allele frequency at position -607, which is associated with lower IL-18 production, was observed in lung cancer patients (48.6% vs. 35%; OR = 1.75; 95% CI 1.13–2.72). Also, patients with the -607 CA and the AA genotypes had a 2.60-fold (95% CI 1.26–5.36) and 3.15-fold (95% CI 1.16–8.55) increase in risk of lung cancer. Subdivision of the patients according to histological type revealed that SC was significantly associated with IL-18 -607 SNPs. Although the percentages of -607 alleles and genotypes in SCLC patients were similar to the results in SC patients, the differences compared to control individuals did not reach statistical significance. Analysis with Arlequin software identified eight haplotypes from three SNPs analyzed here. The distributions of IL-18 gene haplotypes were not significantly different between patients and controls after Bonferroni correction. Discussion. This is the first report to investigate the association between IL-18 polymorphism and lung cancer. Our results suggest that IL-18 polymorphism contributes to the lung cancer risk, particularly among SC patients. Further studies with larger numbers of patients are required to determine the possible association between IL-18 polymorphisms and different histological types of lung cancer.

Regulatory T cells in paraneoplastic neurological syndromes

Focusing on CD4 +CD25 + regulatory T lymphocytes (T reg), we studied the gene expression of T reg functional molecules in peripheral blood lymphocytes of patients with paraneoplastic neurological syndrome (PNS), including Lambert–Eaton myasthenic syndrome (LEMS) with small cell lung carcinoma (SCLC) and anti-Hu- or anti-Yo-antibody-positive PNS. T reg-rich subsets were sorted from the patients' peripheral blood mononuclear cells, and the mRNA expression levels of their functional genes were measured. The expression levels of FOXP3, TGF-β and CTLA4 mRNA in T reg-rich subsets of PNS patients were down-regulated compared with that of SCLC patients without PNS. These results suggest that T reg dysfunction plays a role in PNS development.

Correlation between FDG uptake and glucose transporter type 1 expression in neuroendocrine tumors of the lung

Neuroendocrine (NE) lung tumors are subdivided into the following types; typical (TC) and atypical carcinoids (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung carcinoma (SCLC). Moreover, the determinants of the FDG uptakes of NE lung tumors have not been elucidated. Thus, the aim of the present study was to investigate the relationships between FDG uptake and glucose transporter type 1 (Glut-1) expression in these NE tumors. Tissue-proven NE lung tumor patients (n=32; age, mean+/-S.D.=67.8+/-10 years; male:female=28:4) who had undergone F-18 FDG-PET before treatment were enrolled in this study. There were 1 TC, 3 AC, 5 LCNEC, and 23 SCLC patients. FDG uptakes were quantified using maximum standardized uptake values (maxSUV). Paraffin sections of tumor tissues were immunostained using anti-Glut-1 antibody (Neomarkers, 1:50). Levels of Glut-1 expression are presented as percentages of tumor cells positively immunostained (%Glut-1). Relations between FDG uptakes and Glut-1 expression were assessed using Pearson correlation analysis. The maxSUVs of all NE lung tumors ranged from 0.6 to 29.5 (mean+/-S.D.=7.7+/-5.4) and %Glut-1 expression ranged from 0 to 100% (18+/-24%). The maxSUVs of all NE lung tumors were found to be significantly correlated with %Glut-1 expression (r=0.6471, p=0.0001). By subgroup analysis, maxSUV was also found to be significantly correlated with %Glut-1 expression in SCLC (n=23, r=0.6189, p=0.0016). FDG uptake was found to be highly correlated with Glut-1 expression in NE lung tumors. This result suggests that Glut-1 plays a crucial role in determining FDG uptake in these tumors.

Isolation of &lt;i&gt; Mycobacterium malmoense&lt;/i&gt; in the island of Crete, Greece

Mycobacterium malmoense was isolated from a broncho-alveolar lavage sample of a 73-year-old cancer (small cell lung carcinoma) patient in Crete, representing the first reported case of this pathogen in Greece. The isolate was considered to be a colonizer and the patient did not receive any antimycobacterial treatment while he received chemotherapy to which he responded favourably. No signs of pulmonary infection were noted during the course of his disease. This case provides evidence of the ubiquitous nature of this mycobacterial species, believed until recently to favour cooler climates. We, therefore, propose that the index of suspicion for this pathogen should be raised particularly in patients with underlying immunodeficiency, cancer and chronic lung disease, irrespective of the geographic location.

Autoantibodies against M1 muscarinic acetylcholine receptor in myasthenic disorders

The Lambert-Eaton myasthenic syndrome (LEMS), often associated with small-cell lung carcinoma (SCLC), is a disorder of acetylcholine (ACh) release from motor nerve terminals. In most patients, it is caused by autoantibodies against the P/Q-type voltage-gated calcium channels (VGCC) that trigger ACh release. However, these antibodies are not detected in approximately 15% of clinically and electrophysiologically typical cases. The M1-type pre-synaptic muscarinic ACh receptor (M1 mAChR) modulates cholinergic neuromuscular transmission by linking to P/Q-type VGCC, and may partially compensate for the reduced calcium entry. Immunoblotting against solubilized human M1 mAChR, we detected autoantibodies in: (a) 14 of 20 (70%) anti-VGCC-positive LEMS patients; (b) all five anti-VGCC-negative LEMS patients, one of whose serum had previously passively transferred LEMS-type electrophysiological defects to mice; (c) all five LEMS patients with autonomic symptoms; (d) seven of 25 (28%) myasthenia gravis (MG) patients in whom increased ACh release partially compensates for post-synaptic defects; (e) none of 10 SCLC patients without LEMS. Although not proving primary pathogenicity of anti-M1 mAChR antibodies, the present results highlight their potential to affect synaptic compensatory mechanisms, more in LEMS than MG.

PD2-3-4: Prognostic and predictive value of apoptosis related factors Fas, FasL and survivin in non small cell lung carcinoma patients enrolled in the IALT Trial

PD2-3-4: Prognostic and predictive value of apoptosis related factors Fas, FasL and survivin in non small cell lung carcinoma patients enrolled in the IALT Trial

Tumor response rate as a function of number of prior therapies in phase II and III trials of topotecan (T) and eniluracil/5FU (EU)

2501 Background: Patients with 2 or more prior cytotoxic treatment regimens are often excluded from clinical trials because of expectations for greater tumor resistance to treatment. This retrospective cross-study analysis evaluated the relationship between tumor response rate (RR) and the number of prior therapies received. Methods: Phase II and III studies in the GSK database of topotecan (T, n=18) in patients with ovarian or small cell lung carcinoma (SCLC) and of eniluracil/5FU (EU, n=5) in patients with colorectal (CRC) or breast cancer were analyzed. This provided a total 4,220 patients consisting of 1,898 receiving T, 465 receiving various T comparator chemotherapy (paclitaxel, cyclophosphamide, doxorubicin or vincristine), 1,036 receiving EU, and 821 receiving EU comparator (5FU + leucovorin). Number of prior treatments was defined as the sum of all cytotoxic treatment regimens received. Best response was defined according to standard tumor response criteria with missing data or inevaluable assessments considered as progressive disease. Experimental (T or EU) vs. respective comparator arms were combined and an overall RR (CR + PR) in the analysis populations was assessed as a function of the number of prior treatments. Results: The overall RR for ovarian and SCLC patients receiving first-line treatment was 47%. RR declined to 17% for second-line therapy but was unchanged at 18% for those receiving third-line treatment. For all (CRC + breast cancer) patients in EU studies, there were no significant differences between first-, second-, or third-line treatment (RR=12%, 10% and 10% respectively). However, within the limited subset of breast cancer patients (n=145) in EU studies, RR was 54%, 14%, and 11% for first-, second-, and third-line treatments, respectively, suggesting no difference in RR once second-line treatment was administered. Conclusions: The presumption that a higher number of prior regimens always equates with greater treatment resistance may be incorrect. Patients in this analysis with 1 vs. 2 prior therapies exhibit equivalent RR to a broad range of cytotoxic therapies. Exclusion from clinical trials of patients with &gt;1 prior treatment regimen who otherwise meet study eligibility criteria may not be warranted. No significant financial relationships to disclose.

Prospective Assessment of XPD Lys751Gln and XRCC1 Arg399Gln Single Nucleotide Polymorphisms in Lung Cancer

XRCC1 and XPD play key roles in the repair of DNA lesions and adducts. Contrasting findings have been reported on the effect of polymorphisms of these genes on the response to platinum-based chemotherapy in advanced non-small-cell lung cancer (NSCLC). This study aimed to investigate the relationship between the XPD Lys751Gln and XRCC1 Arg399Gln genotypes and outcome in lung cancer patients. We genotyped 203 NSCLC and 45 small-cell lung carcinoma (SCLC) patients for the two polymorphisms. Most of the patients (81%) received a platinum-based chemotherapy. The patients' genotype frequencies did not significantly differ from controls and both groups were in Hardy-Weinberg equilibrium for the two polymorphisms. The XRCC1399 Gln/Gln variant genotype was associated with a higher median survival time (80 weeks versus 54.6 weeks for the Arg/Gln heterozygous and 55.6 weeks for the wild-type Arg/Arg genotype; P=0.09). At the multivariable analysis adjusted for histology, stage of the disease, performance status, age, and gender, the Gln/Gln genotype was associated with a better survival of borderline significance in the subgroup of patients treated with cisplatin (hazard ratio, 0.55; 95% CI, 0.30-1.00); this association became significant for those with grade 3-4 clinical toxicity (hazard ratio, 0.46; 95% CI, 0.22-0.98). No association between XPD Lys751Gln genotype and clinical outcome was found. This prospective investigation provides suggestive evidence of a favorable effect of the XRCC1399 Gln/Gln genotype on survival in platinum-treated NSCLC and, for the first time, in SCLC patients also. This contrasts with other authors who did not include non-platinum-treated patients, but it does fit the expectation for a suboptimal ability to remove DNA adducts.

Expression of promyelocytic leukaemia protein in lung carcinomas and clinical significance thereof

To investigate the expression of promyelocytic leukaemia (PML) protein in lung carcinomas and the clinical significance thereof. A tumor tissue microarray with lung samples from 148 patients with lung carcinoma and 5 patients with pulmonary benign tumor, and 7 patients with other benign diseases resected during operation. The cases with at least triplicate 0.6-mm cores per tumor or tissue were analyzed. Immunohistochemistry (SP method) was used to detect the expression of PML protein. The association between PML expression and post-operational survival was evaluated. Four cases of lung carcinoma were excluded because their available cores were less than 3. The remaining 144 lung carcinoma cases included 45 cases with squamous cell carcinoma, 62 with adenocarcinoma, 23 with small cell lung carcinoma (SCLC), 7 with large cell carcinoma, 5 with pleomorphic carcinoma, 1 with carcinoid, and 1 with adenosquamous carcinoma. Forty of the 144 cases were PML protein positive in the nucleus, 26 were PML protein positive in the cytoplasm, and 12 were PML protein positive in both the nucleus and cytoplasm. Among the 5 cases with benign lung tumors, two cases with pulmonary leiomyomas had strong expression of PML. Among the 7 normal pulmonary tissues, one case with bronchial mucosa had a moderate expression of PML on the nuclei in the basilar part, and the 6 cases with normal alveolar epithelium did not express PML. The rates of PML expression on cell nuclei were 31.4% and 8.7% respectively in the non-small cell lung carcinoma (NSCLC) and SCLC samples (chi(2) = 4.968, P = 0.026). Farish, but not strong, expression on cytoplasm was found in 39.1% cases of SCLC and in 14% cases of NSCLC (chi(2) = 6.609, P = 0.010). PML protein was found in 9 patients with SCLC, but absent in the other 14 cases. The 5-year cumulative survival rate of the PML positive SCLC patients was 50%, significantly higher than that of the PML-negative SCLC patients (23%, chi(2) = 3.931, P = 0.047). Lack of PML protein (RR = 0.127, 95% CI = [0.027, 0.592]) and senior pathologic TNM stage (RR = 3.148, 95% CI = [1.029, 9.631]) were two hazardous factors that influenced long-term survival of postoperative SCLC patients. As an important suppressor of tumor, PML may be a useful indicator to predict postoperative prognosis in patients with SCLC.

Frequent overexpression of aurora B kinase, a novel drug target, in non–small cell lung carcinoma patients

The serine/threonine protein kinase aurora B, a key regulator of mitosis, is emerging as a novel drug target for cancer treatment. Aurora B overexpression has been previously documented by immunohistochemistry in several types of human tumors. We assessed aurora B expression in a series of 160 non-small cell lung cancer (NSCLC) samples (60% stage I, 21% stage II, 11% stage III, and 8% stage IV). In addition, we determined the expression of survivin and p16, two molecules also involved in cell cycle control. Aurora B was expressed selectively in tumor cells compared with normal epithelium. Aurora B expression was significantly correlated with expression of survivin in the nucleus (P < 0.0001), but not with expression of p16 (P = 0.134). High aurora B expression levels were significantly associated with older age (P = 0.012), male sex (P = 0.013), squamous cell carcinoma histology (P = 0.001), poor tumor differentiation grade (P = 0.007), and lymph node invasion (P = 0.037), in the subset of radically resected patients in our series. In addition, aurora B expression predicted shorter survival for the patients with adenocarcinoma histology, at both univariate (P = 0.020) and multivariate (P = 0.012) analysis. Survivin expression levels were neither associated with patient clinicopathologic characteristics nor with survival. However, expression of survivin in the nucleus was preferentially detected in stage I and II than in stage III and IV (P = 0.007) in the overall series of NSCLC samples. Taken together, our results suggest that aurora B may represent a valid target in NSCLC.

AQUA and FISH analysis of HER‐2/neu expression and amplification in a small cell lung carcinoma tissue microarray

Most small cell lung carcinoma (SCLC) patients have metastatic disease at the time of diagnosis and are faced with poor prognosis and limited treatment options. Reports of HER-2/neu gene amplification and overexpression in this malignancy have raised the possibility of applying targeted immunotherapy with trastuzumab, the monoclonal antibody used to treat metastatic breast cancer. However, a review of the studies measuring HER-2/neu gene amplification and protein expression in SCLC reveals discordant results. The aim of the present study was to re-examine HER-2/neu expression in SCLC in relation to gene copy number using the new, highly sensitive, immunofluorescence automated quantitative analysis (AQUA) technology. Fluorescence in situ hybridization (FISH) was used to measure HER-2/neu gene copy number and amplification status and AQUA was used to measure protein expression in a series of 23 SCLC tumours on a tissue microarray. None of the 17 SCLC specimens assessable by FISH exhibited HER-2/neu gene amplification as defined by a HER-2/neu/chromosome 17 ratio = or > 2. Twelve of 17 (70.1%) SCLC samples were polysomic for chromosome 17 with corresponding increases in HER-2/neu gene copy numbers. Intermediate levels of protein expression corresponding to AQUA scores in the range of 4-24 were detected in all 23 specimens. High protein expression levels corresponding to AQUA scores up to 83, observed previously in association with gene amplification and poor prognosis in breast cancer cases, were not detected in the present study. No statistically significant association was observed between absolute chromosome 17 or HER-2/neu gene copy numbers and protein expression levels in tumour cells (P > 0.45). The lack of gene amplification and robust HER-2/neu protein expression in SCLC tumour cells in this series does not suggest a prominent role for the HER-2/neu gene in SCLC tumour progression and does not support the general applicability of targeted immunotherapy with trastuzumab to this malignancy.

Outcome of non small cell lung carcinoma patients receiving chemotherapy in Kartal State Hospital, Turkey

17142 Background: Lung cancer has been the leading cause of cancer deaths in men worldwide, and is the second most common cause of cancer deaths in women. Non-small cell histology comprises about 70–80% of every diagnosis of lung cancer. Despite advances in the detection and treatment, the long-term survival of patients with advanced non-small cell lung cancer (NSCLC) remains poor, with a 5-year survival of less than 5%. We conducted this trial to determine the influence of treatment with docetaxel given in combination with cisplatin on survival and time to progression, and to evaluate its tolerability in chemotherapy naive patients with metastatic NSCLC. Methods: Patients with histological or cytological confirmed stage IV NSCLC who met the following criteria were eligible for the study: suitable for first-line chemotherapy with no previous chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2, an objective measurable disease, an adequate bone marrow reserve, a normal hepatic and renal function. Cisplatin and docetaxel were delivered to the patients at one dose level through the courses repeated every 3 weeks for 4–6 cycles. Each patient received docetaxel at the doses of 75 mg/m2/day and cisplatin at the doses of 75 mg/m2/day both on day 1. Results: Fifty eligible patients with stage 4 NSCLC were enrolled into the study from June 2003 to September 2005. Median follow-up time was 6 months (1–21). Median age was 61.5 (39–75). Forty eight patients (96%) were male, and 2 patients (8%) were female. Histological type was squamous cell carcinoma in 21 patients (42%), adenocarcinoma in 11 patients (22%) and undifferentiated histologies in 18 patients (36%). The median overall survival time was 16 months (95%CI: 8–24). One-year survival rate was 56.3%. Overall response rate was 44% with 40% partial (PR), 4% complete response (CR). Twenty eight percent of patients had stable disease, and 28% of patients showed disease progression. The median time to progression was 4 months (95%CI: 2.4–5.5). Conclusion: Docetaxel/cisplatin demonstrated efficacy comparable to other platinum agent doublets. No significant financial relationships to disclose.

Relationship Between Cisplatin Administration and the Development of Ototoxicity

To determine the auditory toxicity associated with dose- and schedule- intensive cisplatin/gemcitabine chemotherapy in non-small-cell lung carcinoma patients. Patients were treated with gemcitabine followed by cisplatin according to an interpatient dose-escalation scheme. Patients were randomly assigned to receive treatment once a week for 6 weeks or once every 2 weeks for 4 weeks. The following cohorts of patients were treated with a reversed schedule once every 2 weeks, in which cisplatin was followed by gemcitabine. The dose-intensity of cisplatin was equal in both schedules. Audiometric evaluations were obtained for each ear at several frequencies. Mean hearing loss after cisplatin treatment was computed for each dose level at each tested frequency in each ear at baseline and subsequent follow-up audiometry. Pure tone averages (PTAs) were also calculated. The pharmacokinetics of cisplatin was determined to study the correlation among the maximum drug concentration, the area under the curve of unbound platinum, and the development of ototoxicity. A total of 328 audiograms were analyzed. At the higher frequencies, a more severe hearing impairment was recorded. Most patients showed a decrease in hearing thresholds at dosages above 60 mg/m2 cisplatin at the higher frequencies. PTAs at 1, 2, and 4 kHz show a mean hearing loss of 19 dB after cisplatin administration at dosages above 90 mg/m2. Threshold shifts at 8 and 12.5 kHz after cisplatin administration were experienced at dosages above 60 mg/m2. Hearing loss after cisplatin therapy occurs mainly at high frequencies and at cisplatin dosages more than 60 mg/m2. It is more pronounced when cisplatin is given once every 2 weeks.

A Review of the Treatment Strategies for Small Cell Lung Carcinoma Patients with a Poor Performance Status

Lung cancer is one of the commonest malignancies worldwide and the incidence continues to increase. Small cell lung cancer accounts for approximately 15% of all lung cancer cases although incidence of this subtype appears to be falling. It is an aggressive malignancy but responds well to chemotherapy and radiotherapy. The prognosis for untreated small cell lung cancer is less than 3 months. Small cell lung carcinoma is considered to be either limited-stage (LS) or extensive-stage (ES) on the basis of anatomical staging. In spite of high initial response rates in both limited- and extensive-stage patients, the relapse rate is high and overall median survival in LS and ES is 18 months and 9 months respectively. Standard chemotherapy regimens for small cell lung cancer patients with good performance status are platinum based, the commonest being cisplatin/etoposide. However, many patients present with a poor performance status (ECOG performance status of 2 or more and Karnofsky performance status of 60 or less) and these patients are at higher risk of toxicity from chemotherapy. Furthermore, the lung cancer population is largely elderly, 40% of patients being over 75 years. Whilst age is not an independent poor prognostic factor in itself, 90% of older patients have co-morbidity and may be at increased risk of toxicity due to functional organ impairment. Most clinical trials do not include patients with poor performance status and also the elderly (more than 70 years of age) tend to be under-represented, therefore not really reporting on the elderly. This review summarizes the evidence for treating small cell lung carcinoma patients with a poor performance in order to guide clinical decision-making. Treatment decisions should reflect not only the prognostic groups but take into account performance status and co-morbidities as well. It is important to differentiate between poor performance due to comorbidities and that due to the aggressive nature of small cell carcinoma. In the latter case a patient may have been previously fit and well and compromise on treatment based solely on poor performance may not be desirable, as the performance may improve dramatically if patient responds well to treatment. Keywords: Small cell lung carcinoma (SCLC), limited stage (LS), extensive stage (ES), chemotherapy, poor performance status (PS)

Sex-Specific Survival Advantage with Parathyroid Hormone–Related Protein in Non–Small Cell Lung Carcinoma Patients

Parathyroid hormone-related protein (PTHrP) is commonly expressed in non-small cell lung carcinomas (NSCLC). Expression of the protein could have implications for progression of the disease because it regulates cancer cell growth, apoptosis, and angiogenesis. However, its relationship with survival has not been evaluated in a large-scale investigation. PTHrP expression was assessed in paraffin-embedded tumor samples from 407 patients with NSCLC by immunohistochemistry. A pathologist unaware of the clinical history classified specimens as PTHrP positive or PTHrP negative. The log-rank test was used to compare survivals of PTHrP-positive and PTHrP-negative groups, and Cox regression was used to adjust for additional covariates. Median survival was 55 versus 22 months (P < 0.001) in female patients with and without tumor PTHrP, respectively. Male survival was 38 months independent of PTHrP status. Stage, histology, age, and smoking history were also associated with increased longevity. PTHrP remained a significant predictor of survival for female patients after controlling for stage, histology, and age. In this study, PTHrP expression was associated with a survival advantage in female patients. Additional investigations must be done to ascertain whether the result is reproducible and independent of potential confounding covariates. Sex-dependent effects of PTHrP in lung cancer would open new avenues of research into the role of sex in cancer progression.