Multi-Institutional Randomized Phase II Trial of Gefitinib for Previously Treated Patients With Advanced Non-Small-Cell Lung Cancer.

PURPOSE: To evaluate the efficacy and tolerability of two doses of gefitinib (Iressa [ZD1839]; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with pretreated advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: This was a randomized, double-blind, parallel-group, multicenter phase II trial. Two hundred ten patients with advanced NSCLC who were previously treated with one or two chemotherapy regimens (at least one containing platinum) were randomized to receive either 250-mg or 500-mg oral doses of gefitinib once daily. RESULTS: Efficacy was similar for the 250- and 500-mg/d groups. Objective tumor response rates were 18.4% (95% confidence interval [CI], 11.5 to 27.3) and 19.0% (95% CI, 12.1 to 27.9); among evaluable patients, symptom improvement rates were 40.3% (95% CI, 28.5 to 53.0) and 37.0% (95% CI, 26.0 to 49.1); median progression-free survival times were 2.7 and 2.8 months; and median overall survival times were 7.6 and 8.0 months, respectively. Symptom improvements were recorded for 69.2% (250 mg/d) and 85.7% (500 mg/d) of patients with a tumor response. Adverse events (AEs) at both dose levels were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent in the higher-dose group. Withdrawal due to drug-related AEs was 1.9% and 9.4% for patients receiving gefitinib 250 and 500 mg/d, respectively. CONCLUSION: Gefitinib showed clinically meaningful antitumor activity and provided symptom relief as second- and third-line treatment in these patients. At 250 mg/d, gefitinib had a favorable AE profile. Gefitinib 250 mg/d is an important, novel treatment option for patients with pretreated advanced NSCLC.

Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.

BACKGROUND: Previous, uncontrolled studies have suggested that first-line treatment with gefitinib would be efficacious in selected patients with non-small-cell lung cancer. METHODS: In this phase 3, open-label study, we randomly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib (250 mg per day) (609 patients) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute) plus paclitaxel (200 mg per square meter of body-surface area) (608 patients). The primary end point was progression-free survival. RESULTS: The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% with carboplatin-paclitaxel. The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority, as compared with carboplatin-paclitaxel, with respect to progression-free survival in the intention-to-treat population (hazard ratio for progression or death, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). In the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene (EGFR) mutation, progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin-paclitaxel (hazard ratio for progression or death, 0.48; 95% CI, 0.36 to 0.64; P<0.001), whereas in the subgroup of 176 patients who were negative for the mutation, progression-free survival was significantly longer among those who received carboplatin-paclitaxel (hazard ratio for progression or death with gefitinib, 2.85; 95% CI, 2.05 to 3.98; P<0.001). The most common adverse events were rash or acne (in 66.2% of patients) and diarrhea (46.6%) in the gefitinib group and neurotoxic effects (69.9%), neutropenia (67.1%), and alopecia (58.4%) in the carboplatin-paclitaxel group. CONCLUSIONS: Gefitinib is superior to carboplatin-paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib. (ClinicalTrials.gov number, NCT00322452.)

Patients' perception of the usefulness of a question prompt sheet for advanced cancer patients when deciding the initial treatment: a randomized, controlled trial.

OBJECTIVE: The objective of this study was to evaluate the patients' perception of the usefulness of a question prompt sheet (QPS) in facilitating the involvement of advanced cancer patients during consultation. METHODS: Advanced cancer patients attending their first consultation after diagnosis were randomly assigned to the intervention group (received QPS and a hospital introduction sheet (HIS)) or the control group (received HIS only). Analysis was conducted on an intention-to-treat basis. The primary outcome measure was patient rating of the usefulness of the material(s) (numerical rating scale of 0-10). RESULTS: Sixty-three advanced cancer patients (72.4% response rate) were enrolled and analyzed. Nearly three-quarters of patients in both groups read the material(s) before consultation. The rated usefulness of the material(s) for asking questions of physicians was significantly higher in the intervention group than in controls (4.4 ± 3.6 and 2.7 ± 2.8, respectively; p = 0.033). The mean score of the usefulness of the material(s) for understanding the treatment plan tended to be higher in the intervention group than in the controls (4.9 ± 3.6 and 3.3 ± 2.8; p = 0.051). The mean score of willingness to use the material(s) in the future was significantly higher in the intervention group than in the controls (5.3 ± 3.8 and 2.8 ± 2.8; p = 0.006). There were no significant differences between the groups in the average total number of questions asked by patients (median, 1.0; interquartile range in both groups, 2.0). CONCLUSIONS: QPS provided before oncology consultation may be useful for advanced cancer patients, on the other hand, it did not directly promote patient confidence to ask questions.

Phase I study of topotecan and cisplatin in patients with small cell lung cancer.

OBJECTIVE: A single-agent topotecan has an indication for the treatment of small cell lung cancer in Japan. Previous studies demonstrated that topotecan combined with a platinum agent could provide additional antitumor efficacy. This study was to find the recommended dose of topotecan in combination with cisplatin and preferred administration sequence in untreated patients with extensive disease small cell lung cancer for Phase II study. METHODS: Patients received topotecan as a 30 min infusion for 5 days in escalating doses (starting at 0.5 mg/m(2)/day), and cisplatin at a fixed dose of 60 mg/m(2), 3 weeks cycle. This study employed the following stages: cisplatin was given before topotecan on day 1 to previously treated patients (Stage 1). After the maximum-tolerated dose level was achieved, the same schedule was applied for untreated patients (Stage 2). Subsequently, cisplatin was given after topotecan on day 5 to untreated patients (Stage 3). The recommended doses of cisplatin on day 1 and 5 schedules were estimated by considering results obtained from Stages 2 and 3, respectively. RESULTS: A total of 34 patients were enrolled. The maximum-tolerated doses in Stages 1-3 were estimated at 0.65, 0.65, and 1.4 mg/m(2), respectively. The recommended doses of cisplatin on day 1 and 5 schedules in untreated patients were determined at 0.65 and 1.0 mg/m(2), respectively. The major toxicity in this combination was hematological events. CONCLUSIONS: For treatment-naive patients, the combined use of 0.65/60 mg/m(2) topotecan/cisplatin with cisplatin on day 1 schedule or 1.0/60 mg/m(2) topotecan/cisplatin with cisplatin on day 5 schedule is recommended for Phase II study.

Serum brain-derived neurotrophic factor and antidepressant-naive major depression after lung cancer diagnosis.

Previous studies have reported the existence of an association between brain-derived neurotrophic factor and major depression. However, the possible role of brain-derived neurotrophic factor in the pathophysiology of major depression after cancer diagnosis has not yet been investigated. Subjects were collected using the Lung Cancer Database project. Using the cut-off scores on the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D), 81 subjects with depression (HADS-D > 10) and 81 subjects without depression (HADS-D < 5) were selected. The two groups were matched for age, sex, clinical stage and performance status. The serum brain-derived neurotrophic factor levels were measured using an enzyme-linked immunosorbent assay method. The serum brain-derived neurotrophic factor levels were not statistically different between the subjects in the depression group [29.1 (13.6) ng/ml; mean (SD)] and the non-depression group [31.4 (10.6) ng/ml] (P = 0.22). In a stratified analysis by gender, however, the mean serum brain-derived neurotrophic factor level in the depression group tended to be lower than that in the non-depression group among women (n = 24 pairs, P = 0.06). Major depression after cancer diagnosis is not associated with serum brain-derived neurotrophic factor levels.

Individuals susceptible to lung adenocarcinoma defined by combined HLA-DQA1 and TERT genotypes.

Adenocarcinoma (ADC) is the commonest histological type of lung cancer, and its weak association with smoking indicates the necessity to identify high-risk individuals for targeted screening and/or prevention. By a genome-wide association study (GWAS), we identified an association of polymorphisms in the 6p21.31 locus containing four human leukocyte antigen (HLA) class II genes with lung ADC risk. DQA1*03 of the HLA-DQA1 gene was defined as a risk allele with odds ratio (OR) of 1.36 [95% confidence interval (CI) = 1.21-1.54, P = 5.3 x 10(-7)] by analysis of 1656 ADC cases and 1173 controls. DQA1*03 and the minor allele for a polymorphism, rs2736100, in TERT, another lung cancer susceptibility locus identified in recent GWASs on Europeans and Americans, were indicated to independently contribute to ADC risk with per allele OR of 1.43 (95% CI = 1.31-1.56, P = 7.8 x 10(-16)). Individuals homozygous both for the DQA1*03 and minor TERT alleles were defined as high-risk individuals with an OR of 4.76 (95% CI = 2.53-9.47, P = 4.2 x 10(-7)). The present results indicated that individuals susceptible to lung ADC can be defined by combined genotypes of HLA-DQA1 and TERT.

Synergistic antitumor activity of the SN-38-incorporating polymeric micelles NK012 with S-1 in a mouse model of non-small cell lung cancer.

The combination therapy of CPT-11, a prodrug of SN-38, with S-1, a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, shows a high clinical response rate in non-small cell lung cancer (NSCLC). However, this combination causes severe toxicities such as diarrhea. Here, we investigated the advantages of treatment with the SN-38-incorporating polymeric micelles NK012 over CPT-11 in combination with S-1 in mice bearing a NSCLC xenograft in terms of antitumor activity and toxic effects, particularly intestinal toxicity. In vitro cytotoxic effects were examined in human NSCLC cell lines (A549, PC-9, PC-14, EBC-1 and H520). In vivo antitumor effects were evaluated in PC-14- and EBC-1-bearing mice after NK012 or CPT-11 administration on Days 0 and 7 and S-1 administration on Days 0-13. Pathological changes in the small intestine were also investigated. The in vitro growth inhibitory effects of NK012 were 56.8- to 622-fold more potent than those of CPT-11. NK012/S-1 treatment showed significantly higher antitumor activity both in PC-14-bearing (p = 0.0007) and EBC-1-bearing mice (p < 0.0001) than CPT-11/S-1 treatment. The deformity and decrease in the density of intestinal villi were more severe in CPT-11/S-1-treated mice than in NK012/S-1-treated mice. NK012/S-1 combination is a promising candidate regimen against NSCLC without inducing toxicities such as severe diarrhea and therefore warrants clinical evaluation.

Randomized phase 2 dose-finding study of weekly administration of darbepoetin alpha in anemic patients with lung or ovarian cancer receiving multicycle platinum-containing chemotherapy.

OBJECTIVE: This is the first clinical trial for Japanese to evaluate the dose-response and determine the clinically effective dose of darbepoetin alpha by weekly subcutaneously administration in anemic patients with lung cancer or ovarian cancer receiving chemotherapy. METHODS: Eligible patients were required to have anemia (hemoglobin level of 15.0 g/dl (for men) or 14.0 g/dl (for women), and reinstated at 50% of the previous weekly dose when the hemoglobin level decreased to

Contribution of nicotine acetylcholine receptor polymorphisms to lung cancer risk in a smoking-independent manner in the Japanese.

Recent genome wide association (GWA) studies on European and American populations revealed association with lung cancer risk of single-nucleotide polymorphisms (SNPs) in the locus containing two nicotine acetylcholine receptor (CHRNA) genes, whose involvement in tobacco addiction had been indicated. Association with lung cancer risk in smokers was consistently, but that in non-smokers as well as that with smoking behavior was inconsistently, observed in these studies. To obtain further information on the significance of CHRNA SNPs in lung cancer risk, association of seven SNPs in this locus with lung cancer risk as well as smoking status was examined in a Japanese population by a case-control study of 1250 cases (562 adenocarcinoma, 391 squamous cell carcinoma and 297 small cell carcinoma) and 936 controls. The frequency of the haplotype consisting of minor alleles for three SNPs, rs8034190, rs16969968 and rs1051730, which had been defined as a susceptible haplotype in the GWA studies, was much lower in the Japanese population (0.013) than in European and American populations (0.3-0.4). However, this haplotype was significantly associated with lung cancer risk also in Japanese (odds ratio = 2.3, 95% confidence interval = 1.5-3.7, P = 0.00028, respectively). The association was observed both in smokers and non-smokers and in all histological types of lung cancers. Individuals with this haplotype showed higher smoking doses than those without; however, the difference was not statistically significant. These results strongly indicate that CHRNA SNPs confer lung cancer susceptibility in a small subset of Japanese in a smoking-independent manner.

Low podoplanin expression of tumor cells predicts poor prognosis in pathological stage IB squamous cell carcinoma of the lung, tissue microarray analysis of 136 patients using 24 antibodies.

The aim of this study was to identify clinicopathological and biological prognostic markers for patients who had undergone complete resection of pathological stage IB squamous cell carcinoma (SqCC) of the lung. A total of 136 consecutive stage IB SqCC patients fulfilled eligibility criteria, and their clinicopathological factors were evaluated. Tissue microarrays were also constracted, and immunohistochemical staining with 24 antibodies was performed. Correlations between clinicopathological factors, antibody immunohistochemical reactions, the patients' overall survival (OS) and relapse-free survival (RFS) were evaluated. The univariate analysis showed that 70-year-old and over elderly group had a shorter OS time and RFS time than the younger group (p=0.0086 and p=0.0091, respectively). The univariate analysis for immunohistochemical staining showed that the podoplanin-negative group had a shorter OS time and RFS time than the podoplanin-positive group (p=0.0106 and p=0.0308, respectively). Multivariate analysis revealed a significant correlation between both the 70-year-old and over elderly group and the podoplanin-negative group and poor outcome (OS, p=0.007 and p=0.008, respectively; RFS, p=0.008 and p=0.024, respectively). The results showed that patient age and a novel biological prognostic marker, podoplanin, are useful for predicting a poor outcome of patients after complete resection of stage IB SqCC of the lung.

Immunohistochemical expression of BCRP and ERCC1 in biopsy specimen predicts survival in advanced non-small-cell lung cancer treated with cisplatin-based chemotherapy.

PURPOSE: The aim of this study was to determine the prognostic value of expression of ATP binding cassette (ABC) transporter proteins and DNA repair gene proteins by immunohistochemically staining tumor biopsy specimens from patients with advanced non-small-cell lung cancer (NSCLC) being treated with platinum-based chemotherapy. EXPERIMENTAL DESIGN: Expression of ABC transporter proteins, including BCRP (breast cancer resistance protein) and MRP2 (multidrug resistance proteins 2), and the DNA-repair-related proteins, ERCC1 (excision repair cross-complementation group 1) and BRCA1 (breast cancer type 1 susceptibility protein) was assessed immunohistochemically in 156 tumor samples from untreated stage IV NSCLC patients. All of the patients had received platinum-based chemotherapy. Response to chemotherapy, progression-free survival (PFS), and overall survival were compared in relation to expression of each of the proteins and to clinicopathological factors. RESULTS: High ERCC1 expression was associated with short survival (237 days vs. 453 days, log-rank P = 0.03), but not with response to chemotherapy or PFS. And high BCRP expression was associated with short survival (214 days vs. 412 days, log-rank P = 0.02) but not with response to chemotherapy or PFS. Multivariate analysis confirmed that negativity for the expression of BCRP tends to be an independent variable related to overall survival (P = 0.06). CONCLUSIONS: This study examined ERCC1 and BCRP expression in biopsy specimens as candidates for predictors of the survival of patients with advanced NSCLC treated with platinum-based chemotherapy.

Psychosocial factors and survival after diagnosis of inoperable non-small cell lung cancer.

OBJECTIVE: Although several previous studies have investigated the association between psychosocial factors and the survival of lung cancer patients, most previous studies were flawed by severe methodological limitations. The purpose of the present study was to use a rigorous study design to investigate the association between relevant psychosocial factors and survival after a diagnosis of inoperable non-small cell lung cancer (NSCLC). METHODS: The subjects were 122 consecutive newly diagnosed patients with inoperable NSCLC. Patients coping with cancer, psychological distress, clinical depression, and social support were evaluated after diagnosis but before treatment and 2 months later. After a 2-year follow-up period, 108 patients had died. The survival data were censored for the remaining 14 patients. The influence of psychosocial factors after diagnosis but before treatment on survival time was analyzed using a Cox regression, with adjustments for well-established (definite and/or possible) prognostic factors. The stability of the investigated psychosocial factors was also examined. RESULTS: None of the examined psychosocial factors significantly predicted survival time among the patients with inoperable NSCLC. Among the biomedical factors that were examined, advanced clinical stage, a high serum lactate dehydrogenase level, and not receiving chemotherapy were independently associated with shorter survival periods. Most of the psychosocial factors exhibited a moderate to high stability. CONCLUSIONS: We found little convincing evidence that psychosocial factors after cancer diagnosis had a clinically relevant effect on the survival of inoperable patients with NSCLC.

Efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B12 in previously treated patients with non-small cell lung cancer.

PURPOSE: The objective of this study was to evaluate the efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B(12) in pretreated Japanese patients with advanced non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Patients with an Eastern Cooperative Oncology Group performance status 0 to 2, stage III or IV, and who received previously one or two chemotherapy regimens were randomized to receive 500 mg/m(2) pemetrexed (P500) or 1,000 mg/m(2) pemetrexed (P1000) on day 1 every 3 weeks. The primary endpoint was response rate. RESULTS: Of the 216 patients evaluable for efficacy (108 in each arm), response rates were 18.5% (90% confidence interval, 12.6-25.8%) and 14.8% (90% confidence interval, 9.5-21.6%), median survival times were 16.0 and 12.6 months, 1-year survival rates were 59.2% and 53.7%, and median progression-free survival were 3.0 and 2.5 months for the P500 and P1000, respectively. Cox multiple regression analysis indicated that pemetrexed dose was not a significant prognostic factor. Drug-related toxicity was generally tolerable for both doses; however, the safety profile of P500 showed generally milder toxicity. Main adverse drug reactions of severity grade 3 or 4 were neutrophil count decreased (20.2%) and alanine aminotransferase (glutamine pyruvic transaminase) increased (15.8%) in P500 and neutrophil count decreased (24.3%), WBC count decreased (20.7%), and lymphocyte count decreased (18.0%) in P1000. One drug-related death from interstitial lung disease occurred in the P500. CONCLUSION: P500 and P1000 are similarly active with promising efficacy and acceptable safety outcomes in pretreated patients with NSCLC. These results support the use of P500 as a second- and third-line treatment of NSCLC.

A phase I study of gemcitabine and carboplatin in patients with advanced non-small cell lung cancer and a performance status of 2.

OBJECTIVE: The aim of this study was to determine the maximum-tolerated dose (MTD) and the recommended dose of combination chemotherapy with gemcitabine (GEM) and carboplatin (CBDCA) in non-small cell lung cancer (NSCLC) patients with a performance status (PS) of 2. METHODS: Chemotherapy-naïve NSCLC patients with PS 2 were enrolled. Chemotherapy consisted of an escalated dose of GEM on days 1 and 8 and CBDCA on day 1 every 3 weeks. Patients were scheduled to receive GEM (mg/m(2))/CBDCA (area under the curve: AUC) at four dose levels: 800/4 (level 1), 1000/4 (level 2), 1000/4.5 (level 3) and 1000/5 (level 4), respectively. RESULTS: Between February 2004 and August 2006, 13 patients were enrolled in this study. Dose-limiting toxicities (DLTs) were thrombocytopenia, febrile neutropenia and hyponatremia. DLTs were observed in two of six patients at dose level 1 and in three of six patients at dose level 2. Dose level 2 was thus determined to be the MTD. Among 12 evaluable patients, 7 patients had stable diseases and 5 patients had progressive diseases, and the median survival time was 3.8 months. CONCLUSIONS: The MTD and the recommended dose for Phase II studies of this regimen were determined to be GEM 1000 mg/m(2) and CBDCA AUC of 4. Additional objective measures are needed to evaluate patients' risk and benefit in future clinical trials for PS 2 patients.

Interstitial lung disease in Japanese patients with lung cancer: a cohort and nested case-control study.

RATIONALE: Interstitial lung disease (ILD) occurs in Japanese patients with non-small cell lung cancer (NSCLC) receiving gefitinib. OBJECTIVES: To elucidate risk factors for ILD in Japanese patients with NSCLC during treatment with gefitinib or chemotherapy. METHODS: In a prospective epidemiologic cohort, 3,166 Japanese patients with advanced/recurrent NSCLC were followed for 12 weeks on 250 mg gefitinib (n = 1,872 treatment periods) or chemotherapy (n = 2,551). Patients who developed acute ILD (n = 122) and randomly selected control subjects (n = 574) entered a case-control study. Adjusted incidence rate ratios were estimated from case-control data by odds ratios (ORs) with 95% confidence intervals (CIs) using logistic regression. Crude (observed) incidence rates and risks were calculated from cohort data. MEASUREMENTS AND MAIN RESULTS: The observed (unadjusted) incidence rate over 12 weeks was 2.8 (95% CI, 2.3-3.3) per 1,000 person-weeks, 4.5 (3.5-5.4) for gefitinib versus 1.7 (1.2-2.2) for chemotherapy; the corresponding observed naive cumulative incidence rates at the end of 12-week follow-up were 4.0% (3.0-5.1%) and 2.1% (1.5-2.9%), respectively. Adjusted for imbalances in risk factors between treatments, the overall OR for gefitinib versus chemotherapy was 3.2 (1.9-5.4), elevated chiefly during the first 4 weeks (3.8 [1.9-7.7]). Other ILD risk factors in both groups included the following: older age, poor World Health Organization performance status, smoking, recent NSCLC diagnosis, reduced normal lung on computed tomography scan, preexisting chronic ILD, concurrent cardiac disease. ILD-related deaths in patients with ILD were 31.6% (gefitinib) versus 27.9% (chemotherapy); adjusted OR, 1.05 (95% CI, 0.3-3.2). CONCLUSIONS: ILD was relatively common in these Japanese patients with NSCLC during therapy with gefitinib or chemotherapy, being higher in the older, smoking patient with preexisting ILD or poor performance status. The risk of developing ILD was higher with gefitinib than chemotherapy, mainly in the first 4 weeks.

Vinorelbine plus gemcitabine followed by docetaxel versus carboplatin plus paclitaxel in patients with advanced non-small-cell lung cancer: a randomised, open-label, phase III study.

BACKGROUND: Platinum-containing two-drug combinations improve survival and cancer-related symptoms in patients with advanced non-small-cell lung cancer (NSCLC). However, survival benefit is modest and platinum-containing regimens cause substantial toxic effects. We did a prospective randomised open-label phase III study to compare an experimental platinum-free, triplet, sequential regimen of vinorelbine plus gemcitabine followed by docetaxel with the standard platinum-containing, doublet regimen paclitaxel plus carboplatin in patients with advanced NSCLC. METHODS: Between March, 2001, and April, 2005, patients with stage IIIB (positive pleural effusion) or IV NSCLC, performance status 0 to 1, and adequate organ function, were randomly assigned to experimental treatment or to standard treatment. Randomisation was done centrally by use of a dynamic balancing algorithm. Patients were stratified by weight loss, lactate dehydrogenase concentration, and disease stage. Patients in the experimental group were scheduled to receive intravenous vinorelbine (25 mg/m(2)) plus gemcitabine (1000 mg/m(2)) on days 1 and 8 every 21 days for three cycles, followed by intravenous docetaxel (60 mg/m(2)) on day 1 every 21 days for three cycles. Patients in the standard group were scheduled to receive intravenous paclitaxel (225 mg/m(2)) plus carboplatin (area under the curve=6) for 3 h on day 1, every 21 days for six cycles. The primary endpoint was overall survival, and secondary endpoints were progression-free survival, response, and toxic effects. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00079287. FINDINGS: Of the 401 patients enrolled and randomised in the trial, five patients in the experimental group and three in the standard group were ineligible for analysis; thus 196 patients in the experimental group and 197 in the standard group were included in analyses. Patient characteristics were well-balanced between the two groups with regard to major prognostic factors. Median overall survival was 13.6 months (range 12.0-16.4) in the experimental group versus 14.1 months (11.9-17.5) in the standard group (p=0.97). 49 of 196 patients (25%) in the experimental group had a partial response compared with 73 of 197 patients (37%) in the standard group (p=0.012). There were no complete responses. Median progression-free survival was 5.5 months (95% CI 4.9-6.3) in the experimental group compared with 5.8 months (5.3-6.1) in the standard group (p=0.74). The incidence of grade 3 and 4 neutropenia, neuropathy, arthralgia, and myalgia was lower in the experimental group than in the standard group, although the incidence of pulmonary toxic effects was higher. INTERPRETATION: Although platinum-containing regimens remain the standard treatment for advanced NSCLC, non-platinum regimens could provide equivalent efficacy with a different toxicity profile.

Mutational status of EGFR and KIT in thymoma and thymic carcinoma.

This study was conducted to evaluate the prevalence of EGFR and KIT mutations in thymomas and thymic carcinomas as a means of exploring the potential for molecularly targeted therapy with tyrosine kinase inhibitors. Genomic DNA was isolated from 41 paraffin-embedded tumor samples obtained from 24 thymomas and 17 thymic carcinomas. EGFR exons 18, 19, and 21, and KIT exons 9, 11, 13, and 17, were analyzed for mutations by PCR and direct sequencing. Protein expression of EGFR and KIT was evaluated immunohistochemically. EGFR mutations were detected in 2 of 20 thymomas, but not in any of the thymic carcinomas. All of the EGFR mutations detected were missense mutations (L858R and G863D) in exon 21. EGFR protein was expressed in 71% of the thymomas and 53% of the thymic carcinomas. The mutational analysis of KIT revealed only a missense mutation (L576P) in exon 11 of one thymic carcinoma. KIT protein was expressed in 88% of the thymic carcinomas and 0% of the thymomas. The results of this study indicate that EGFR and KIT mutations in thymomas and thymic carcinomas are rare, but that many of the tumors express EGFR or KIT protein.

Marital status and non-small cell lung cancer survival: the Lung Cancer Database Project in Japan.

OBJECTIVE: Previous studies have suggested that marital status is associated with survival from lung cancer; however, its association is not conclusive. The association between marital status and survival in Japanese patients with non-small cell lung cancer (NSCLC) was prospectively investigated. METHODS: Between July 1999 and July 2004, a total of 1230 NSCLC patients were enrolled. The baseline survey consisted of the collection of clinical information and various demographic data, including marital status. A Cox regression model was used to estimate the hazards ratio (HR) of all-cause mortality adjustments for age, BMI, education level, performance status, histology type, clinical stage, smoking status, choice of definitive treatment, and depression. RESULTS: The multivariable adjusted HR of male widowed patients versus male married patients was 1.7 (95% confidence interval=1.2-2.5, p=0.005). However, no significant increased risk of death in female widowed patients compared with female married patients was observed (HR=0.7, 95% confidence interval=0.5-1.1, p=0.15). With regard to separated/divorced and single patients no significant increased risk of death in male and/or female compared with married patients was observed. CONCLUSIONS: The present data suggest that male widowed patients with NSCLC have a higher mortality rate than male married patients with NSCLC, after controlling for various factors.

Negative psychological aspects and survival in lung cancer patients.

We conducted a prospective cohort study in Japan to investigate associations between negative psychological aspects and cancer survival. Between July 1999 and July 2004, a total of 1178 lung cancer patients were enrolled. The questionnaire asked about socioeconomic variables, smoking status, clinical symptoms, and psychological aspects after diagnosis. Negative psychological aspects were assessed for the subscales of helplessness/hopelessness and depression. Clinical stage, performance status (PS), and histologic type were obtained from medical charts. The subjects were followed up until December 2004, and 686 had died. A Cox regression model was used to estimate the hazards ratio (HR) of all-cause mortality. After adjustment for socioeconomic variables and smoking status in addition to sex, age, and histologic type, both helplessness/hopelessness and depression subscales showed significant linear positive associations with the risk of mortality (p for trend<0.001 for both). However, after adjustment for clinical state variables in addition to sex, age, and histologic type, these significant linear positive associations were no longer observed (p for trend=0.41 and 0.26, respectively). Our data supported the hypothesis that the association between helplessness/hopelessness and depression and the risk of mortality among lung cancer patients was largely confounded by clinical state variables including clinical stage, PS, and clinical symptoms.

Pleomorphic carcinoma of the lung expressing podoplanin and calretinin.

Pleomorphic carcinoma (PC) of the lung is classified as a subtype of sarcomatoid carcinoma of the lung, and peripheral PC is sometimes difficult to differentiate from the sarcomatoid component of mesothelioma. An 80-year-old man was referred to National Cancer Center Hospital East because a chest X-ray showed an abnormal shadow. CT scans of the chest indicated two solid masses located in the right lower lobe, and CT-guided needle biopsy yielded spindle-shaped tumor cells that were immunoreactive for both podoplanin and calretinin. Mesothelioma could not be ruled out, and the tumors were surgically resected to facilitate definitive pathological diagnosis. Both tumors were composed of undifferentiated carcinoma, bronchioloalveolar carcinoma and spindle cell carcinoma, and spindle cell component was immunoreactive for podoplanin and calretinin. Ten other tumors diagnosed as peripheral PC were also tested for podoplanin and calretinin expression. The sarcomatoid component in four of the 11 cases (36%) was immunoreactive with podoplanin, and it was calretinin positive in nine of the 11 cases (82%). When making the differential diagnosis between PC and the sarcomatoid component of mesothelioma, care is required in diagnosing biopsy specimens of peripheral lung spindle-cell tumors that are positive for both podoplanin and calretinin.