Aspirin and non-aspirin non-steroidal anti-inflammatory drug use and risk of lung cancer.

There is evidence that aspirin and non-aspirin non-steroidal anti-inflammatory drug (NSAID) have anti-carcinogenic properties, but their effect on lung cancer, in particular in never-smokers, is unclear. Information on past or current use of anti-inflammatory medication was obtained in 398 Chinese female primary lung cancer cases and 814 controls in a hospital-based study in Singapore. 65% of cases and 88% of controls were never-smokers. Controls were excluded if they had been admitted for conditions associated with aspirin or NSAID use (n=174). Regular aspirin use (twice a week or more, for a month or more) was associated with a reduced risk of lung cancer (adjusted odds ratio [OR] 0.50, 95% confidence intervals [95%CI] 0.31-0.81 in non-smokers; OR 0.38, 95%CI 0.16-0.93 in smokers). Regular use of non-aspirin NSAID, paracetamol, steroid creams and steroid pills was uncommon and no association with lung cancer was detected. Our results suggest that aspirin consumption may reduce lung cancer risk in Asian women and are consistent with current understanding of the role of cyclooxygenase in lung carcinogenesis.

Female reproductive factors, gene polymorphisms in the estrogen metabolism pathway, and risk of lung cancer in Chinese women.

The authors examined relations between reproductive factors and 5 estrogen pathway gene polymorphisms (CYP17 rs743572, CYP19A1 rs10046, ERß rs1256049, ERß rs4986938, and COMT rs4680) among 702 Singapore Chinese female lung cancer cases and 1,578 hospital controls, of whom 433 cases (61.7%) and 1,375 controls (87.1%) were never smokers. Parity (per child, odds ratio (OR) = 0.92, 95% confidence interval (CI): 0.87, 0.97) and menstrual cycle length (for ≥30 days vs. <30 days, OR = 0.50, 95% CI: 0.32, 0.80) were inversely associated with lung cancer in never smokers, while age at first birth (for ages 21-25, 26-30, and ≥31 years vs. ≤20 years, ORs were 1.54, 2.17, and 1.30, respectively), age at menopause (for ages 49-51 and ≥52 years vs. ≤48 years, ORs were 1.37 and 1.59; P(trend) = 0.003), and reproductive period (for 31-33, 34-36, 37-39, and ≥40 years vs. ≤30 years, ORs were 1.06, 1.25, 1.45, and 1.47; P(trend) = 0.026) were positively associated. Among smokers, parity was inversely associated with lung cancer, but there was no association with other reproductive factors. The COMT rs4680 A allele was positively associated with lung cancer in never smokers (for G/A or A/A vs. G/G, OR = 1.46, 95% CI: 1.12, 1.90) but not in ever smokers. No associations were seen with other polymorphisms. These results support a risk-enhancing role of estrogens in lung carcinogenesis among never smokers.

Meat consumption and risk of lung cancer among never-smoking women.

The relationship between diet and lung cancer, apart from the protective effect of fruit and vegetables, is poorly understood. Reports on the role of dietary components such as meat are inconsistent, and few studies include sufficient numbers of nonsmokers. We examined the relationship between meat consumption and never-smoking lung cancer in a hospital-based case-control study of Singapore Chinese women, a population with low smoking prevalence. Three hundred and ninety-nine cases and 815 controls were recruited, of whom 258 cases and 712 controls were never smokers. A standardized questionnaire (which included a food frequency questionnaire module) was administered by trained interviewers. Among these never smokers, fruit and vegetable intake were inversely associated with lung cancer risk. Seventy-two percent of meat consumed was white meat (chicken or fish). Meat consumption overall was inversely associated with lung cancer [adjusted odds ratio (OR), 0.88, 0.59 for second, third tertiles, P (trend) = .012]. An inverse relationship between fish consumption and lung cancer (adjusted OR, 0.81, 0.47 for 2nd, 3rd tertiles, P (trend) < .001) was observed. No association was seen between consumption of processed meats and lung cancer, nor between dietary heterocyclic amines and lung cancer. Our data suggest that fish consumption may be protective against lung cancer in never smokers.

A Phase II study of pazopanib in Asian patients with recurrent/metastatic nasopharyngeal carcinoma.

PURPOSE: Nasopharyngeal carcinoma is endemic in Asia and angiogenesis is important for growth and progression. We hypothesized that pazopanib would have antiangiogenic activity in nasopharyngeal carcinoma. EXPERIMENTAL DESIGN: A single arm monotherapy study of pazopanib in patients with WHO type II/III nasopharyngeal carcinoma who had metastatic/recurrent disease and failed at least one line of chemotherapy. A Simon's optimal 2-stage design was used. Patients with Eastern Cooperative Oncology Group (ECOG) 0-2 and adequate organ function were treated with pazopanib 800 mg daily on a 21-day cycle. The primary endpoint was clinical benefit rate (CR/PR/SD) achieved after 12 weeks of treatment. Secondary endpoints included toxicity and progression-free survival. Exploratory studies of dynamic-contrast enhanced computed tomography (DCE-CT) paired with pharmacokinetics (PK) of pazopanib was done. RESULTS: Thirty-three patients were accrued. Patients were ECOG 0-1 with median age of 50 years (range 36-68). There were 2 (6.1%) partial responses, 16 (48.5%) stable disease, 11 (33.3%) progressive disease, 4 (12.1%) were not evaluable for response. The clinical benefit rate was 54.5% (95% CI: 38.0-70.2). Ten patients (30.3%) received more than 6 cycles (4 months) of treatment and 7 (21.2%) had PR/SD that lasted at least 6 months. One patient each died from epistaxis and myocardial infarction. Common grade 3/4 toxicities included fatigue (15.2%), hand-foot syndrome (15.2%), anorexia (9.1%), diarrhea (6.1%), and vomiting (6.1%). Serial DCE-CT scans show significant reductions in tumor blood flow, permeability surface area product, and fractional intravascular blood volume. CONCLUSION: Pazopanib showed encouraging activity in heavily pretreated nasopharyngeal carcinoma with an acceptable toxicity profile.

Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS).

PURPOSE: The results of the Iressa Pan-Asia Study (IPASS), which compared gefitinib and carboplatin/paclitaxel in previously untreated never-smokers and light ex-smokers with advanced pulmonary adenocarcinoma were published previously. This report presents overall survival (OS) and efficacy according to epidermal growth factor receptor (EGFR) biomarker status. PATIENTS AND METHODS: In all, 1,217 patients were randomly assigned. Biomarkers analyzed were EGFR mutation (amplification mutation refractory system; 437 patients evaluable), EGFR gene copy number (fluorescent in situ hybridization; 406 patients evaluable), and EGFR protein expression (immunohistochemistry; 365 patients evaluable). OS analysis was performed at 78% maturity. A Cox proportional hazards model was used to assess biomarker status by randomly assigned treatment interactions for progression-free survival (PFS) and OS. RESULTS: OS (954 deaths) was similar for gefitinib and carboplatin/paclitaxel with no significant difference between treatments overall (hazard ratio [HR], 0.90; 95% CI, 0.79 to 1.02; P = .109) or in EGFR mutation-positive (HR, 1.00; 95% CI, 0.76 to 1.33; P = .990) or EGFR mutation-negative (HR, 1.18; 95% CI, 0.86 to 1.63; P = .309; treatment by EGFR mutation interaction P = .480) subgroups. A high proportion (64.3%) of EGFR mutation-positive patients randomly assigned to carboplatin/paclitaxel received subsequent EGFR tyrosine kinase inhibitors. PFS was significantly longer with gefitinib for patients whose tumors had both high EGFR gene copy number and EGFR mutation (HR, 0.48; 95% CI, 0.34 to 0.67) but significantly shorter when high EGFR gene copy number was not accompanied by EGFR mutation (HR, 3.85; 95% CI, 2.09 to 7.09). CONCLUSION: EGFR mutations are the strongest predictive biomarker for PFS and tumor response to first-line gefitinib versus carboplatin/paclitaxel. The predictive value of EGFR gene copy number was driven by coexisting EGFR mutation (post hoc analysis). Treatment-related differences observed for PFS in the EGFR mutation-positive subgroup were not apparent for OS. OS results were likely confounded by the high proportion of patients crossing over to the alternative treatment.

Polymorphisms in inflammatory pathway genes, host factors and lung cancer risk in Chinese female never-smokers.

Inflammation appears to be important in lung carcinogenesis among smokers, but its role among never-smokers is not well established. We hypothesized that inflammatory medical conditions and gene polymorphisms interact to increase lung cancer risk in never-smokers. We interviewed 433 Singaporean female never-smoker lung cancer patients and 1375 hospital controls, and evaluated six polymorphisms in the interleukin 1-ß, interleukin 6 (IL6), cyclooxygenase-2, peroxisome proliferator-activated receptor-γ and interleukin 1-ß receptor antagonist (IL1RN) genes. Tuberculosis was associated with a non-significant elevated risk of lung cancer [odds ratio (OR) 1.58, 95% confidence interval (CI) 0.95-2.62]. There was no effect of asthma, atopy or chronic productive cough individually. However, the presence of one or more of these conditions (asthma, cough or atopy) increased risk (OR 2.24, 95%CI 1.15-4.38) in individuals possessing the T/T genotype at interleukin 1-ß -31T/C, but not in those possessing the C/T (OR 0.87, 95%CI 0.51-1.57) or C/C genotypes (OR 0.58, 95%CI 0.27-1.27), and in individuals having the *2 variable number of tandem repeat allele of IL1RN [OR 5.09 (1.39-18.67)], but not in those without (OR 0.93, 95%CI 0.63-1.35). The IL6-634 G allele increased the risk of lung cancer (OR 1.44, 95%CI 1.07-1.94). Lung cancer risk also increased with the number of polymorphism sites where at least 1 'risk' allele was present [interleukin 1-ß -31T/C (T allele), IL1RN (*2 allele) and IL6-634C/G (G allele)] among those with asthma, cough or atopy (Ptrend 0.001) but not in those without (Ptrend 0.47). Our results suggest that the effect of inflammatory medical conditions on lung cancer in never-smokers is modulated by host genetic susceptibility and will need to be confirmed in other studies conducted in similar populations.

Lung cancer in Chinese women: evidence for an interaction between tobacco smoking and exposure to inhalants in the indoor environment.

BACKGROUND: Epidemiologic data suggest that Chinese women have a high incidence of lung cancer in relation to their smoking prevalence. In addition to active tobacco smoke exposure, other sources of fumes and airborne particles in the indoor environment, such as cooking and burning of incense and mosquito coils, have been considered potential risk factors for lung cancer. OBJECTIVES: We used a case-control study to explore effects of inhalants from combustion sources common in the domestic environment on lung cancer and their modification by active tobacco smoking. METHODS: We analyzed 703 primary lung cancer cases and 1,578 controls. Data on demographic background and relevant exposures were obtained by face-to-face interviews in the hospital. RESULTS: We observed a positive relationship with daily exposure to incense or mosquito coils and to cooking fumes only among smokers, and no association among lifetime nonsmokers. Interactions between smoking and frequency of cooking, or exposure to incense or mosquito coils were statistically significant and consistent with synergistic effects on lung cancer. The odds ratio (OR) comparing smokers without daily incense or mosquito coil exposure with nonsmokers without daily exposure was 2.80 [95% confidence interval (CI), 1.86-4.21], whereas the OR comparing smokers with daily exposure to the same referent group was 4.61 (95% CI, 3.41-6.24). In contrast, daily exposure to incense or mosquito coils was not associated with lung cancer among nonsmokers (OR = 0.91; 95% CI, 0.72-1.16). We observed the same pattern of associations for smokers without (OR = 2.31; 95% CI, 1.52-3.51) and with (OR = 4.50; 95% CI, 3.21-6.30) daily cooking exposure compared with nonsmokers, with no evidence of an association with daily cooking exposure among nonsmokers. CONCLUSION: Our results suggest that active tobacco smoking not only is an important risk factor for development of lung cancer, but also may cause smokers to be more susceptible to the risk-enhancing effects of other inhalants.

Impact of comorbidities on clinical outcomes in non-small cell lung cancer patients who are elderly and/or have poor performance status.

AIM: We evaluated the effect of comorbidities on clinical outcomes in patients with advanced non-small cell lung cancer (NSCLC) who have poor performance status (PS 2/3) and/or are elderly (≥70 years old). SUMMARIZED DESCRIPTION: The impact of age (<70 versus >70), PS, and comorbidity score - Cumulative Illness Rating Scale for Geriatrics (CIRS-G) on treatment response, toxicities, QOL and overall survival (OS) was analyzed using data from a completed phase II trial that randomly assigned patients with advanced NSCLC who had PS 2/3 and/or were aged ≥70 to receive gemcitabine (GEM), vinorelbine (VIN) or docetaxel (DOC). RESULTS: Data from records of 134 patients accrued during the trial were available for analysis. Eighty-eight patients (66%) were aged ≥70 years. 59 patients (67%) had PS of ECOG 0-2 and 29 patients (33%) had ECOG 3. In those aged ≥70, 53 (60%) had at least one comorbidity rated CIRS-G category 3/4 while those aged <70, 12 (26%) had at least one CIRS-G 3/4 comorbidity. Age, PS, and comorbidity scores had no significant association with PFS and QOL scores changes, although PS had marginal influence on OS (0.05

Correlation between epidermal growth factor receptor mutations and expression of female hormone receptors in East-Asian lung adenocarcinomas.

INTRODUCTION: Epidermal growth factor receptor (EGFR) mutations are more common in lung adenocarcinoma and in female patients of East-Asian origin. We aimed to assess the expression of female hormone receptors in East-Asian lung adenocarcinomas, their correlation with EGFR mutations, and prognostic significance. METHODS: Estrogen receptor (ER)alpha, ERbeta, progesterone receptor (PR), and Her-2 expression were examined using immunohistochemical methods on 109 lung adenocarcinoma cases. EGFR mutations were analyzed by partially denaturing high performance liquid chromatography. Association of hormone receptor with clinical factors was assessed using the Fisher's exact test. Associations with survival were assessed using the Cox proportional hazard model. RESULTS: Using scoring criteria routinely used for breast cancer, there were four (4%) ERalpha, one (1%) ERbeta, six (6%) PR, and one (1%) Her-2 positive cases. Considering any staining as positive, 14 (14%) ERalpha, 10 (9%) ERbeta, 12 (12%) PR, and 26 (24%) Her-2 cases were positive. Thirty-nine patients (39%) had EGFR mutations. ERalpha positivity was significantly associated with ERbeta and PR positivity. There were more EGFR mutations seen in tumors with ERbeta positivity (60%) compared with those with negative expression (37.9%), and there was a trend toward a poorer outcome for patients with tumor that were positive for ERbeta and Her-2. CONCLUSIONS: We found that ERalpha, ERbeta, PR, and Her-2 expression in lung adenocarcinoma are present but limited. This suggests that hormonal influence may not be an important factor to account for the high prevalence of lung cancer among the East-Asian women.

A phase II trial of induction gemcitabine and vinorelbine followed by concurrent vinorelbine and radiotherapy in locally advanced non-small cell lung cancer.

This is phase II study evaluating a non-platinum-containing regimen, used in conjunction with radiotherapy, in patients with locally advanced non-small cell lung cancer (NSCLC). Patients with non-resectable stage III NSCLC were treated with two cycles of induction gemcitabine (1000mg/m(2)) and vinorelbine (25mg/m(2)) given on D(1,8) every 21 days, followed by thoracic radiotherapy (60-66Gy) with concurrent weekly vinorelbine (15mg/m(2)). The primary objective was to assess response rate and secondary objectives to assess tolerability and to determine the progression-free survival (PFS) and overall survival (OS). Of the 42 patients enrolled on the study, 15 (36%) achieved a partial response (PR) after induction chemotherapy. After chemo-radiotherapy, five patients had complete response (CR) and 19 patients had PR, giving an overall response rate of 52%. The median PFS was 8 months and median OS was 17 months. The regimen was tolerable, with a 21% grade 3/4 neutropenia rate and 38% grade 2/3 esophagitis rate.

Gefitinib in combination with gemcitabine and carboplatin in never smokers with non-small cell lung carcinoma: a retrospective analysis.

INTRODUCTION: Randomized placebo-controlled phase III trials failed to show a survival benefit with the addition of gefitinib to platinum-based combination chemotherapy as first-line therapy in unselected patients with advanced non-small cell lung cancer (NSCLC). We conducted a retrospective analysis of the outcome in never smokers with advanced NSCLC who received gemcitabine-carboplatin-gefitinib (GCI) as first-line therapy and compared these patients with a historical control group who received gemcitabine-carboplatin (GC) alone in our center. METHODS: Never-smoker patients with chemonaive stage IIIB or IV NSCLC were treated with GCI. These patients were compared with a historical control group of never smokers who had been treated with GC alone as the first-line therapy. RESULTS: A total of 80 patients were reviewed: 51 patients were treated with GCI and 29 with GC. Most patients were women, and adenocarcinoma was the most common histologic subtype. The response rate for patients in the GCI group was 62.7% (95% confidence interval [CI] = 48.08-75.87), which was higher than that of the GC group, 27.6% (95% CI = 12.73-47.24). The GCI group showed a significant improvement in progression-free survival compared with the GC group (hazard ratio of 0.19, 95% CI = 0.105-0.351, p < 0.001). The median overall survival for the patients on GCI was 20.5 months compared 14.1 months (p = 0.05) for patients on GC. CONCLUSION: The addition of gefitinib to first-line chemotherapy improved progression-free survival and overall survival when used as a first-line therapy in never smokers with advanced NSCLC in this retrospective study. A prospective randomized phase III study is needed to confirm this finding.

Assessment of human papillomavirus and Epstein-Barr virus in lung adenocarcinoma.

The association of human papillomavirus (HPV) and Epstein-Barr virus (EBV) infection with non-small cell lung cancer is controversial. HPV and EBV prevalence in a uniform population of lung adenocarcinoma was investigated, hypothesizing that there would be differences seen between smokers and non-smokers and between sexes. Patients involved in this study were selected from a single institution database of lung cancer. In total 497 patients with adenocarcinoma were identified and 110 patients had sufficient tissue for analysis with an in situ hybridization method that probed for high-risk and low-risk HPV and EBV. There were 65 males and 45 females, 78 patients with stage I-IIIA disease and 32 patients with stage IIIB-IV disease. There were similar number of smokers and non-smokers. Across all stages HPV and EBV staining was absent from all tissues examined. It is unlikely that HPV or EBV is an important etiological agent in adenocarcinoma of the lung, even among the never-smokers.

Triplet combination of gemcitabine, paclitaxel, and carboplatin followed by maintenance 5-fluorouracil and folinic acid in patients with metastatic nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a disease that is highly responsive to various chemotherapeutic agents. In the metastatic setting, 2-drug combination chemotherapy generally provides a response rate of 55% to 75%, and median survival of 10 to 12 months. The objective of the current study was to assess the efficacy of a 3-drug combination followed by maintenance treatment in patients with metastatic NPC. METHODS: Patients with metastatic NPC were treated with a combination of gemcitabine at a dose of 1,000 mg/m(2), paclitaxel at a dose of 70 mg/m(2), and carboplatin at an area under the concentration-time-curve (AUC) of 2.5 on Days 1 and 8 every 21 days. Patients who achieved partial or complete response continued to receive weekly 5-fluorouracil at a dose of 450 mg/m(2) and leucovorin at a dose of 30 mg/m(2) for 48 weeks. RESULTS: Twenty-eight patients were recruited. Twenty-two (79%) patients had >or=2 sites of disease. Toxicities were mainly from bone marrow suppression, with 79% grade 3/4 neutropenia, 32% grade 3/4 anemia, and 29% grade 3/4 thrombocytopenia (according to the National Cancer Institute Common Toxicity Criteria). The overall response rate to the 3-drug regimen was 86%, with a complete response rate of 11%. The median duration of response was 8 months and the median overall survival was 22 months. CONCLUSIONS: This regimen of a 3-drug combination followed by maintenance is feasible and has demonstrated an encouraging response rate and overall survival.

Induction concurrent chemoradiotherapy using Paclitaxel and Carboplatin combination followed by surgery in locoregionally advanced non-small cell lung cancer--Asian experience.

INTRODUCTION: It has been established that combined chemoradiotherapy treatment benefits selected patients with stage III Non Small Cell Lung Cancer (NSCLC). However, locoregional recurrence still poses a problem. The addition of surgery as the third modality may provide a possible solution. We report our experience of using the triple-modality approach in this group of patients. MATERIALS AND METHODS: This is a retrospective review of 33 patients with stage III NSCLC treated between 1997 and 2005. Patients have good performance status and no significant weight loss. There were 26 males (79 %) with median age of 63 years (range, 43 to 74) and median follow-up of 49 months. Seventy-six percent had Stage IIIA disease. Chemotherapy consisted of paclitaxel at 175 mg/m2 over 3 hours followed by carboplatin at AUC of 5 over 1 hour. Thoracic radiotherapy was given concurrently with the second and third cycles of chemotherapy. All patients received 50 Gray in 25 fractions over 5 weeks. RESULTS: The main toxicities were grade 3/4 neutropenia (30%), grade 3 infection (15 %) and grade 3 oesophagitis (9%). Twenty-five patients (76%) underwent surgery. Of the 8 who did not undergo surgery, 1 was deemed medically unfit after induction chemoradiotherapy and 4 had progressive disease; 3 declined surgery. Nineteen patients (58 %) had lobectomy and 6 had pneumonectomy. The median overall survival was 29.9 months and 12 patients are still in remission. CONCLUSION: The use of the triplemodality approach is feasible, with an acceptable tolerability and resectability rate in this group of patients.

Cisplatin-based three drugs combination (NIP) as induction and adjuvant treatment in locally advanced non-small cell lung cancer: final results.

INTRODUCTION: This phase III trial was conducted in non-small cell lung cancer patients with locally advanced stage II B (only T3N0) III A and III B (only T4 N0). Primary endpoint was 2-year survival; secondary were toxicity, disease-free survival, and overall survival. METHODS: After three cycles of vinorelbine (N) 25 mg/m2 on days 1 and 5, ifosfamide/mesna (I) 3 g/m2 on day 1, cisplatin (P) (NIP), patients were treated by surgery and within 45 days were randomized to two additional cycles of NIP versus observation. RESULTS: Median tumor diameter was 5.5 cm (1.2-10.6). Overall, 155 of 156 patients received chemotherapy: 133 (85%) men, median age: 59 years (35-75). Sixty-five percentage of patients were stage III A, 28% II B, and 7% III B. The study has been closed prematurely because of the low inclusion rate. After three cycles of induction in 143 assessable patients, 82 reported an objective response (57.3%) (95% CI: 48.8-65.6), with 3.5% complete response and 53.8% partial response. Relative dose intensity during neoadjuvant NIP (%) was 97, 98, and 98.5 for vinorelbine, ifosfamide/mesna, and cisplatin, respectively. Tolerance: G3 to 4 neutropenia in 3% of patients and G3 to 4 anemia in 4%; nonhematological toxicities included G3 nausea/vomiting in 11%, G3 anorexia and G3 to 4 infection in 6.5%, G3 asthenia in 10% and G3 to 4 alopecia in 25.5%. After a median of 32 days after NIP, 107 patients (69%) underwent operation with complete resection (R0) in 74% (79 of 107 patients). Downstaging (N2 to N0) after surgery was 29%. Operative mortality rate was 2.8%. Twenty-one days (median) after surgery, 79 patients were randomized to adjuvant NIP (47%) or control (53%). Tolerance of adjuvant NIP: 12.5% G3 to 4 nausea/vomiting, 19% G3 alopecia, 6% G3 infection, and G3 asthenia. Overall median survival 32.3 versus 31.8 months in the observation and NIP arms, respectively. CONCLUSIONS: NIP allows 74% of R0 with no surgery delay. The few number of randomized patients did not allow to conclude on the efficacy of adjuvant chemotherapy.

A multicenter phase II trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine) and gemcitabine in advanced non-small-cell lung cancer with pharmacokinetic evaluation using peripheral blood mononuclear cells.

BACKGROUND: We tested the hypothesis that 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine) may enhance response to re-treatment with gemcitabine by enhancing intracellular uptake of gemcitabine in a phase II study. METHOD: Patients who had prior exposure to gemcitabine as a first-line treatment of advanced non-small-cell lung cancer (NSCLC) were given weekly infusions of 3-AP and gemcitabine for 3 weeks followed by 1 week of rest, repeated every 28 days. Plasma and peripheral blood mononuclear cells (PBMCs) were collected to evaluate the effect of 3-AP on pharmacokinetics and intracellular uptake of gemcitabine. RESULT: Twelve patients were treated with a median of two treatment cycles without objective response, hence the study was terminated at interim analysis. Four patients had stable disease and the median time to progression was 3 months (95% confidence interval, CI: 1.7 to 9.1 months). Grade 3 toxicities included neutropenia (two patients), hypoxia (three patients) and dyspnea (one patient). Four patients developed reversible symptomatic methemoglobinemia during 3-AP infusion, with mild to moderately elevated methemoglobin levels that ranged from 7.8 to 17.6% of the total hemoglobin concentration. Limited pharmacokinetic data did not suggest any clinically relevant pharmacological influence of 3-AP on gemcitabine. CONCLUSION: 3-AP did not enhance clinical response to gemcitabine in this cohort of patients with prior exposure to gemcitabine for advanced NSCLC. Further development of 3-AP in lung cancer is challenged by its potential of causing methemoglobinemia and hypoxia, which could be problematic in patients with compromised pulmonary reserves.

A randomized phase II trial of single-agent gemcitabine, vinorelbine, or docetaxel in patients with advanced non-small cell lung cancer who have poor performance status and/or are elderly.

BACKGROUND: Patients with poor performance status and/or are elderly are frequently considered a compromised group at high risk of chemotherapy-related morbidities and less likely to benefit from treatment. We aimed to evaluate tolerability and efficacy of three single-agent regimens in these patients. PATIENTS AND METHODS: Patients with advanced non-small cell lung cancer who had performance status 2/3 and/or were aged 70 and older were randomly assigned to receive gemcitabine, vinorelbine, or docetaxel. Objective response, toxicities, and quality of life were evaluated. RESULTS: One hundred thirty-five patients were registered, of whom one was ineligible. Of the 134 patients, 43 received gemcitabine, 45 vinorelbine, and 46 docetaxel. The response rate was 16%, 20%, 22% for gemcitabine, vinorelbine, and docetaxel, respectively. The main grade 3/4 toxicities were fatigue (18%) and neutropenia (16%). There was improvement in global health scores, cough, and dyspnea for all treatment groups. The improvement in dyspnea was most marked in patients with performance status 3. CONCLUSION: There was no significant advantage of any of the treatment arms over the rest. There was benefit seen with improvement of quality of life in patients who were able to receive more cycles of chemotherapy.

Survival of small-cell lung cancer and its determinants of outcome in Singapore.

INTRODUCTION: The survival and epidemiology of small-cell lung cancer (SCLC) in Singapore has not been described. We aim to present the characteristics as well as determine the survival outcome and important prognostic factors for SCLC patients. MATERIALS AND METHODS: A retrospective analysis of SCLC patients diagnosed from 1999 to 2002 was conducted at the Outram campus, Singapore. Clinical characteristics and treatment data were obtained from case records and survival data were checked with the registry of births and deaths on 30 May 2005. RESULTS: One hundred and eleven patients were analysed. There were 38 (34.2%) limited-disease (LD) patients and 73 (65.8%) extensive-disease (ED) patients. The majority were current or former smokers (94.7% among LD and 94.5% among ED). More patients with LD had good performance status (92% versus 63%, P = 0.0003) and were treated with combined chemotherapy and radiotherapy (82% versus 48%, P = 0.012). The median survival time of LD patients treated with curative chemoradiotherapy was 14.2 months (95% CI, 10.96 to 17.44). Those given prophylactic cranial irradiation had a median survival time of 16.9 months (95% CI, 11.83 to 21.97). For ED patients, the median survival time was 8.17 months (95%CI, 5.44 to 10.89). None of the factors analysed were significant prognostic factors for LD patients while performance status and type of treatment given were significant among ED patients. CONCLUSIONS: We found that the characteristics and survival of SCLC patients in Singapore are fairly similar to that of other countries.

Differences between small-cell lung cancer and non-small-cell lung cancer among tobacco smokers.

It is known that smoking increases the risk for all histological subtypes of lung cancer. To date, the factors that determine why some patients develop small-cell lung cancer (SCLC) while others develop non-small-cell lung cancer (NSCLC) remain unknown. We compared the characteristics of 774 smokers with SCLC and NSCLC diagnosed during the period January 1999 till December 2002. Multivariate logistic regression was used to estimate the odds ratio (OR) with 95% CI. Testing of linear trend across categories of pack-years was also conducted. Six hundred and sixty-five NSCLC were compared to 109 SCLC. Among SCLC, there were significantly more females (20.2% versus 12.8%), current-smokers (81.7% versus 71.9%) as well as smokers who had smoked more than 40 pack-years (75.6% versus 50.3%). Comparing SCLC with NSCLC among the men only, having smoked more than 40 pack-years was associated with a significantly elevated odds ratio (OR) of 3.71 of developing SCLC (95% CI, 1.05-13.1; p=0.041). There was a decreasing trend in OR with increasing smoking cessation period. When comparing SCLC with adenocarcinoma, the women had a higher OR of 2.37 of developing SCLC (95% CI, 1.05-5.31; p=0.037) compared to the men. Our findings suggest that cumulative smoking exposure in terms of pack-years smoked is an important determining factor for the preferred development of SCLC among smokers.

Never-smokers with lung cancer: epidemiologic evidence of a distinct disease entity.

PURPOSE: Tobacco smoke is a definite causative agent for lung cancer. It is increasingly being recognized that never-smokers can be afflicted with non-small-cell lung cancer (NSCLC). We aim to assess survival differences between smokers and never-smokers with NSCLC. PATIENTS AND METHODS: We analyzed 975 NSCLC patients who presented from January 1999 to December 2002. Clinical characteristics among current-, former- and never-smokers were tested using chi2 or Kruskal-Wallis test. The hazard ratio (HR) for death and its 95% CI were calculated by Cox regression. RESULTS: Of 975 patients, 59 had no smoking history and 33 had no quit time recorded. Of 883 patients analyzed, 286 patients (32.4%) were never-smokers. One hundred ninety-six never-smokers (68.5%) were females compared with 12% among current- and 13% among former-smokers (P < .001). There was a significant difference in histologic subtype between never-smokers and smokers: 69.9% with adenocarcinoma versus 39.9% (current-smokers) versus 47.3% (former-smokers); 5.9% with squamous cell carcinoma versus 35.7% (current-smokers) versus 28% (former-smokers; P < .001). Smokers had significantly poorer performance status (P = .002) and higher median age at diagnosis (P < .001) while more never-smokers presented with advanced disease (P = .002). Eight hundred and five patients (82.6%) died by May 30, 2005. The HR for smokers was significantly higher on both univariate and multivariate analysis (HR, 1.297; 95% CI, 1.040 to 1.619). CONCLUSION: Never-smokers comprised a high proportion of NSCLC patients in Singapore. Definite epidemiologic differences exist between never-smokers and smokers. Differences in survival outcome further suggest that the biology underlying the pathogenesis and behavior of the disease may be different for never-smokers.