Vascular endothelial growth factor gene polymorphisms and risk of primary lung cancer.

Angiogenesis is an essential process in the development, growth, and metastasis of malignant tumors including lung cancer. DNA sequence variations in the vascular endothelial growth factor (VEGF) gene may lead to altered VEGF production and/or activity, thereby causing interindividual differences in the susceptibility to lung cancer via their actions on the pathways of tumor angiogenesis. To test this hypothesis, we investigated the potential association between three VEGF polymorphisms (-460T > C, +405C > G, and 936C > T)/haplotypes and the risk of lung cancer in a Korean population. VEGF genotypes were determined in 432 lung cancer patients and 432 healthy controls that were frequency matched for age and sex. VEGF haplotypes were predicted using Bayesian algorithm in the phase program. Compared with the combined +405 CC and CG genotype, the +405 GG genotype found associated with a significantly decreased risk of small cell carcinoma [SCC; adjusted odds ratio (OR), 0.36; 95% confidence interval (95% CI), 0.17-0.78]. The 936 CT genotype and the combined 936 CT and TT genotype were also associated with a significantly decreased risk of SCC compared with the 936 CC genotype (adjusted OR, 0.47; 95% CI, 0.26-0.85 and adjusted OR, 0.44; 95% CI, 0.24-0.80, respectively). Haplotype CGT was associated with a significantly decreased risk of SCC (adjusted OR, 0.39; 95% CI, 0.18-0.87), whereas haplotype TCC conferred a significantly increased risk of SCC (adjusted OR, 1.63; 95% CI, 1.14-2.33). None of the VEGF polymorphisms studied significantly influenced the susceptibility to lung cancer except SCC. However, haplotypes TCT and TGT were significantly associated with the risk of overall lung cancer, respectively (adjusted OR, 0.38; 95% CI, 0.25-0.60 and adjusted OR, 3.94; 95% CI, 2.00-7.76, respectively). These effects of haplotypes TCT and TGT on lung cancer risk were observed in three major histologic types of lung cancer. These results suggest that the VEGF gene may be contribute to an inherited predisposition to lung cancer.     

Implications of the prostate cancer prevention trial: a decision analysis model of survival outcomes.

PURPOSE: To assess the estimated effect of finasteride prevention of prostate cancer on overall survival. METHODS: Data for our decision tree model came from men in the two arms (finasteride or placebo) of the Prostate Cancer Prevention Trial (PCPT) and from clinically localized prostate cancer patients studied for long-term survival outcomes. Our model compared survival outcomes for men treated with finasteride or placebo. Prostate cancer rates were based on the 7-year period prevalence of prostate cancer detected in the PCPT; survival probabilities were abstracted from the long-term outcome studies. We assessed variability in the PCPT and long-term survival studies to test the variability of our model. RESULTS: Survival advantages for a finasteride-treated (v those not treated with finasteride) population include gains of 1.7 months in 15-year cause-specific survival (assuming finasteride-altered Gleason scores and prostate cancer prevalence rates in the PCPT), of up to 3 months for cancers treated conservatively or surgically (assuming finasteride does not alter Gleason scores), and of 0.35 months (assuming the rate of cancers detected by for-cause biopsies in the PCPT), which increased to 1.7 months when assuming a 30% rate of biopsy-detected cancer in the PCPT placebo group. Model-variability analyses support several survival benefits associated with finasteride (eg, the uniform benefits assuming finasteride does not alter Gleason scores) but question certain others (eg, in 15-year recurrence-free survivals assuming finasteride does alter Gleason scores). CONCLUSION: Finasteride can impart survival benefits according to our model, especially when we assume that finasteride does not alter Gleason scores.     

Gemcitabine plus carboplatin versus mitomycin, ifosfamide, and cisplatin in patients with stage IIIB or IV non-small-cell lung cancer: a phase III randomized study of the London Lung Cancer Group.

PURPOSE: This phase III randomized trial compared two chemotherapy regimens, gemcitabine plus carboplatin and mitomycin, ifosfamide, and cisplatin, in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC). The regimens were compared with regard to effects on survival, response rates, toxicity, and quality of life. PATIENTS AND METHODS: Eligible patients had previously untreated stage IIIB or IV NSCLC suitable for cisplatin-based chemotherapy. Randomly assigned patients were to receive four cycles, each at 3-week intervals, of carboplatin area under the curve of 5 on day 1 plus gemcitabine 1,200 mg/m(2) on days 1 and 8 (GCa) or mitomycin 6 mg/m(2), ifosfamide 3g/m(2), and cisplatin 50 mg/m(2) on day 1 (MIC). RESULTS: Between February 1999 and August 2001, 422 patients (GCa, n = 212; MIC, n = 210) were randomly assigned in the United Kingdom. The majority of patients received the intended four cycles (GCa, 64%; MIC, 61%). There was a significant survival advantage for GCa compared with MIC (hazard ratio, 0.76; 95% CI, 0.61 to 0. 93; P = .008). Median survival was 10 months with GCa and 7.6 months with MIC (difference, 2.4 months; 95% CI, 1.0 to 4.0), and 1-year survival was 40% with GCa and 30% with MIC (difference, 10%; 95% CI, 3% to 18%). Overall response rates were similar (42% for GCa v 41% for MIC; P = .84). More thrombocytopenia occurred with GCa (P = .03), but this was not associated with increased hospital admission or fatality. GCa caused less nausea, vomiting, constipation, and alopecia and was associated with fewer admissions for administration and better quality of life. CONCLUSION: In patients with advanced NSCLC, GCa chemotherapy was shown to be a better-tolerated treatment that conferred a survival advantage over MIC.     

Phase I study of gefitinib plus celecoxib in recurrent or metastatic squamous cell carcinoma of the head and neck.

PURPOSE: Effective and tolerable palliative treatments are needed for patients with incurable squamous cell carcinoma of the head and neck (SCCHN). Single-agent targeted therapies have limited activity in this setting. The feasibility of adding celecoxib to gefitinib for the treatment of incurable SCCHN is unknown. PATIENTS AND METHODS: Nineteen patients with unresectable recurrent locoregional and/or distant metastatic SCCHN with progressive disease after at least one prior chemotherapy or chemoradiotherapy regimen were enrolled onto this single-institution phase I study. Three dose levels were explored: (1) celecoxib 200 mg twice daily plus gefitinib 250 mg daily; (2) celecoxib 400 mg twice daily plus gefitinib 250 mg daily; and (3) celecoxib 400 mg twice daily plus gefitinib 500 mg daily. RESULTS: No dose-limiting toxicities were encountered at any dose level. The most common toxicities were acneiform rash, diarrhea, hand reaction, dyspepsia, and anemia. Four of 18 patients assessable for response (22%; 95% CI, 2% to 42%) achieved a confirmed partial response. CONCLUSION: The combination of gefitinib 500 mg daily plus celecoxib 400 mg twice daily is well-tolerated. The encouraging responses seen in this early study suggest further evaluation of epidermal growth factor receptor and cyclooxygenase-2 inhibitors in SCCHN is warranted.     

Phase I trial of a monoclonal antibody specific for alphavbeta3 integrin (MEDI-522) in patients with advanced malignancies, including an assessment of effect on tumor perfusion.

At present, a variety of agents targeting tumor angiogenesis are under clinical investigation as new therapies for patients with cancer. Overexpression of the alpha(v)beta(3) integrin on tumor vasculature has been associated with an aggressive phenotype of several solid tumor types. Murine models have shown that antibodies targeting the alpha(v)beta(3) integrin can affect tumor vasculature and block tumor formation and metastasis. These findings suggest that antibodies directed at alpha(v)beta(3) could be investigated in the treatment of human malignancies. The current phase I dose escalation study evaluated the safety of MEDI-522, a monoclonal antibody specific for the alpha(v)beta(3) integrin, in patients with advanced malignancies. Twenty-five patients with a variety of metastatic solid tumors were treated with MEDI-522 on a weekly basis with doses ranging from 2 to 10 mg/kg/wk. Adverse events were assessed weekly; pharmacokinetic studies were done; and radiographic staging was done every 8 weeks. In addition, dynamic computed tomography imaging was done at baseline and at 8 weeks in patients with suitable target lesions amenable to analysis, to potentially identify the effect of MEDI-522 on tumor perfusion. Treatment was well tolerated, and a maximum tolerated dose was not identified by traditional dose-limiting toxicities. The major adverse events observed were grade 1 and 2 infusion-related reactions (fever, rigors, flushing, injection site reactions, and tachycardia), low-grade constitutional and gastrointestinal symptoms (fatigue, myalgias, and nausea), and asymptomatic hypophosphatemia. Dynamic computed tomography imaging suggested a possible effect on tumor perfusion with an increase in contrast mean transit time from baseline to the 8-week evaluation with increasing doses of MEDI-522. No complete or partial responses were observed. Three patients with metastatic renal cell cancer experienced prolonged stable disease (34 weeks, >1 and >2 years) on treatment. With this weekly schedule of administration, and in the doses studied, MEDI-522 seems to be without significant toxicity, may have effects on tumor perfusion, and may have clinical activity in renal cell cancer. These findings suggest the MEDI-522 could be further investigated as an antiangiogenic agent for the treatment of cancer.     

Simultaneous equations in ordered discrete responses with regressor-dependent thresholds

Summary The parameters of ordered discrete response (ODR) models are identified only up to a positive scale. In this paper, we examine the identification issue for simultaneous equations with ODR, where the well-known identification problem in simultaneous equations of recovering structural-form parameters from reduced-form parameters is compounded with the ODR identification problem. We allow the thresholds in ODR to be regressor dependent as well as constant; the former is particularly challenging because threshold parameters get mixed with regression parameters, adding one more dimension to the identification problem. We also explore a cross-equation restriction on threshold differences, under which the structural form parameters are fully identified as if the dependent variables are continuously distributed. An empirical example with farm–household joint labour supply is provided to illustrate the identification issues, to show how our proposals work and to apply tests devised for the threshold constancy and cross-equation restrictions.