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Background: The combination of chemotherapy with thoracic radiotherapy (TRT) compared with TRT alone has been shown to confer a survival advantage for good performance status patients with stage III non-small cell lung cancer. However, it is not known whether sequential or concurrent delivery of these therapies is the optimal combination strategy.Methods: A total of 610 patients were randomly assigned to two concurrent regimens and one sequential chemotherapy and TRT regimen in a three-arm phase III trial. The sequential arm included cisplatin at 100 mg/m2 on days 1 and 29 and vinblastine at 5 mg/m2 per week for 5 weeks with 63 Gy TRT delivered as once-daily fractions beginning on day 50. Arm 2 used the same chemotherapy regimen as arm 1 with 63 Gy TRT delivered as once-daily fractions beginning on day 1 [corrected]. Arm 3 used cisplatin at 50 mg/m2 on days 1, 8, 29, and 36 with oral etoposide at 50 mg twice daily for 10 weeks on days 1, 2, 5, and 6 with 69.6 Gy delivered as 1.2 Gy twice-daily fractions beginning on day 1. The primary endpoint was overall survival, and secondary endpoints included tumor response and time to tumor progression. Kaplan-Meier analyses were used to assess survival, and toxic effects were examined using the Wilcoxon rank sum test. All statistical tests were two-sided.Results: Median survival times were 14.6, 17.0, and 15.6 months for arms 1-3, respectively. Five-year survival was statistically significantly higher for patients treated with the concurrent regimen with once-daily TRT compared with the sequential treatment (5-year survival: sequential, arm 1, 10% [20 patients], 95% confidence interval [CI] = 7% to 15%; concurrent, arm 2, 16% [31 patients], 95% CI = 11% to 22%, P = .046; concurrent, arm 3, 13% [22 patients], 95% CI = 9% to 18%). With a median follow-up time of 11 years, the rates of acute grade 3-5 nonhematologic toxic effects were higher with concurrent than sequential therapy, but late toxic effects were similar.Conclusion: Concurrent delivery of cisplatin-based chemotherapy with TRT confers a long-term survival benefit compared with the sequential delivery of these therapies. [ABSTRACT FROM AUTHOR]

Background: Retinoids can reverse neoplastic lesions and prevent second primary tumors in the aerodigestive tract. These effects are thought to be mediated by nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs), each receptor group including three subtypes (alpha, beta, and gamma). Previously, we found that RARbeta expression was suppressed in lung cancer. In this study, we investigated whether expression of RARbeta is modulated by chemopreventive intervention.Methods: Using in situ hybridization, we analyzed RARbeta messenger RNA (mRNA) expression in bronchial biopsy specimens from heavy smokers, at baseline and after 6 months of treatment with 13-cis-retinoic acid (13-cis-RA) or placebo. Since we had previously detected RARbeta expression in 90% of bronchial specimens from nonsmokers, we considered loss of RARbeta mRNA expression in at least one of six biopsy specimens at baseline in this study to be aberrant.Results: RARbeta mRNA expression was aberrant in 30 (85.7%) of 35 subjects in the 13-cis-RA group and in 24 (72.7%) of 33 subjects in the placebo group. After 6 months of 13-cis-RA treatment, the number of subjects who were RARbeta positive in all six biopsy specimens increased from five of 35 to 13 of 35 (2.6-fold), so that the percentage of individuals with aberrant RARbeta expression decreased to 62.9% (22 of 35), which represents a statistically significant difference from baseline expression (two-sided P =.01). In the placebo group, no statistically significant difference in RARbeta expression was observed between baseline and 6 months. RARbeta expression was not related to current smoking status or reversal of squamous metaplasia.Conclusions: These results indicate that RARbeta is an independent marker of response to 13-cis-RA and may serve as an intermediate biomarker in chemoprevention trials of upper aerodigestive tract cancers. [ABSTRACT FROM AUTHOR]

Background: Preclinical studies in animal models have demonstrated tumor regression following intratumoral administration of an adenovirus vector containing wild-type p53 complementary DNA (Ad-p53). Therefore, in a phase I clinical trial, we administered Ad-p53 to 28 patients with non-small-cell lung cancer (NSCLC) whose cancers had progressed on conventional treatments.Methods: Patients received up to six, monthly intratumoral injections of Ad-p53 by use of computed tomography-guided percutaneous fine-needle injection (23 patients) or bronchoscopy (five patients). The doses ranged from 10(6) plaque-forming units (PFU) to 10(11) PFU.Results: Polymerase chain reaction (PCR) analysis showed the presence of adenovirus vector DNA in 18 (86%) of 21 patients with evaluable posttreatment biopsy specimens; vector-specific p53 messenger RNA was detected by means of reverse transcription-PCR analysis in 12 (46%) of 26 patients. Apoptosis (programmed cell death) was demonstrated by increased terminal deoxynucleotide transferase-mediated biotin uridine triphosphate nick-end labeling (TUNEL) staining in posttreatment biopsy specimens from 11 patients. Vector-related toxicity was minimal (National Cancer Institute's Common Toxicity Criteria: grade 3 = one patient; grade 4 = no patients) in 84 courses of treatment, despite repeated injections (up to six) in 23 patients. Therapeutic activity in 25 evaluable patients included partial responses in two patients (8%) and disease stabilization (range, 2-14 months) in 16 patients (64%); the remaining seven patients (28%) exhibited disease progression.Conclusions: Repeated intratumoral injections of Ad-p53 appear to be well tolerated, result in transgene expression of wild-type p53, and seem to mediate antitumor activity in a subset of patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]

Background: New methods are needed to detect precancerous lesions in lung tissue. We conducted a study to determine the utility of LIFE (laser-induced fluorescence emission) autofluorescence bronchoscopy for the detection of squamous metaplasia and dysplasia in current and former smokers.Methods: In this prospective, single-center study, 53 participants underwent standard white-light bronchoscopy and 39 underwent both white-light and LIFE bronchoscopy. Bronchial biopsy specimens were obtained from all participants at six pre-determined sites using white-light bronchoscopy and from all other sites that appeared to be abnormal in participants who underwent LIFE bronchoscopy. Relationships between LIFE imaging and histologic findings were examined for 245 biopsy specimens obtained from those participants who had undergone LIFE bronchoscopy.Results: LIFE imaging revealed abnormalities designated as either class II or class III in 89 (36.3%) and 16 (6.5%) of the 245 sites examined, respectively, and histopathologic examination showed dysplasia and metaplasia in eight (3.3%) and in 52 (21.2%) of the 245 specimens, respectively. Among the 105 biopsy specimens obtained from sites with abnormal LIFE imaging, only 26 (24.8%) exhibited squamous metaplasia and/or dysplasia, similar to the findings for sites with normal LIFE imaging (34 [24.3%] of 140). Comparison of individuals examined by LIFE imaging with those who underwent white-light bronchoscopy alone revealed no increase in the detection of dysplasia or metaplasia with LIFE bronchoscopy.Conclusion: In this population of current and former smokers, abnormalities detected by LIFE bronchoscopy did not improve the detection of squamous metaplasia or dysplasia. [ABSTRACT FROM AUTHOR]

Examines protein expression in primary tumor specimens of patients with head and neck squamous cell carcinoma to determine whether expression of p53 protein has prognostic significance or is associated with patterns of treatment failure. Clinical and pathologic characteristics of patients; Survival according to p53 expression.

Background: Proliferating cell nuclear antigen (PCNA) is a 36-kd nuclear protein whose expression is associated with DNA synthesis and cell proliferation. Tumorigenesis in head and neck squamous cell carcinoma is proposed to be a multistep process; dysregulation of proliferation is a potential marker of this process.Purpose: PCNA dysregulation was analyzed in squamous cell carcinoma tissue samples containing premalignant lesions (hyperplasia and/or dysplasia) and in adjacent normal epithelium to better understand proliferative changes during head and neck tumor development.Methods: Immunohistochemical analysis was performed on formalin-fixed, paraffin-embedded sections by using a monoclonal anti-PCNA antibody. PCNA expression was analyzed in 33 head and neck squamous cell carcinomas and in their adjacent premalignant lesions from different sites and compared with that in the control samples, which had never been exposed to first-hand tobacco smoke. PCNA expression was assessed by semiquantitative scoring (scale 0-3) in three epithelial layers (basal, parabasal, and superficial). The labeling index and the weighted mean index of PCNA expression were calculated.Results: Normal epithelium adjacent to the tumor had much more proliferative activity than the controls: The weighted mean index of PCNA expression was four-fold higher in the basal layer and sixfold higher in the parabasal layer. PCNA expression increased as tissues progressed from adjacent normal epithelium to hyperplasia (P < .001), hyperplasia to dysplasia (P < .001), and dysplasia to squamous cell carcinoma (P = .065); the total increase in PCNA expression ranged from fourfold to 10-fold from adjacent normal epithelium to squamous cell carcinoma. PCNA expression was higher in the parabasal than in the basal layer at all premalignant stages (23 of 25 samples in adjacent normal epithelium, 12 of 13 in hyperplasia, and 17 of 22 in dysplasia). As the tissue progressed from normal through premalignant stages to squamous cell carcinomas, we observed not only incremental increases in the labeling index, but also incremental increases in PCNA expression per labeled cells.Conclusions: These results indicate that PCNA could be a useful biomarker for multistep carcinogenesis in head and neck cancer and may serve as an intermediate end point in chemopreventive trials. [ABSTRACT FROM AUTHOR]