PURPOSE: Chemotherapy, followed by radiation therapy, improves the survival of patients with locally advanced non-small cell lung cancer (NSCLC). However, it is not clear whether chemotherapy, followed by concurrent chemo-radiation therapy, can improve survivals compared to only concurrent chemo-radiation therapy. We conducted this study to evaluate the role played by induction chemotherapy followed by concurrent chemo-radiation therapy. MATERIALS AND METHODS: Between 1995 and 2000, 55 patients with locally advanced NSCLC were treated with concurrent chemo-radiation therapy. Twenty-seven patients received the induction chemotherapy prior to the chemo-radiation therapy, and their characteristics and survival compared. RESULTS: There were no significant differences in patient characteristics, with the exception of weight loss. The group receiving the induction chemotherapy showed a lesser weight loss, but with no statistical difference in the survival results. CONCLUSION: No advantage was shown with the induction chemotherapy when followed by concurrent chemo-radiation therapy in the treatment of locally advanced NSCLC.
Carcinoma, Non-Small-Cell Lung* ; Drug Therapy ; Humans ; Induction Chemotherapy ; Weight Loss

DNA modification in vertebrate genomes is confined to the self-complementary sequence CpG. Between 60% and 90% of CpGs are methylated at the 5 position of cytosine, and the remainder is unmodified. Attempts to understand the function of CpG methylation have centered on its relationship to transcription. Introduction of methylated and nonmethylated genes into cells has shown that CpG methylation when applied near the promotor of a gene is often incompatible with efficient transcription. In addition, de novo methylation of sequences can occur naturally during development, and this has also been shown to interfere with transcription. Although there is no direct evidence that smoking induces DNA methylation, recent reports have associated DNA methylation with exposure to tobacco carcinogen. The p16INK4a protein inhibits cyclin-dependent kinase 4, a key regulator of progression through the G1 phase of the cell cycle. Methylation of CpG islands in the promotor region is an important avenue for inactivation of p16. The mechanism of methylation of the p16 promotor region, however, has not been elucidated. Recent reports investigating p16 methylation in non-small cell lung cancer (NSCLC) suggest that carcinogens in tobacco smoke induce the DNA methylation process. Methylation of CpG islands in tobacco-associated cancers occurs in a gene and tissue specific manner and is induced directly or indirectly by exposure to tobacco smoke in NSCLC.
Carcinogens ; Carcinoma, Non-Small-Cell Lung ; Cell Cycle ; CpG Islands ; Cyclin-Dependent Kinase 4 ; Cyclin-Dependent Kinase Inhibitor p16 ; Cytosine ; DNA Methylation* ; DNA* ; G1 Phase ; Genes, vif ; Genome ; Lung Neoplasms* ; Lung* ; Methylation ; Promoter Regions, Genetic ; Smoke ; Smoking ; Tobacco ; Vertebrates

Lung cancer is the leading cause of cancer deaths. Non-small cell lung cancer constitutes approximately 75% of lung cancers, and 40% will present as advanced stage IIIa or IIIb, which are ineffectively treated by primary surgery. Radiation of a primary tumor, and the regional lymphatics, has been the traditional treatment for an unresectable locally advanced disease, but few patients achieved a complete response. Due to the limited benefits provided by radiation therapy, we explored the use of combined chemoradiotherapy in patients with locally advanced, unresectable NSCLC. Combined chemoradiotherapy appears to have improved the outcome of patients with locally advanced unresectable stage III NSCLC, with a median survival of 13 to 14 months, with 5 year survival rates as high as 15 to 20%, nearly three times that reported with radiation therapy alone. Various agents have been used either sequentially or concomitantly in clinical trials of combined chemoradiotherapy for NSCLC. The interactions of chemotherapy and radiation therapy are complex, and Texanes interact with radiation at many levels. Cell-cycle synchronization, through mitotic arrest, has been consistently shown to play a major role in radiation enhancement, but increased apoptosis and tumor reoxygenation may be additional mechanisms. Clearly, the interaction is multifactorial, and the dominant mechanism may be affected by specific settings, which include drug exposure and concentration, tumor type and radiation dosimetry. Recent studies have demonstrated that shorter, high-dose, radiotherapy schedules cause a statistically significant increase in the control of a local tumor in NSCLC. Radiation dose escalation, utilizing conventional fractionation techniques, would be likely to cause prohibitive toxicity. Threedimensional conformal radiation therapy (3-DCRT) has the potential to deliver high dose radiation >70 Gy), with minimal under-dosing and concomitant relative sparing of normal tissues. This technical demonstration of the enhanced therapeutic ratio is used as the basis for the evolving clinical utilization of 3-DCRT for NSCLC. Preliminary experience of the technique has resulted in promising survival rates, following three-dimensional conformal radiation therapy alone, for locally advanced NSCLC. A greater follow-up and experience will help determine its late toxicity, maximum dose and efficacy of dose escalation. Strategies should be developed to integrate this modality into combined treatments for locally advanced NSCLC. Biotechnological developments within the last decade have resulted in the identification of important biological and biophysiological pathways in lung carcinogenesis, and new agents are being developed to target difficult levels of these important pathways. Preclinical and clinical studies using these specific targeted therapies in lung cancer have been very promising. Targeted therapies in lung cancer, and the potential of combining these agents with chemotherapy and radiotherapy, are under investigation.
Apoptosis ; Appointments and Schedules ; Carcinogenesis ; Carcinoma, Non-Small-Cell Lung ; Chemoradiotherapy ; Drug Therapy ; Follow-Up Studies ; Humans ; Lung Neoplasms* ; Lung* ; Radiometry ; Radiotherapy* ; Survival Rate

Surgical resection of locally advanced lung cancer is a challenging subject for thoracic surgeons. Although the operative mortality and morbidity have recently decreased, extended pulmonary resection still remains a high-risk procedure. In selective patients an extended resection would offer an increased chance of a cure from the disease. The most important prognostic factors for a locally advanced lung cancer are the mediastinal lymph node status and the completeness of the resection. Careful preoperative evaluations are required, and every effort to achieve a negative resection margin is of utmost importance during the operation. The recent development of neoadjuvant chemotherapy seems to be promising, but to draw any conclusion regarding the long-term survival benefits, multi-centered randomized trials are mandatory.
Carcinoma, Non-Small-Cell Lung* ; Drug Therapy ; Humans ; Lung Neoplasms ; Lymph Nodes ; Mortality

(NSCLC) accounts for more than 80% of all lung cancer cases. Even though surgery plays a key role in the curative management of NSCLC, especially the stage I or II disease, 80%, or more, of NSCLC patients have the locally advanced or disseminated disease. Despite the tremendous progress made in the molecular biological understanding of lung cancer during recent decades, the overall 5-year survival rate still remains very disappointing. The stage of the disease at diagnosis is the most important factor in the choice of treatment. For patients with the stage I or II disease, surgery is central to most management plans. Except for the stage IA disease, roughly 50% of surgical patients eventually relapse; more frequently in the metastatic form rather than from a local relapse. Randomized trials have not found consistent survival benefits with the use of postoperative (adjuvant) chemotherapy or radiation. However, the role of induction chemotherapy in the early stages of NSCLC is under investigation. The management of the stage III locally advanced disease is complicated, and although the stage IIIA disease has been considered borderline for an operation, there is still substantial controversy in the management of the N2 disease. Minimal N2 is a definite surgical indication, but the clinically evident N2 disease is generally regarded as unresectable. The standard management of the resectable IIIA disease is moving toward neoadjuvant treatment, followed by surgery. Approximately 40% of NSCLC patients present with a locally advanced, unresectable disease. Traditionally radiotherapy has been the treatment of choice in these patients, but their long-term survival is very poor. The recent development of new radiation techniques to enhance local control, including altered radiation fractionation schedule or three-dimensional treatment planning techniques, might further improve survival outcomes. Nevertheless, multimodality therapy, with a combination of chemotherapy and radiation, has recently become the mainstream in the management of these diseases. The newer chemotherapeutic agents, such as paclitaxel, docetaxel and gemcitabine, have been proven to have a radio sensitizing effect. A comparison of the efficacy and toxicity of concurrent vs. sequential chemoradiotherapy is currently underway to compare. The stage IV and IIIB diseases, with malignant effusion, are candidates for systemic chemotherapy. In the last decade, cisplatin-based regimens have been shown to prolong survival, improve symptom control and the quality of life. The introduction of gemcitabine, vinorelbine, paclitaxel, docetaxel and irrinotecan has raised the possibility of new platinum-based combination drugs. However, there is no clear superiority of the various new combination regimens, which could lead to the possibility of customize chemotherapy on an individual basis, according to the toxicity profiles. Most recently targeted therapy has opened new horizons. The introduction of biological agents, which target highly specific intracellular pathways, could potentially enhance the efficacy of cytotoxic chemotherapy. The anti-EGFR agents ZD 1839 (Iressa) and cetuximab (C225, Erbitux) have been clinically investigated, and preclinical evidence of an additive or synergistic interaction, with chemotherapy, is also available for farnesyl transferase inhibitors, matrix metalloproteinase inhibitors, adenovirally-mediated p53 gene transfer, selectively replicating adenovirus ONYX-015 and flavopiridol.
Adenoviridae ; Appointments and Schedules ; Biological Factors ; Carcinoma, Non-Small-Cell Lung* ; Chemoradiotherapy ; Diagnosis ; Drug Therapy ; Genes, p53 ; Humans ; Induction Chemotherapy ; Lung Neoplasms ; Matrix Metalloproteinase Inhibitors ; Neoadjuvant Therapy ; Paclitaxel ; Planning Techniques ; Quality of Life ; Radiotherapy ; Recurrence ; Survival Rate ; Transferases ; Cetuximab

Photodynamic therapy (PDT) can be used as palliative therapy to reduce obstructive symptoms in patients with advanced lung cancer. Herein, we report on the case of a patient with fatal broncho-mediastinal fistula after PDT. A 57-year-old woman was diagnosed as non-small cell lung cancer (squamous cell carcinoma, cT4N3). She received PDT on the endobronchial mass obstructing her right main bronchus twice in 48 hours interval. Two weeks later, concurrent chemoradiation therapy (CCRT) with weekly Paclitaxel/Carboplatin was started. During maintenance chemotherapy, a new nodule in her scalp developed and turned out to be a metastatic nodule. A broncho-mediastinal fistula was suspicious on follow-up chest computed tomography and a broncoscopy revealed an extensively damaged medial right main bronchial wall. On the day following bronchoscopy, the patient died of sudden massive hemoptysis.
Bronchi ; Bronchoscopy ; Carcinoma, Non-Small-Cell Lung ; Female ; Fistula ; Follow-Up Studies ; Hemoptysis ; Humans ; Lung Neoplasms ; Maintenance Chemotherapy ; Middle Aged ; Palliative Care ; Photochemotherapy ; Scalp ; Thorax ; Triazenes

PURPOSE: Inconclusive results from computed tomography (CT)-guided transthoracic needle aspiration and biopsy (TNAB) performed for lung lesions presents a clinical dilemma. The purpose of this study was to determine the factors affecting an inconclusive result from a CT guided TNAB, and to evaluate the final outcomes of these inconclusive results. MATERIALS AND METHODS: The medical records and radiologic features of 331 patients with lung lesion who received CT guided TNAB were analyzed retrospectively. The results of the TNAB were classified as conclusive (malignancy or specific benign diagnosis) or inconclusive (nonspecific benign or nondiagnostic). RESULTS: Of the 331 cases, 269 (81.3%) were diagnosed as a malignancy (210) or a specific benign lesion (59) after the first TNAB. The remaining 62 (18.7%) were inconclusive. Benign disease, a lesion size < or =15 mm, and morphology of the consolidation type were features significantly correlated with inconclusive results. Of these 62 inconclusive cases a second TNAB was performed in 23, and conclusive diagnoses were obtained in 19 (82.6%). Surgery or radiographic follow up was done in other cases. Finally, among the 62 inconclusive results on the first CT guided TNAB, 16 lesions were diagnosed as malignant, 26 were classified as specific benign disease, and the remaining 20 were defined as nonspecific inflammation. Age over 50 and morphology of a nodule or a mass type were significantly correlated with a malignancy in these 62 cases with inconclusive results on the first TNAB. CONCLUSION: A final diagnosis of benign disease was significantly higher after the CT guided TNAB was inconclusive for lesions < or =15 mm that had consolidation type morphology. Despite the application of core biopsy procedures, there continue to be appreciable numbers of inconclusive results after the first CT guided TNAB. A repeat CT guided TNAB had a high diagnostic yield in these cases and therefore should be considered for cases with inconclusive results.
Biopsy ; Follow-Up Studies ; Humans ; Inflammation ; Lung ; Medical Records ; Needles ; Retrospective Studies

PURPOSE: The anaplastic lymphoma kinase (ALK) gene is a potential molecular target in non-small cell lung carcinoma (NSCLC). The clinicopathologic implication of a change in the ALK gene copy number (GCN) is unclear. MATERIALS AND METHODS: A total of 434 primary NSCLC samples were analyzed by fluorescence in situ hybridization (FISH) for ALK GCN. RESULTS: Ninety-six cases (22.1%) showed ALK GCN gain with amplification in 16 (3.7%) cases. The cases with ALK GCN gain consisted of 47 adenocarcinomas (49.0%), 41 squamous cell carcinomas (42.7%), 5 adenosquamous carcinomas (5.2%) and 3 other NSCLCs (3.1%). ALK gene amplification was identified in 7 adenocarcinomas (43.7%) and 9 squamous cell carcinomas (56.3%). There was no significant difference between ALK GCN gain/amplification and histologic subtypes. Univariate survival analysis revealed that patients with ALK GCN gain/amplification showed shorter progression-free survival durations and decreased overall survival rates (p<0.001). However, multivariate analysis proved that ALK GCN gain/amplification is not an independent prognostic factor for progression-free survival or overall survival. CONCLUSION: ALK GCN gain is frequently identified in NSCLCs and the incidence is similar among histologic subtypes. Although ALK GCN gain/amplification is not an independent prognostic marker, it is associated with tumor progression in NSCLC.
Adenocarcinoma ; Carcinoma, Adenosquamous ; Carcinoma, Non-Small-Cell Lung ; Carcinoma, Squamous Cell ; Disease-Free Survival ; Fluorescence ; Gene Amplification ; Gene Dosage ; Humans ; In Situ Hybridization ; Incidence ; Lung ; Lymphoma ; Multivariate Analysis ; Phosphotransferases ; Receptor Protein-Tyrosine Kinases ; Survival Rate

Microarray comparative genomic hybridization (CGH) has proven to be a specific, sensitive, and rapid technique, with considerable advantages compared to other methods used for analysis of DNA copy number changes. Array CGH allows for the mapping of genomic copy number alterations at the sub-microspecific level, thereby directly linking disease phenotypes to gene dosage alterations. The whole human genome can be scanned for deletions and duplications at over 30,000 loci simultaneously by array CGH (~40 kb resolution). Array CGH can be used for analysis of DNA copy number aberrations that cause not only cancer and human genetic disease, but also normal human variation. This review gives the various array CGH platforms and their applications in cancer and human genetics.
Coat Protein Complex I ; Comparative Genomic Hybridization ; DNA ; DNA Copy Number Variations ; Gene Dosage ; Genetics, Medical ; Genome ; Genome, Human ; Humans ; Phenotype

Lung cancer is a deadly disease that is difficult to diagnose and even more difficult to treat effectively. Many pathways are known to affect tumor growth, and targeting these pathways provides the cornerstone by which cancer is treated. Somatostatin receptors (SSTR) are a family of G protein coupled receptors that signal to alter hormonal secretion, increase apoptosis, and decrease cellular proliferation. These receptors are expressed in many normal and malignant cells, including both small cell and non-small cell lung cancer. Synthetic analogs of SSTRs are commercially available, but their effects in lung cancer are still largely uncertain. Signaling pathway studies have shown that SSTRs signal through phosphotyrosine phosphatases to induce apoptosis as well as to decrease cell proliferation. Radiolabeled SSTR2 analogs are utilized for radiographic imaging of tumors, which, when combined with positron emission tomography-computed tomography (PET-CT) may improve detection of lung cancer. These radiolabeled SSTR2 analogs also hold promise for targeted chemotherapy as well as radiotherapy. In this review, we summarize what is known about SSTRs and focus our discussion on the knowledge as it relates to lung cancer biology, as well as discuss current and future uses of these receptors for imaging and therapy of lung cancer.
Apoptosis ; Biology ; Carcinoma, Non-Small-Cell Lung ; Cell Proliferation ; Electrons ; Humans ; Lung ; Lung Neoplasms ; Molecular Imaging ; Neuroendocrine Tumors ; Phosphoric Monoester Hydrolases ; Phosphotyrosine ; Receptors, G-Protein-Coupled ; Receptors, Somatostatin ; Somatostatin