Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Even when diagnosed at the earliest stages, non-small-cell lung cancer (NSCLC) has often begun to metastasize, leading to frequent systemic relapses and a poor prognosis. There is an urgent need for effective adjuvant systemic therapy in conjunction with surgery to reverse or control further growth of micrometastases in early-stage NSCLC. Several approaches have been investigated in the search for such a therapy, including various chemotherapies, applied preoperatively or postoperatively, chemopreventive agents, and molecular-targeted agents. This article presents an overview of clinical trials for these adjunctive therapies, including completed trials and trials whose results are anticipated. Although standard postoperative chemotherapy has been found to offer little benefit, likely because of the acquisition of resistance in advanced tumors, some clinical trials with neoadjuvant or alternative chemotherapies have produced encouraging results. Targeted agents such as the epidermal growth factor receptor/tyrosine kinase inhibitor gefitinib have shown early promise for effective disease control. A combination of these new approaches and standard therapy for NSCLC may improve long-term survival in patients with lung cancer
Clin Lung Cancer 2003 Sep
PMID:Adjuvant systemic therapies in early-stage non-small-cell lung cancer. 1464 92

The aims of chemoprevention in lung cancer are to prevent the appearance of disease (primary prevention) and to stop or reverse the progression of premalignant lesions (secondary prevention). Until recently, there was little hope that these goals could be attained. However, the results achieved with tamoxifen in the prevention of breast cancer, and the emergence of new therapies specifically targeted to molecules involved in the pathogenesis of lung cancer have set the stage for investigation of these agents for chemoprevention of lung cancer. Two of these new molecular targeted agents are gefitinib, an inhibitor of epidermal growth factor receptor-tyrosine kinase activity, and tipifarnib (R115777, Zarnestra ), an inhibitor of the farnesyltransferase enzyme, which is required for the proper localization and function of the ras oncogene. Tumor responses and disease stabilization have been achieved with both agents in clinical trials. In the Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL)-1 and IDEAL-2 phase II trials, gefitinib was demonstrated to be effective for disease control in patients with advanced non-small-cell lung cancer. The SPORE (Specialized Program of Research Excellence) Trials of Lung Cancer Prevention (STOP) are 2 parallel studies that will investigate the potential effectiveness of gefitinib and tipifarnib in preventing the appearance and progression of premalignant lesions in former or current smokers with a history of smoking-related cancer. These trials should provide information not only about the potential role of gefitinib and tipifarnib in lung cancer chemoprevention, but also about the molecular changes that underlie tumorigenesis and that may serve as markers of disease progression. The STOP trial objectives are to evaluate the effect of gefitinib and tipifarnib on histologic and biologic parameters in patients with evidence of sputum atypia, to evaluate various parameters as potential predictors of the effectiveness of these agents, and to evaluate the tolerability of these agents over a 6-month course of treatment. Histologic response, defined as prevention of appearance or progression of premalignant lesions, is the primary endpoint of these trials. New targeted molecular therapies such as gefitinib and tipifarnib may offer the opportunity to make chemoprevention a viable treatment modality in lung cancer as well as in other human solid tumors.
Clin Lung Cancer 2003 Sep
PMID:Primary and secondary prevention of non-small-cell lung cancer: the SPORE Trials of Lung Cancer Prevention. 1464 93

Chemotherapy is the standard of care for patients with advanced non-small cell lung cancer (NSCLC). Over the past 20 years, advances in chemotherapy have shown minimal incremental improvement in the survival outcomes of patients with advanced NSCLC. With the identification of molecular and genetic alterations in lung cancer, several new potential rationally designed therapeutic targets have emerged. One of these is the epidermal growth factor receptor (EGFR) and member of the ErbB family of receptor tyrosine kinases. Several inhibitors, both antibodies directed at the extra-cellular portion of the receptor, and small molecule inhibitors directed at the tyrosine kinase domain of EGFR are in clinical development in lung cancer. This article will review the pre-clinical rationale and the clinical studies of EGFR inhibitors alone and/or in combination with chemotherapy that have been performed to date in advanced NSCLC.
 ...
PMID:The role of epidermal growth factor receptor in advanced non-small cell lung carcinoma. 1464 27

The epidermal growth factor receptor (EGFR) signaling pathway plays an important role in a number of processes that are key to tumor progression, including cell proliferation, angiogenesis, metastatic spread, and inhibition of apoptosis. EGFR is expressed or overexpressed in non-small-cell lung cancer (NSCLC), and EGFR-mediated growth has been associated with advanced disease and poor prognosis in NSCLC patients. ZD1839 (Iressa) is an orally active, selective EGFR-tyrosine kinase inhibitor that blocks EGFR signal transduction. In preclinical studies using NSCLC cell lines, ZD1839 has been shown to inhibit tumor cell growth. In addition, ZD1839, as monotherapy and in combination with commonly used cytotoxic agents, has produced growth delay in NSCLC human xenografts. Preliminary results from phase I trials in patients with advanced disease have shown that ZD1839 has excellent bioavailability, an acceptable tolerability profile, and promising clinical activity in patients with a variety of tumor types, particularly in NSCLC. ZD1839 is currently in phase III clinical development for the treatment of advanced NSCLC.
Clin Lung Cancer 2001 Aug
PMID:ZD1839 (Iressa) in non-small-cell lung cancer. 1465 86

Traditionally, the efficacy of an anticancer agent has been measured by response rate. With the development of biological molecular-targeted agents, which have a different mechanism of action from conventional agents, it may be appropriate to consider alternative criteria that reflect the positive effect of these biological agents on disease control, palliation, symptom improvement and quality of life. One such targeted agent is the orally active epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ("Iressa", ZD1839). This article reviews the clinical experience of patients with advanced/metastatic non-small-cell lung cancer, who have received gefitinib as part of a clinical trial or through the "Iressa" Expanded Access Programme. Disease-control rates of approximately 50% were observed in some Expanded Access Programme series, comparable with results obtained from Phase II trials. Symptom improvement was also reported. Information that will help identify those patients most likely to respond to treatment will become increasingly important. Therefore, the possible role of prognostic markers and the relationship between epidermal growth factor receptor status and response to gefitinib has been investigated. No clear association between epidermal growth factor receptor expression and response was observed. Future studies of other biomarkers in the epidermal growth factor receptor pathway should help to identify which patients are likely to benefit most from gefitinib.
 ...
PMID:Extensive experience of disease control with gefitinib and the role of prognostic markers. 1466 Oct 46

Gefitinib ("Iressa", ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, has recently been approved in several countries for use in advanced or metastatic non-small-cell lung cancer (NSCLC). In contrast to chemotherapies, which are generally used at or near their maximum-tolerated dose (MTD), gefitinib is used at an optimal biological dose (250 mg day(-1)), which is substantially below its MTD, minimising the risk of adverse events without compromising efficacy. Tolerability data from the compassionate use of gefitinib in the "Iressa" Expanded Access Programme support the favourable safety profile of the agent reported in Phase I and II trials. In both settings, the majority of adverse drug reactions were mild/moderate and consisted mainly of grade 1/2 diarrhoea and skin rash. Although skin rash has been suggested to predict response to gefitinib, available data do not support this hypothesis. Overall, these tolerability data demonstrate that gefitinib has a relatively benign side-effect profile and is a well-tolerated treatment option for patients with previously treated NCSLC, who currently have few alternatives.
 ...
PMID:Tolerability of gefitinib in patients receiving treatment in everyday clinical practice. 1466 Oct 47

The value of platinum compounds has come into question with the advent of newer chemotherapy agents in the management of patients with advanced non-small-cell lung cancer. These newer agents, which include the taxanes, topoisomerase I inhibitors, gemcitabine, and vinorelbine, appear to have higher single-agent response rates and more favorable toxicity profiles when compared to the platinum compounds. However, the toxicity of the platinum compounds is now minimized with the advent of more effective antiemetics. In addition, phase III clinical trials have demonstrated that the strategy of cisplatin dose intensity and prolonged duration of therapy with platinum compounds does not improve overall survival; therefore, moderate doses of cisplatin and a shorter duration of therapy can be given to further decrease toxicity. Furthermore, while phase II trials utilizing nonplatinum-based combination chemotherapy appear to demonstrate superior response rates and survival in comparison to platinum-based doublets, results of phase III trials have demonstrated no improvement in survival. Platinum combination chemotherapy remains the standard approach for stage IV non-small-cell lung cancer. More substantial advances will likely be made with novel molecular targeted therapy, such as the epidermal growth factor receptor inhibitors, which demonstrate synergy with the platinum compounds.
Clin Lung Cancer 2002 May
PMID:The value of platinum compounds in non-small-cell lung cancer. 1466 32

We present a series of cases that illustrate potential benefits of the targeted agent gefitinib for patients with advanced and heavily pretreated non-small-cell lung cancer (NSCLC). In 2 phase II clinical trials, 250 mg/day of gefitinib produced objective tumor response rates of 18% and 11%, with excellent tolerance in patients with advanced NSCLC who had previously received standard chemotherapy. Treatment with gefitinib also led to improvements in disease-related symptoms in approximately 40% of cases. Gefitinib is one of a class of agents that selectively inhibit the epidermal growth factor receptor-tyrosine kinase, which is aberrantly activated in many human solid tumors. Gefitinib treatment resulted in objective radiographic regressions of tumor and symptom improvement in patients with advanced, heavily pretreated NSCLC in clinical trials and in the Expanded Access Program. This series illustrates that the benefits of gefitinib are not limited to patients selected for clinical trial participation but can be generalized to the broader population of patients with NSCLC.
Clin Lung Cancer 2003 Nov
PMID:Antitumor activity and tolerability of gefitinib in patients with non-small-cell lung cancer treated in an expanded access program. 1466 75

Fifteen% or fewer of patients with non-small cell lung cancer (NSCLC) survive 5 years. The current standard of care for patients with locally advanced or metastatic NSCLC is systemic chemotherapy with a two-drug combination regimen that includes a platinum agent. Although systemic chemotherapy reduces the rate of death attributable to lung cancer, disease progression is inevitable and dose-limiting toxicities restrict their use. New molecularly targeted therapies aim to inhibit specific pathways and key molecules implicated in tumor growth and progression while sparing normal cells. Several therapies, which target signal transduction pathways involved in angiogenesis, metastasis, and apoptosis, are in clinical development to treat lung cancer. Among these targeted therapies are the oral, small-molecule epidermal growth factor receptor-tyrosine kinase (EGFR-TK) inhibitors gefitinib and erlotinib. Both therapies have been validated preclinically as new treatment approaches for NSCLC and have shown single-agent activity against advanced, chemorefractory NSCLC in clinical trials. This article focuses on the biology of the EGFR-TK signal transduction pathway, its role in the proliferation of solid tumors, and the rationale for the clinical development of EGFR-TK inhibitors. We also review clinical trials with EGFR-TK inhibitors in NSCLC and future directions of investigation with these targeted agents.
 ...
PMID:Targeting the epidermal growth factor receptor in non-small cell lung cancer. 1467 1

Rash is a class effect of HER1/epidermal growth factor receptor (EGFR)-targeted agents, and has occurred with high frequency and in a dose-dependent manner in clinical trials of these agents in cancer patients. Analysis of phase II trials of erlotinib (Tarceva) in non-small-cell lung cancer, head and neck cancer, and ovarian cancer shows a significant association between rash severity and objective tumor response. Rash severity was highly significantly associated with survival in patients with non-small-cell lung cancer receiving erlotinib; median survival in patients with no rash was 46.5 days, compared with 257 days in those with grade 1 rash (P < .0001) and 597 days in those with grade 2/3 rash (P < .0001). Similarly, for the combined non-small-cell lung cancer, head and neck cancer, and ovarian cancer studies, median survival in patients with no rash was 103 days, compared with 191 days in those with grade 1 rash (P = .0001) and 266 days in those with grade 2/3/4 rash (P = .0001). Similar findings have been made with cetuximab (Erbitux) and in some settings with gefitinib (Iressa). The strong association of rash severity with response/survival suggests that rash may serve as a marker of response to erlotinib treatment and may be used to guide treatment to obtain optimal response. Dosing erlotinib at the maximum tolerated dose, which is associated with more frequent and more severe rash, may improve response rates and survival durations. Further study of the potentially important association between rash and outcome of treatment with EGFR-targeted agents is needed.
 ...
PMID:Can rash associated with HER1/EGFR inhibition be used as a marker of treatment outcome? 1468 20


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>