Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0242379 (lung cancer)
71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gefitinib is active and well tolerated in patients with advanced non-small cell lung cancer (NSCLC); however, its role in patients with brain metastases has not been clearly defined. We had conducted a prospective study to give gefitinib to NSCLC patients irrespective of their performance status (PS), number of prior treatment regimens and the presence of brain metastases. A total of 76 patients were enrolled. Fifty-seven patients had measurable lesions and the objective response rate was 33.3% (95% confidence interval [95% CI], 20.7-46.0%). For all enrolled patients, the disease control rate was 63.2% (95% CI, 52.1-74.3%) with a median progression-free survival of 5.0 months (95% CI, 3.6-6.5 months) and median overall survival 9.9 months (95% CI, 4.9-14.8 months). Twenty-one patients had simultaneously assessable intracranial lesions (ICLs) and extracranial lesions (ECLs), 17 of them (81.0%) showed comparable tumor response. There was no survival difference between the patients with and without metastatic brain disease. Most drug-related adverse events were mild. Intolerable toxicities happened in five patients, four of them were interstitial pneumonia (5.8%). Severity of skin toxicity was tightly associated with tumor response and patient survival (P = 0.007 and <0.001) and the association was consistent in the analysis using early toxicity profile (P = 0.033 and 0.001). In conclusion, gefitinib is active in patients with brain metastasis from NSCLC and tumor response is related to skin toxicity. It is feasible to conduct randomized trials to identify the role of gefitinib alone or in combination with other modality for treatment of NSCLC patients who have metastatic brain lesion(s).
Lung Cancer 2005 Jan
PMID:Gefitinib is active in patients with brain metastases from non-small cell lung cancer and response is related to skin toxicity. 1560 63

Gefitinib is a small molecule that specifically inhibits the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) type 1 by interfering with the adenosine triphosphate (ATP) binding site. At doses that maximally inhibit EGFR tyrosine kinase activity chosen for phase II trials, the most common side effects of gefitinib are low-grade rash or diarrhea. An infrequent but serious side effect of gefitinib is interstitial lung disease (ILD). The Iressa dose evaluation for advanced lung cancer phase II trials (IDEAL 1 and IDEAL 2) of single agent gefitinib, 250 or 500 mg orally per day in pretreated patients with non-small cell lung cancer (NSCLC), found about 20% of patients on IDEAL-1 and 10% of patients on IDEAL-2 had major objective responses and improvement of symptoms. The data from the IDEAL trials and the extensive experience from the 21,000 patients treated on the expanded access program, suggests that the patients who have a major objective response probably have a significant survival benefit in addition to palliative benefit. In addition, approximately 40% of patients on the IDEAL trials experienced improvement in symptoms. Gefitinib was approved for third line treatment of NSCLC. Gefitinib is effective, safe, and well-tolerated single-agent therapy in previously treated NSCLC. Although there have been no direct comparisons, the small molecule inhibitors of EGFR gefitinib and erlotinib appear to have similar efficacy. Erlotinib has been shown to produce a survival advantage compared to best supportive care in an unselected group of previously treated patients with NSCLC. Until similar trials are completed comparing gefitinib to best supportive care, there is a similar survival advantage for gefitinib. Nonsmokers, women, and patients with adenocarcinoma, are more likely to have major objective responses than other patients. Bronchioalveolar lung cancer is a subtype of NSCLC that is more likely to respond to gefitinib. Several groups have now reported that most, but not all, tumors experiencing a major objective response to gefitinib have mutations associated with the ATP-binding site of EGFR. It is reasonable to move gefitinib in to second-line therapy for patients who are known to have a tumor that is more likely to respond to gefitinib. Also, I would treat such patients with gefitinib as first-line therapy on an appropriate clinical trial approved by the Institutional Review Board (IRB). Outside of a clinical trial, patients with advanced disease should initially be treated with a combination of doublet chemotherapy. There is strong evidence that there is no benefit to concurrent chemotherapy and gefitinib. Gefitinib should not be given concurrently with cytotoxic chemotherapy as initial treatment for NSCLC. Sequential therapy combining chemotherapy and gefitinib in advanced disease or as adjuvant therapy should only be done in the context of a clinical trial approved by the IRB. There is preclinical evidence suggesting that gefitinib is a radiosensitizer. Early results from trials combining radiation, or chemoradiotherapy with gefitinib have shown that these combinations are without excessive additive toxicity. There is no proven clinical benefit for concurrent Gefitinib and radiation. Gefitinib should only be given with radiation as part of an appropriate clinical trial approved by the IRB.
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PMID:Gefitinib therapy for non-small cell lung cancer. 1561 Jul 17

Molecular targeting strategies for cancer therapy are distinct from conventional chemotherapy and radiotherapy in their potential to provide increased tumor specificity. One particular molecular target of high promise in oncology is the epidermal growth factor receptor (EGFR). The EGFR is overexpressed, dysregulated or mutated in many epithelial malignancies, and EGFR activation appears important in tumor growth and progression. Advances in signal transduction biology continue to sharpen our understanding regarding specific contributions of EGFR signaling networks to cancer behavior. Two predominant classes of EGFR inhibitors have been developed including monoclonal antibodies (mAbs) that target the extracellular domain of EGFR, such as cetuximab (Erbitux), and small molecule tyrosine kinase inhibitors (TKIs) that target the receptor catalytic domain of EGFR, such as gefitinib (Iressa) and erlotinib (Tarceva). Mechanisms of action for EGFR inhibitors have been investigated in preclinical model systems. Safety, activity, pharmacokinetics and pharmacodynamics have been assessed in clinical trials. The anti-EGFR mAbs and TKIs have partially overlapping toxicity profiles, but distinct routes of administration, serum half-lives and therefore dosing schedules. Both classes of agents show clear antitumor activity, and cetuximab and gefitinib have been recently FDA approved for colorectal and lung cancer indications respectively. However, the absence of survival benefit for EGFR TKIs in combination with chemotherapy in large-scale phase III lung cancer trials in 2003 underscores a major challenge in anti-EGFR oncology therapeutics; namely to identify those tumors and patients that will respond predictably to EGFR inhibitor approaches. Newly identified mutations in the EGFR catalytic domain that appear to confer sensitivity to EGFR TKIs promise to open new doors of investigation regarding response prediction. Advances will also require enhanced molecular understanding of the overall EGFR signaling network, and improved methods to gauge the dependence of individual tumors on EGFR signaling pathways for growth advantage. Results from newly reported phase III trials in 2004 now confirm a survival advantage for the use of EGFR inhibitors in combination with high-dose radiation in head and neck cancer, and in refractory lung cancer respectively. It appears likely that EGFR inhibitors (and other rationally designed molecular growth inhibitors) will play a meaningful role in cancer therapy in the years to come.
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PMID:Epidermal growth factor receptor inhibition strategies in oncology. 1561 46

PURPOSE Evaluation of disease-related symptom improvement rate by the Lung Cancer Subscale (LCS) of the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire was a coprimary end point of the pivotal phase II trial of gefitinib (Iressa; AstraZeneca, Wilmington, DE) conducted in the United States. This report includes the results of analyses exploring the relationship between weekly LCS scores and radiographic response and survival, as well as detailed protocol-specified analysis of symptom and quality-of-life data. PATIENTS AND METHODS In this trial, 216 symptomatic patients with advanced non-small-cell lung cancer (NSCLC) who had at least two prior chemotherapy regimens received gefitinib 250 or 500 mg/d. Disease-related symptoms were assessed weekly and quality of life was assessed monthly by LCS and FACT-L, respectively. Results Symptom improvement was rapid and correlated with tumor response and survival. At the recommended gefitinib dose of 250 mg/d, median overall survival times were 13.6 and 4.6 months for patients with and without symptom improvement, respectively, and 9.7 months for patients with symptom improvement without tumor response. Among patients with stable disease or disease progression, those with symptom improvement had significantly better overall survival than those without improvement. At 250 mg/d, 30% of patients showed a quality-of-life improvement that was correlated with tumor response. CONCLUSION This triadic analysis of response, survival, and symptom data supports the hypothesis that tumor response and symptom response are related and that each predicts survival. Among these NSCLC patients treated with gefitinib, symptom improvement was complementary to and, for most patients, preceded evidence of radiographic regression.
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PMID:Clinically meaningful improvement in symptoms and quality of life for patients with non-small-cell lung cancer receiving gefitinib in a randomized controlled trial. 1569 77

Patients with advanced non-small-cell lung cancer (NSCLC) have a poor prognosis and suffer many disease-related symptoms. Treatments should therefore aim to palliate these symptoms as well as improve overall quality of life. Gefitinib ("Iressa") is a novel epidermal growth factor receptor tyrosine kinase inhibitor that targets cell signaling involved in tumor growth and differentiation. In Phase II trials in recurrent NSCLC, gefitinib provided objective responses and symptom relief, and was generally well tolerated. Now approved for the treatment of advanced NSCLC in over 25 countries, including Japan and the USA, gefitinib has demonstrated significant clinical benefit in a disease area with limited treatment options.
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PMID:Gefitinib ("Iressa"): a new therapy for advanced non-small-cell lung cancer. 1573 5

This report highlights the case of a symptomatic 77-year-old non-smoking female patient who was diagnosed with advanced non-small-cell lung cancer (NSCLC), metastatic to the liver and contralateral lung. After tumor progression in the liver and lung following polychemotherapy, multiple diffuse brain and cerebellar metastases were apparent. Oral treatment with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa') 250 mg/day resulted in progressive and durable symptom relief, and improvements in quality of life and performance status. Reductions in the size of the primary pulmonary tumor and brain, cerebellar, and liver metastases were observed. Furthermore, gefitinib was well tolerated with an absence of adverse events. These results provide evidence that oral gefitinib is active in patients with advanced NSCLC and central nervous system metastases.
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PMID:Gefitinib ('Iressa', ZD1839) is active against brain metastases in a 77 year old patient. 1573 17

Gefitinib (Iressa, ZD1839) is an orally active inhibitor selective for the epidermal growth factor receptor tyrosine kinase and has shown promise in the treatment of non-small cell lung cancer (NSCLC). There has been no report to date of the effect of gefitinib treatment in patients with small-cell lung cancer (SCLC). Here we report a case of metastatic SCLC that was successfully treated with gefitinib. This case is the first reported of objective clinical response after gefitinib treatment in a patient with SCLC. Our report suggests that treatment with gefitinib is a novel option for a subset of patients with SCLC.
Lung Cancer 2005 Apr
PMID:Efficacy of the tyrosine kinase inhibitor gefitinib in a patient with metastatic small cell lung cancer. 1577 82

Gefitinib (Iressa), the first commercially available epidermal growth factor receptor-tyrosine kinase (EGFR-TK) inhibitor, is indicated in the management of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). However, approved uses differ between countries; in most markets, gefitinib is approved for third-line use only (e.g. the US, Canada and Switzerland), although in some it is approved for both second- and third-line use (e.g. Japan and Australia) and, additionally, in patients considered unsuitable for chemotherapy (e.g. Indonesia and the Philippines). Few third-line treatment options exist for patients with inoperable advanced NSCLC who have failed both docetaxel and platinum-based chemotherapy regimens. Gefitinib represents a significant advance in the treatment of this population; a once-daily oral dosage of 250 mg/day was well tolerated, produced objective tumour responses and disease stabilization, and improved disease-related symptoms and quality of life. It also produced overall survival outcomes that compared favorably with historical outcomes in a similar group of patients treated with three or four different chemotherapy regimens. These findings have been supported by observations from a global compassionate-use program. Ongoing or planned clinical trials are designed to confirm and/or further define the role of the drug in the above and other clinical settings. Preliminary data demonstrate the presence of activating mutations in EGFR-TK among patients whose disease was highly responsive to treatment with gefitinib, although such mutations have not been correlated to all patients who benefit from the drug. Further studies are needed to fully elucidate the clinical implications of EGFR mutations and to identify patients likely to benefit from EGFR-targeted therapy.
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PMID:Spotlight on gefitinib in non-small-cell lung cancer. 1581 76

Gefitinib, an orally active, selective inhibitor of epidermal growth factor-receptor tyrosine kinase, is an effective treatment for patients with advanced non-small-cell lung cancer (NSCLC). Most drug-related adverse events are mild to moderate; however, some patients may develop acute interstitial pneumonia that is sometimes fatal. In a prospective study of gefitinib in 76 patients with advanced NSCLC, 69 patients were evaluable for toxicity, and 4 cases (5.8%) of gefitinib-related interstitial pneumonia were diagnosed: 1 occurred in the second week; 2 in the second month; and 1 during the fourth month of treatment. When interstitial pneumonia occurred, the patients had stable disease (n = 2), a partial response (n = 1), or progressive disease (n = 1). All 4 patients recovered when gefitinib treatment was stopped and glucocorticosteroid therapy was started; no deaths related to gefitinib therapy were noted in this series. While treating NSCLC patients with gefitinib, it is important to carefully evaluate any new-onset respiratory symptoms and promptly arrange radiographic examinations, and to stop gefitinib treatment and begin glucocorticosteroid therapy whenever pulmonary toxicity is highly suspected.
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PMID:Interstitial pneumonia during gefitinib treatment of non-small-cell lung cancer. 1585 69

Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor effective in patients with lung cancer with mutations in exons 19 and 21 of the EGFR tyrosine kinase domain. In this study, the authors tested the presence of such mutations in 95 gliomas including glioblastomas, anaplastic oligodendrogliomas, and low-grade gliomas. No mutation was found, which suggests that the biology of EGFR in gliomas is different from lung cancer and that this may be a factor in the resistance of glioblastomas to gefitinib.
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PMID:EGFR tyrosine kinase domain mutations in human gliomas. 1585 41


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