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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aberrant expression of growth factor receptor systems and dysregulation of the downstream cell signalling molecules have been reported in a wide range of epithelial tumours including head and neck cancer. In some cases, such alterations have been associated with a poor prognosis. In the past 25 years, several antigen specific monoclonal antibodies (mAbs, mouse, chimeric, humanized and human versions), and small molecule kinase inhibitors have been developed that are at different stages of preclinical and clinical developments. Some of these agents (e.g. Herceptin, Iressa, cetuximab, avastin) have already been approved for the treatment of epithelial tumours and may also have potential in the treatment of head and neck cancer patients. This review discusses, the development and potential of these antigen specific agents, in particular the human epidermal growth factor receptor (EGFR) inhibitors, either as a single agent or in combination with other EGFR inhibitors, biological agents (e.g. inhibitors of cycloogenase-2, angiogenesis, insulin like growth factor-I receptor and others), and conventional forms of therapy in the prevention and treatment of head and neck cancer. From preclinical and clinical studies with some of these compounds, it is evident that further detailed studies of biopsies from cancer patients are needed in order to identify markers that can be used not only in the selection of the specific population of cancer patients who would benefit from such antigen specific therapeutic strategies, but also those factors which are responsible for the poor response and the development of a phenotype resistance to such inhibitors. The results of such studies could in turn facilitate the widespread use of such agents in the treatment of a wide range of human cancers including head and neck cancer.
Cancer Metastasis Rev 2005 Jan
PMID:Molecular therapy of head and neck cancer. 1578 77

Paclitaxel (Taxol) and carboplatin are an effective combination regimen for treating advanced breast cancer. Gefitinib (IRESSA) is the first epidermal growth factor receptor tyrosine kinase inhibitor to be approved for cancer treatment. This multicenter phase II trial treated 68 patients with advanced breast cancer with paclitaxel (175 mg/m(2) over 3 h) and 3-weekly carboplatin (area under the curve of 6) for six cycles, and 250 mg/day gefitinib orally. Median age was 57 (range 35-77) years, patients had performance status 0 (69.1%), 1 (27.9%) 2 (2.9%), 82.4% of patients had visceral metastases and 63.2% had received adjuvant chemotherapy. Forty-eight (70.6%) patients completed six cycles of chemotherapy and 20 (29.4%) patients discontinued treatment (seven [10.3%] due to disease progression, seven [10.3%] due to toxicity, five [7.4%] withdrew consent and one [1.5%] died after the first cycle). Sixty-three (92.7%) patients were evaluable for response; nine (13.2%) had complete responses, 30 (44.1%) had partial responses, 21 (30.9%) had stable disease and three (4.4%) had disease progression. Grade 3/4 adverse events in > or =5% of patients except of alopecia, included neutropenia (17.7%), anemia (10.3%), diarrhea (7.4%), thrombocytopenia (5.9%) and peripheral neuropathy (5.9%). Of those tumor biopsies available for immunohistochemical analysis (n=60), 5.0% were positive and 35.0% negative for expression of all HER-family receptors. Comparable numbers of tumor biopsies were nuclear p27(kipl) positive and negative (39.7 and 42.7%, respectively), with the majority (72.1%) negative for cytoplasmic p27(kipl). The observed efficacy data in this study were similar to those reported for the combination of paclitaxel and carboplatin alone.
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PMID:Paclitaxel and carboplatin as first-line chemotherapy combined with gefitinib (IRESSA) in patients with advanced breast cancer: a phase I/II study conducted by the Hellenic Cooperative Oncology Group. 1598 Sep 85

Carcinomatous meningitis (CM) and spinal cord metastases (SCM) are uncommon, yet fatal complication for patients with non-small cell lung cancer (NSCLC). Gefitinib, developed to inhibit the tyrosine kinase of the epidermal growth factor receptor (EGFR), represents the first new treatment modality for NSCLC to emerge from the last decade. Furthermore, it is an attractive option for lung cancer patients with CNS metastasis because of its mild toxicity profile, but there are not much data on the ability of gefitinib to cross the blood-brain barrier. And also, the response of patients with CM and SCM to gefitinib has rarely been reported on. We report here a good response to gefitinib by a heavily pretreated 59-year-old man with CM and SCM.
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PMID:Gefitinib is also active for carcinomatous meningitis in NSCLC. 1602 35

Brain metastases are a frequent finding in patients with non-small cell lung cancer (NSCLC). The present case reports the clinical course of a patient who was treated with gefitinib alone for progressive brain metastases after whole-brain irradiation treatment (WBRT). A 50-year-old women with primary stage IV NSCLC (bone metastases) developed brain metastases after 3 cycles of chemotherapy consisting of paclitaxel and carboplatin (CBDA). After completion of the WBRT, magnetic resonance imaging (MRI) indicated further progression. Two cycles of temozolomide and topotecan were applied; this was ineffective in preventing central nervous system progression. For symptomatic brain metastatic disease the patient received gefitinib as single-agent treatment. Within a few weeks of treatment there was an obvious clinical improvement. Follow-up of the brain 2 months after the start of treatment showed a decrease in both the size and number of brain metastases. Additional manifestations in the lungs and the skeletal system were re-assessed as stable disease during the treatment with gefitinib. Within 4 months of treatment there were no side-effects such as skin rash or any other systemic toxicity. Gefitinib may therefore have a role in the treatment of brain metastases from NSCLC.
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PMID:Brain metastases in metastatic non-small cell lung cancer responding to single-agent gefitinib: a case report. 1602 24

Studies of cell models and profiling of clinical breast cancer material to reveal the mechanisms of resistance to anti-oestrogen therapy, and to tamoxifen in particular, have reported that this phenomenon can be associated with increased expression and signalling through erbB Type 1 growth factor receptors, notably the epidermal growth factor receptor (EGFR) and HER2. Further molecular studies have revealed an intricate interlinking between such growth factor receptor pathways and oestrogen receptor (ER) signalling. Inhibition of receptor tyrosine kinase activity involved in the EGFR signalling cascade forms the basis for the use of EGFR specific tyrosine kinase inhibitors exemplified by gefitinib (ZD1839, Iressa) and erlotinib (OSI-774, Tarceva). Such agents have proved promising in pre-clinical studies and are currently in clinical trials in breast cancer, where gefitinib has been studied more extensively to date. Here, we present an overview of the current development of gefitinib in clinical breast cancer. This includes results from our clinical breast cancer trial 1839IL/0057 that demonstrate the efficacy of gefitinib within ER-positive, tamoxifen-resistant patients with locally advanced/metastatic disease, where parallel decreases in EGFR signal transduction and the Ki67 (MIB1) proliferation marker can be detected as predicted from model system studies. We also consider trials examining combination treatment with gefitinib and anti-hormonal strategies that will begin to address the clinically important question of whether gefitinib can delay/prevent onset of anti-hormone resistance.
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PMID:Overview of tyrosine kinase inhibitors in clinical breast cancer. 1611 90

Gefitinib is the first inhibitor of the epidermal growth factor receptor that has shown activity in non-small-cell lung cancer (NSCLC), but its potential value in the treatment of central nervous system (CNS) metastases has been rarely assessed. We report 2 cases of patients with CNS metastases responding to gefitinib and a review of all the cases previously published in the literature. Computerized and manual searches were performed to identify reports of patients with NSCLC with CNS metastases treated with gefitinib. Ten reports including 16 cases were identified. Of 18 patients, which included our 2 cases, 14 (78%) were female and 4 (22%) were male. Histologic type was reported in 15 cases, and 12 of them (80%) were adenocarcinomas. Five patients exhibited a complete response (28%) and the rest were partial responses. In addition, we identified 5 series of NSCLC patients with CNS metastases treated with gefitinib, and response rates ranged from 0 to 33%. In conclusion, gefitinib can induce long-lasting responses in NSCLC patients with CNS metastases. Responses have been most frequently observed in female patients with adenocarcinoma. Gefitinib may be an effective and well-tolerated option for selected NSCLC patients with CNS metastases.
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PMID:Activity of gefitinib in central nervous system metastases in patients with non-small-cell lung cancer: two case reports and a review of the literature. 1617 2

We have shown that the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) inhibits the development of intrahepatic metastases of hepatocellular carcinoma CBO140C12, and EGFR transactivation by tumor necrosis factor-alpha is a possible target of gefitinib. In the present study, we focused on the fibronectin (FN)-dependent signaling pathway to further elucidate the antimetastatic activity of gefitinib in CBO140C12 cells. We initially observed that FN induced activation of extracellular signal-regulated kinase (ERK), p38 and Akt, as well as cell proliferation and CBO140C12 cell invasion. These responses were mediated by EGFR tyrosine kinase, because gefitinib inhibited these effects of FN. FN-induced ERK, p38 and Akt activation was partly blocked by the Arg-Gly-Asp (RGD)-pseudo-peptide FC-336, anti-alphav integrin antibody RMV-7, the broad-spectrum matrix metalloprotease inhibitor GM6001 and the broad spectrum a disintegrin and metalloprotease (ADAM) inhibitor TAPI-1. But these inhibitors had no effect on EGF-induced signaling pathways, suggesting that integrins and ADAM may be upstream components of EGFR in these responses. These results suggest that FN-induced activation of ERK, p38, Akt, cell proliferation and invasion was mediated, at least in part, via integrins, ADAM and EGFR, and that this FN-induced signaling pathway might be involved in the antimetastatic activity of gefitinib.
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PMID:Activation of MEK/ERK and PI3K/Akt pathways by fibronectin requires integrin alphav-mediated ADAM activity in hepatocellular carcinoma: a novel functional target for gefitinib. 1644 27

Human esophageal cancers have been shown to express high levels of epidermal growth factor receptor (EGFR) and a relationship between high EGFR expression and local advance, the number of lymph node metastases, life expectancy, and sensitivity to chemo-radiotherapy has been demonstrated. We examined the use of gefitinib, an orally active EGFR-selective tyrosine kinase inhibitor, as a new strategy for treatment of esophageal carcinoma. The effects of gefitinib were evaluated in monotherapy and in combination with radiotherapy in human esophageal carcinoma cell lines. Gefitinib produced a dose-dependent inhibition of cellular proliferation in all of the 8 esophageal carcinoma cell lines examined, with IC50 values ranging from 5.7 microM to 36.9 microM. In combination, gefitinib and radiotherapy showed a synergistic effect in 2 human esophageal carcinoma cell lines and an additive effect in 5 cell lines. Western blotting demonstrated that gefitinib blocked activation of the EGFR-extracellular signal-regulated kinase (Erk) pathway and the EGFR-phosphoinositide-3 kinase (PI3K)-Akt pathway after irradiation. These results suggest that further evaluation of EGFR blockade as a treatment for esophageal cancer should be performed, and that radiotherapy combined with EGFR blockade may enhance the response of esophageal carcinoma to therapy.
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PMID:Gefitinib, an epidermal growth factor receptor blockade agent, shows additional or synergistic effects on the radiosensitivity of esophageal cancer cells in vitro. 1650 86

Anti-EGFR (epidermal growth factor receptor) therapies, including tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, demonstrate activity in a variety of tumor types. While both inhibit the EGFR pathway, they act via different mechanisms. Monoclonal antibodies bind to the extracellular domain of EGFR, preventing ligand binding and interrupting the signaling cascade. Tyrosine kinase inhibitors bind to the intracellular domain of EGFR and inhibit the downstream effects of EGFR ligand binding. Both categories of agents have been evaluated in a variety of clinical settings and tumor types, including colorectal cancer, non-small-cell lung cancer (NSCLC), and squamous cell carcinoma of the head and neck (SCCHN). Phase II/III trials in patients with previously treated or untreated metastatic colorectal cancer, including those with documented refractory disease, demonstrate activity of the monoclonal antibody cetuximab (Erbitux) as a single agent or in combination with both irinotecan (Camptosar)- and oxaliplatin (Eloxatin)-based chemotherapy. Activity of cetuximab added to chemotherapy in patients who previously progressed on the same regimen suggests an ability to overcome chemotherapy resistance in some patients. In NSCLC, phase II trials of the TKI gefitinib (Iressa) plus combination chemotherapy showed impressive activity with considerable toxicity. Large, randomized, phase II trials (IDEAL 1 and 2) reported modest activity of gefitinib in NSCLC; however, phase III trials (INTACT 1 and 2)failed to demonstrate a benefit to adding gefitinib to chemotherapy. A similar trend was noted in trials of erlotinib (Tarceva) (TALENT and TRIBUTE). Phase II/III trials have shown promising activity of cetuximab in SCCHN, generating significantly improved survival in combination with radiotherapy over radiotherapy alone in locally advanced disease and significantly improved response rates in combination with chemotherapy over chemotherapy alone in recurrent/metastatic disease, with little enhancement of toxicity profiles. Limited clinical experience with TKIs in SCCHN suggests similar degrees of single-agent activity and dermatologic toxicities. Levels of EGFR expression and the presence of EGFR mutations correlate with responsiveness to TKI therapy, while it remains unclear whether a relationship exists between level of EGFR expression and cetuximab efficacy in colorectal cancer. Anti-EGFR therapies are good candidates for combination with other treatment modalities, including chemotherapy and radiotherapy, due to their tolerable safety profile and nonoverlapping toxicities. In addition, these agents represent important treatment options in patients ineligible for chemotherapy due to refractory or resistant disease. Ongoing trials continue to investigate both the monoclonal antibodies and TKIs in various treatment settings.
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PMID:Anti-EGFR therapies: clinical experience in colorectal, lung, and head and neck cancers. 1673 79

Lung cancer is one of the most common solid tumors to develop metastases to bone. The prognosis of patients with metastatic lung cancer to bones is short,usually less than 6 months. The treatment requires a multidisciplinary approach that addresses radiotherapy, surgery, chemotherapy, and medical therapy with analgesics and bisphosphonates. Radiotherapy for metastatic bone tumor is a mainstay to relieve pain and control the localized disease. Doses in the range of 20 Gy in 5 fractions, 30 Gy in 10 fractions are acceptable in most circumstances. Prophylactic fixation for long bone fractures is recommended in cases where 30 to 50% of the cortex has been destroyed, pain is present after radiotherapy, or life expectancy is more than 3 months. Systemic chemotherapy has been proved to prolong survival of patients with metastatic non-small-cell lung cancer (NSCLC) as well as extensive small cell lung cancer (SCLC). Combination chemotherapy of platinum and a new drug is recommended in NSCLC patients with good performance status (PS). Gefitinib in upfront or second-line treatment is an optional therapy in adenocarcinoma patients without a history of smoking. Cisplatin combined with etoposide or irinotecan is a standard therapy in SCLC patients with PS 0 or 1. Carboplatin and etoposide is a treatment of choice in SCLC patients with PS 2 or 3. Medical management of cancer pain requires nonsteroidal anti-inflammatory drugs and opioids. Cancer pain that necessitates more than 120 mg of oral morphine is morphine-resistant pain and requires some adjuvant drugs such as corticosteroids, ketamine,anticonvulsants, or local anesthetics. The third generation bisphosphonate zoledronate has been demonstrated to improve cancer pain and to prevent skeletal morbidity in lung cancer patients with metastatic bone disease.
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PMID:[Lung cancer with bone metastasis]. 1691 19


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