Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Significant advances have been made in the treatment of advanced colorectal cancer over the past 5 years, namely due to the introduction of three novel cytotoxic agents-capecitabine (Xeloda), irinotecan (Camptosar), and oxaliplatin (Eloxatin)-and the recent approval of two biologic agents-bevacizumab (Avastin) and cetuximab (Erbitux). During this time period, the median survival of patients with advanced, metastatic disease has gone from 10 to 12 months to nearly 24 months. Intense efforts have focused on identifying novel targeted therapies that target specific growth factor receptors, critical signal transduction pathways, and/or key pathways that mediate the process of angiogenesis. Recent clinical trial results suggest that the anti-VEGF antibody bevacizumab can be safely and effectively used in combination with each of the active anticancer agents used in colorectal cancer. Despite the development of active combination regimens, significant improvements in the actual cure rate have not yet been achieved. Combination regimens with activity in advanced disease are being evaluated in the adjuvant and neoadjuvant settings. The goal is to integrate these targeted strategies into standard chemotherapy regimens so as to advance the therapeutic options for the treatment of advanced colorectal cancer. Finally, intense efforts are attempting to identify the critical molecular biomarkers that can be used to predict for either clinical response to chemotherapy and/or targeted therapies and/or the drug-specific side effects. The goal of such studies is to facilitate the evolution of empiric chemotherapy to individually tailored treatments for patients with colorectal cancer.
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PMID:Current therapies for advanced colorectal cancer. 1594 40

The purpose of this study was to determine the tolerability and activity of rofecoxib (Vioxx; Merck & Co., Inc., Whitehouse Station, NJ, http://www.merck.com) combined with weekly irinotecan (Camptosar; Pfizer Pharmaceuticals, New York, http://www.pfizer.com) and infusional 5-fluorouracil (5-FU) as second-line therapy in metastatic colorectal cancer (MCRC). Enrolled patients had previously treated metastatic disease, were aged > or =18 to < or =75 years, and had adequate performance status. A cycle of treatment consisted of i.v. irinotecan on days 1, 8, 15, and 22, rofecoxib at an oral dose of 50 mg/day, and infusional 5-FU at a fixed dose of 200 mg/m(2) per day for 5 weeks followed by 3 weeks of therapy with rofecoxib alone. In the dose-finding study, the starting dose of irinotecan was 87.5 mg/m(2) and further dose escalations were planned by increments of 12.5 mg/m(2) up to 125 mg/m(2). Forty-eight consecutive patients were enrolled in the study. Among the 15 cases enrolled in the dose-finding study, one patient experienced grade 3 reversible diarrhea as the dose-limiting toxicity, at the fourth dose level tested. Therefore, the dose of irinotecan for the phase II study was 125 mg/m(2), and 33 patients were enrolled and received a total of 75 cycles. Hematological side effects were moderate, with grade 4 neutropenia recorded in only two patients. The most common nonhematological toxicity was diarrhea, occurring in 25 patients (75.8%) and considered to be of grade 3 in 12 patients (36.4%). Sixteen patients achieved partial responses (48.5%; 95% confidence interval [CI], 30.8%-66.5%), and another 10 patients (30.3%) had stable disease. The median time to progression was 7 months (95% CI, 5-12) and the median overall survival (OS) was 18 months; the 1-year estimated OS rate was 69.4%. The unique schedule tested in this study is feasible, is well-tolerated, and has promising activity in patients with MCRC after progression on oxaliplatin (Eloxatin; Sanofi-Synthelabo Inc., New York, http://www.sanofi-synthelabo.us)-based chemotherapy.
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PMID:Combined therapy with weekly irinotecan, infusional 5-fluorouracil and the selective COX-2 inhibitor rofecoxib is a safe and effective second-line treatment in metastatic colorectal cancer. 1624 51

A large number of patients with colorectal cancer have relatively early disease, and thus, adjuvant therapy has the potential to save lives. In stage III patients, there has been a steady improvement in 3-year disease-free survival with the use of 5-fluorouracil/leucovorin (5-FU/LV) regimens and capecitabine (Xeloda); Hoffmann-La Roche Inc., Nutley, NJ, http://www.rocheusa.com) regimens. A median survival longer than 20 months was observed in patients with metastatic disease when treated with combination chemotherapy containing oxaliplatin (Eloxatin); Sanofi-Synthelabo Inc., New York, http://www.sanofi-synthelabo.us) or irinotecan (Camptosar); Pfizer Pharmaceuticals, New York, http://www.pfizer.com). This has led to 5-FU/LV/oxaliplatin becoming standard therapy, along with 5-FU/LV/irinotecan. New data confirm the beneficial effect on disease-free survival of adding oxaliplatin to adjuvant colorectal cancer regimens based on 5-FU. These regimens show an effect when given in bolus as well as in infusional schedules. Interest in future adjuvant regimens focuses on the potential additional benefit of molecularly targeted agents, such as bevacizumab (Avastin); Genentech, Inc., South San Francisco, CA, http://www.gene.com), and on the ability of applied genomics to distinguish between high- and low-risk populations.
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PMID:Rapid evolution in colorectal cancer: therapy now and over the next five years. 1627 53

Liver is the main target for colorectal cancer (CRC) metastases. About 50% of all patients affected by CRC develop liver metastases. Surgery remains the only potentially curative strategy and indications to surgery and resectability criteria are now less restrictive than before so that a more aggressive attitude in the treatment of metastatic lesions is the rule. However surgery is not possible in the majority of patients. For non resectable patients two options are available: local treatment strategies (Radio-frequency ablation and Cryosurgery: alone or in combination with surgery) and chemotherapy. High rates of objective response achieved with Fluoropyrimidines, Oxaliplatin (OHP) and Irinotecan (CPT-11) based chemo-therapy, enable initially unresectable patients to undergo surgery, with a 5-year survival rate comparable to that observed for primary resectable patients. Therefore chemotherapy has not only a palliative aim, but becomes a fundamental moment of a combined medical and surgical treatment with curative purpose. After surgery two-thirds of patients will relapse in first two years, so that adjuvant therapy has been investigated to reduce recurrence rates, mainly testing hepatic arterial infusion (HAI) schedules. So far no randomized trials have been published on the role of systemic intravenous adjuvant chemo-therapy. Finally we report the results of our monoinstitutional experience, suggesting a possible role of systemic adjuvant chemotherapy in reducing recurrence rates after liver metastasectomy. Probably in the next years new targeted drugs and locoregional therapies will contribute to further improve prognosis of such patients, in a neoadjuvant, adjuvant and palliative setting.
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PMID:[Treatment of colorectal cancer liver metastases]. 1656 3

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

Irinotecan, a water-soluble, semisynthetic derivative of camptothecin, is a key component of first- and second-line treatment regimens for metastatic colorectal cancer (CRC). In the first-line treatment of metastatic CRC, the results of two prospective, multicenter phase III trials have shown that the combination of irinotecan with bolus or infusional 5-fluorouracil (5FU)/leucovorin (LV) can significantly prolong survival compared with 5FU/LV alone, with a manageable side effects profile. In addition, irinotecan-based regimens, with or without oxaliplatin, may improve resectability of metastases and further increase patient survival. Studies of irinotecan in the first-line setting in combination with newer agents, such as bevacizumab, have shown impressive overall survival. In the second-line setting, irinotecan has demonstrated efficacy superior to that of best supportive care. Initial studies of irinotecan plus bolus 5FU/LV, and the preliminary results from trials of irinotecan plus infusional 5FU/LV in the adjuvant setting, have been disappointing; however, for the largest trial, the Pan-European Trial in Adjuvant Colon Cancer, results with sufficient follow-up are pending. Irinotecan has an acceptable tolerability profile and is not associated with cumulative toxicities in patients with metastatic CRC; regimens containing irinotecan extend treatment duration and improve survival. New regimens and adjunctive therapies are being explored to reduce the incidence of common complications of irinotecan treatment, such as diarrhea and neutropenia.
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PMID:Irinotecan in the treatment of colorectal cancer. 1695 32

Some investigators have suggested that preoperative chemotherapy for hepatic colorectal metastases may cause hepatic injury and increase perioperative morbidity and mortality. The objective of the current study was to examine whether treatment with preoperative chemotherapy was associated with hepatic injury of the nontumorous liver and whether such injury, if present, was associated with increased morbidity or mortality after hepatic resection. Two-hundred and twelve eligible patients who underwent hepatic resection for colorectal liver metastases between January 1999 and December 2005 were identified. Data on demographics, clinicopathologic characteristics, and preoperative chemotherapy details were collected and analyzed. The majority of patients received preoperative chemotherapy (n = 153; 72.2%). Chemotherapy consisted of fluoropyrimidine-based regimens: 5-FU monotherapy, 31.6%; irinotecan, 25.9%; and oxaliplatin, 14.6%. Among those patients who received chemotherapy, the type of chemotherapy regimen predicted distinct patterns of liver injury. Oxaliplatin was associated with increased likelihood of grade 3 sinusoidal dilatation (p = 0.017). Steatosis >30% was associated with irinotecan (27.3%) compared with no chemotherapy, 5-FU monotherapy, and oxaliplatin (all p < 0.05). Irinotecan also was associated with steatohepatitis, as two of the three patients with steatohepatitis had received irinotecan preoperatively. Overall, the perioperative complication rate was similar between the no-chemotherapy group (30.5%) and the chemotherapy group (35.3%) (p = 0.79). Preoperative chemotherapy was also not associated with 60-day mortality. In patients with hepatic colorectal metastases, preoperative chemotherapy is associated with hepatic injury in about 20 to 30% of patients. Furthermore, the type of hepatic injury after preoperative chemotherapy was regimen-specific.
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PMID:Preoperative chemotherapy for colorectal liver metastases: impact on hepatic histology and postoperative outcome. 1749 35

Adjuvant treatment of colon cancer is a relatively new concept, having been first validated less than 20 years ago. Fluoropyrimidines including 5-fluorouracil (5-FU), introduced in clinical trials in the 1950s, are an integral component of the treatment of colon cancer in the adjuvant setting. Whereas both irinotecan and oxaliplatin have demonstrated clinical activity in metastatic colorectal cancer, only oxaliplatin has demonstrated efficacy in the adjuvant setting when added to 5-FU-based therapy. Irinotecan, despite showing a survival advantage in the second-line metastatic cancer setting and a survival advantage when added to first-line metastatic cancer treatment, has failed to show a survival or disease-free survival benefit in the adjuvant setting. In contradistinction, the addition of oxaliplatin to 5-FU plus leucovorin has improved disease-free survival in 2 large randomized adjuvant trials. Oxaliplatin/5-FU/leucovorin should therefore be regarded as a reference standard for adjuvant therapy. This comprehensive review of adjuvant therapy for colon cancer will cover the role of fluoropyrimidines and oxaliplatin, the controversies of adjuvant therapy for patients with stage II cancer, and the ongoing clinical trials that will define the future role, or lack thereof, of newer agents in adjuvant therapy.
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PMID:Adjuvant therapy of colon cancer: current status and future directions. 1762 Jul 69

A 61-year-old male had undergone distal gastrectomy followed by right hepatectomy for alpha-fetoprotein-producing gastric cancer and liver metastasis. Subsequently, multiple lung metastases were detected by follow-up chest examinations. Despite treatment with TS-1/Irinotecan (CPT-11)/Cisplatin (CDDP) combination therapy, the metastases increased gradually in size and number. Combination therapy with TS-1/Paclitaxel (TXL)/CDDP was effective, as confirmed by marked reduction in tumor size on chest computed tomography. TS-1/TXL/CDDP chemotherapy was administered repeatedly for relapse of lung metastases. The relapse was controlled twice with this chemotherapy regimen, and the patient remains alive at 52 months after gastrectomy without pulmonary symptoms such as hemosputum. Although patients with postoperative lung metastases from AFP-producing gastric cancer have a dismal prognosis, our clinical experience suggests that TS-1/TXL/CDDP combination therapy may be a useful regimen for such conditions.
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PMID:Combination chemotherapy using TS-1, Paclitaxel and cisplatin for multiple lung metastases from AFP-producing gastric cancer: a case report. 1762 94

In many cases unresectable or recurrent pulmonary metastases do not respond to systemic chemotherapy or the side-effects are not acceptable. Based on the results of our experiments the isolated lung perfusion could improve the option of local chemotherapy. Parameters for lung edema formation (relative increase in weight, gas exchange, histopathology) were evaluated during extracorporal ventilation and reperfusion of lobes resected for lung cancer. Drug concentration was measured in lung tissue, tumour and hilar lymphnodes. Irinotecan was detected in concentrations from 0.06 to 35.3 mg/g in correlation to the content of drug in the perfusate. None of the preparations perfused with a concentration up to 20 times higher than the concentration for systemic application generated a drug-dependent reperfusion edema. A toxic injury of lung parenchyma could be excluded histopathologically. Therefore, we documented that even a perfusion with 2000 mg/l does not cause any relevant acute toxic damages of the lung parenchyma. The transferability of pharmacological data gained through the IHLP is excellent and minimises potential adverse reactions for the patients during phase I trials. As an alternative to systemically applied cytostatic drugs the isolated lung perfusion with irinotecan deserves further attention due to its interesting pharmacological profile with regard to tumor selectivity.
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PMID:Acute toxicity of irinotecan in the ex-vivo isolated perfused human lung model--high-dose therapy during isolated perfusion without acute toxic lung edema. 1767 Jul 37


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