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)

Combination chemotherapy with newer, more active drugs in patients with advanced and/or metastatic bladder cancer might show improved response rate and survival. Gemcitabine (GEM) and Epidoxorubicin (EPI) have demonstrated activity in this disease. In addition, experimental studies in vitro have shown that the two agents have additive-synergistic effects when used in combination. Our prior phase I dose-finding study in previously untreated patients with advanced or metastatic bladder cancer defined recommended doses for further trials of GEM 1000 mg/m2 and EPI 25 mg/m2 on days 1, 8 and 15 every 28 days. A phase II trial at this dose level was initiated in previously untreated patients to assess efficacy and toxicity. Eligible patients had measurable disease; Karnofsky performance status (PS) of > 40; no prior chemotherapy; and adequate bone marrow reserve, cardiac, hepatic and renal function. Thirty- one patients (22 males, 9 females) with median age of 64 (range 44-75) and median PS of 80 were accrued, and all were eligible. Twelve patients had T4N1-2 M0, 8 had lymph node only metastases, while 11 had visceral metastases (liver, bone, lung). A total of 181 cycles was administered (range 3-7 per patient). Major toxicities (WHO grade > or = 3) were: neutropenia in 5 patients, thrombocytopenia in 2 patients, and anemia in 2 patients. Three patients had febrile neutropenic episodes and only 3 patients required dose reduction. Grade 1-2 non-hematological toxicities included nausea/vomiting, stomatitis and alopecia. No cardiac toxicity was observed. Of the 30 response evaluable patients, 17 (57%) demonstrated a major response (3 complete and 14 partial) (95% CI: 39%-75%), 7 had stable disease (23%) and 6 progressed (20%). These preliminary results confirm the phase I observation that the combination of GEM--EPI is highly active in the treatment of advanced and metastatic bladder cancer with a favourable toxicity profile.
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PMID:Gemcitabine plus Epi-doxorubicin as first-line chemotherapy for bladder cancer in advanced or metastatic stage: a phase II. 1253 29

The background, rationale, and preliminary results of a phase II trial of gemcitabine plus trastuzumab in heavily pretreated metastatic breast cancer patients are presented. Gemcitabine and trastuzumab both exhibit single-agent activity in previously treated metastatic breast cancer. Preclinical studies of gemcitabine and trastuzumab in combination showed additive or synergistic antitumor effects in human breast cancer cell lines that overexpress HER2. A multicenter phase II trial was thus conducted to define the safety and efficacy of gemcitabine/trastuzumab in patients previously treated for metastatic breast cancer. Women with measurable metastatic breast cancer whose primary or secondary tumor overexpressed HER2 were eligible for inclusion. Gemcitabine 1,200 mg/m(2) was administered on days 1 and 8 of a 21-day cycle. Trastuzumab was administered at a loading dose of 4 mg/kg initially, then at 2 mg/kg weekly thereafter. Preliminary analysis of 38 evaluable patients showed that gemcitabine/trastuzumab was well tolerated and had significant antitumor activity in this patient population. The study is now concluded, and final analysis of the data is nearing completion. Publication of the results is anticipated in 2003.
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PMID:Gemcitabine and trastuzumab in metastatic breast cancer. 1272 22

A 46-year-old woman with a 3-month history of upper abdominal pain was referred to our hospital because of the presence of a pancreatic mass and multiple hepatic nodules on abdominal ultrasonography (US) and computed tomography (CT). We concluded that the patient had pancreatic cancer with multiple hepatic metastases on the findings of endoscopic retrograde cholangiopancreatography (ERCP) and fine needle aspiration biopsy of the hepatic nodule. The patient received gemcitabine treatment. Gemcitabine 1,000 mg/m2 was administered once a week for 3 weeks followed by a week of rest, this constituting 1 cycle of treatment. Partial responses (PR) of both pancreatic and hepatic lesions were observed after the first cycle of the gemcitabine treatment, and serum concentrations of CEA and CA19-9 remarkably decreased. We considered that clinical benefit was obtained because Karnofsky performance status improved and analgesic consumption decreased. Such effectiveness of the gemcitabine treatment lasted for the following 4 cycles. In general, chemotherapy has few effects on an advanced pancreatic cancer. We report a case of advanced pancreatic cancer that could obtain remarkable antineoplastic effect and clinical benefit with gemcitabine treatment.
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PMID:[A case of advanced pancreatic cancer showing remarkable response to gemcitabine treatment]. 1451 16

Drug-induced hepatotoxicity accounts for more than a third of the cases of acute liver failure in the United States. In complex medical conditions, the diagnosis of drug-induced liver injury may be confounding and, specifically, the potential hepatotoxicity of chemotherapeutic agents may be easily overlooked. Two fatal cases of cholestatic hepatotoxicity have been previously reported, clearly implicating gemcitabine therapy. We report a third fatal case of cholestatic liver failure that we think is strongly linked to the use of gemcitabine. This chemotherapeutic agent is a fluorine analog with broad-spectrum antitumor activity commonly used in the treatment of breast, lung, prostate, and cervical cancer. The case we report is of a 45-year-old woman with a history of metastatic breast cancer to her spine. The patient was in remission for two years before she presented with a compensated mixed hepatitis of mild to moderate severity. Inpatient work-up found metastases to the right humerus and inferior pubic ramus, but none in the liver. Gemcitabine and carboplatin therapy was initiated for relapse of breast cancer. The patient's liver enzyme elevation diminished, but did not normalize before the start of chemotherapy. She received four courses of gemcitabine/carboplatin and subsequently presented with decompensated, severe cholestatic hepatitis. Transjugular liver biopsy displayed marked cholestasis and hepatocellular injury consistent with drug-induced hepatoxicity. Gemcitabine has been extensively studied in the oncology literature and at this time is thought to be a low-risk hepatotoxin causing hepatic adaptation and transient, reversible liver enzyme elevation, rarely leading to termination of gemcitabine therapy for solid tumors. We believe that gemcitabine therapy, particularly in the setting of preexisting liver injury or metastases to the liver, increases the relative risk of severe and potentially fatal hepatic injury possibly by idiosyncratic and dose-dependent mechanisms. We recommend careful monitoring and dose adjustment of gemcitabine in patients with abnormal liver function tests or evidence of hepatic metastases until further study clarifies this issue.
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PMID:Fatal cholestatic liver failure associated with gemcitabine therapy. 1456 Oct 5

The treatment of patients with metastatic soft tissue sarcomas (STS) is complex. There are limited agents available and many are associated with significant toxicity. When evaluating a patient with metastatic disease, physicians should ask themselves whether there is a role for surgery to render the patient free of disease. Combination chemotherapy in patients who have not received chemotherapy in the adjuvant setting is one option, particularly in a young patient with a good performance status. Sequential single-agent therapy for patients who are more elderly or debilitated by their disease may be more appropriate. Gemcitabine appears to be an agent with activity, particularly in patients with leiomyosarcomas. The data regarding prolonged gemcitabine infusions suggest improved activity that was predicted based on prolonged intracellular gemcitabine levels. Because of these data, the prolonged infusion schedule should be used. In addition, because of the paucity of effective agents, consideration of clinical trial participation for patients with newly diagnosed metastatic disease is appropriate, particularly in chemotherapy-insensitive histologies. The role of the newer agents (eg, ecteinascidin-743, epothilones, and mammalian target of rapamycin) is undefined. Ecteinascidin-743 has been the most extensively tested agent, and its ability to slow growth kinetics of a tumor and stabilize it clinically is intriguing. Data regarding the response to BMS-247550 will be published shortly and will help define the further role of epothilones in this disease. There is a preclinical rationale that makes the mammalian target of rapamycin inhibitors attractive for the treatment of muscle-derived neoplasms. In addition, there are cell-line data suggesting activity in rhabdomyosarcoma. These agents are being tested in adult STS and will likely be tested in pediatric histologies when there are more safety data available in that population. SU11248 will continue to be tested in patients refractory to imatinib mesylate and may well prove to be another active agent for patients with gastrointestinal stromal tumors. As depicted by the analysis of gemcitabine efficacy, agents with activity in a subgroup of STS may be overlooked by the "come one come all" approach to clinical trials in STS. Identifying key targets in specific STS will be helpful in the testing of newer molecularly targeted agents. Biologic differences will support histology-specific trials to better understand the activity of an agent in a specific disease site or specifically target a biologic pathway with relevance to the malignant potential of the disease. For future clinical trials in STS to achieve the goal of histology-specific trials, cooperative group and multi-institutional trials will be required to obtain the appropriate patients with these rare histologies. It will also be increasingly important to be committed to obtaining tumor tissue in these patients to validate hypotheses regarding tumor biology and the effectiveness of therapeutic agents.
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PMID:New therapeutic strategies for soft tissue sarcomas. 1458 25

Primary leiomyosarcomas (LMSs) of the lung are extremely rare malignancies that have been the subject of single or small series of case reports. Today, the gold standard of treatment in patients with locally advanced and metastatic disease includes one of the many possible regimens containing an anthracycline and/or ifosfamide. Few chemotherapy agents are active in the second-line setting. In particular, gemcitabine is considered quite ineffective in the treatment of first- as well as second-line chemotherapy of soft tissue sarcoma and responses to this agent are seldom reported. In this paper, we report a single patient with primary LMS of the lung previously treated with a combination of epirubicin and ifosfamide. The patient responded to second-line chemotherapy with gemcitabine 1250 mg/m2 given as a 30-minute infusion on days 1, 8, and 15 of a 28-day cycle and showed an 8-month response duration and negligible toxicity. Gemcitabine may represent an alternative to the best supportive care in patients affected with soft tissue sarcoma who fail first-line chemotherapy.
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PMID:Unusual response to second-line single-agent gemcitabine in locally advanced primary leiomyosarcoma of the lung: a case report. 1460 82

Many active cytotoxic drugs and several regimens exist for breast cancer therapy. However, these conventional treatments have not changed the outcome of patients with locally advanced and metastatic disease. As a consequence, the dynamic balance between chemotherapy-induced side effects and benefits attributable to relief of cancer-related symptoms must be carefully considered in this setting. Gemcitabine is a pyrimidine nucleoside antimetabolite that has shown activity in a variety of solid tumors, a good toxicity profile, and non-overlapping toxicity with other chemotherapeutic drugs. As a single agent, gemcitabine yields response rates ranging from 14 to 37% as first-line treatment for advanced breast cancer and 12-30% as salvage therapy for patients previously treated with anthracycline and/or taxane treatment. Combined with vinorelbine, platinum, anthracyclines, and taxanes as doublets or triplets, response rates of 50 to 80% have been reported in phase II clinical studies. Gemcitabine in combination with anthracyclines and taxanes has been evaluated in the neoadjuvant setting in patients with early-stage breast cancer with interesting clinical and pathological response rates. Preliminary results of gemcitabine in combination with the biologic agent, trastuzumab, are encouraging. Phase III trials of gemcitabine combinations compared to standard regimens are ongoing with the aim to assess the independent contribution of gemcitabine.
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PMID:Rationale for the use of gemcitabine in breast cancer (Review). 1471 16

Gemcitabine (Gemzar) and paclitaxel show good activity as single agents and combined in metastatic breast cancer, and the combination of paclitaxel/trastuzumab (Herceptin) has been shown to prolong time to disease progression and survival significantly in this setting. Preclinical data indicate additive or synergistic effects of gemcitabine and trastuzumab in HER2-positive human breast cancer cell lines. In a phase II trial, patients with HER2-overexpressing metastatic breast cancer who had received no prior chemotherapy for metastatic disease received gemcitabine at 1,200 mg/m2 on days 1 and 8 and paclitaxel at 175 mg/m2 on day 1 every 21 days for six cycles plus trastuzumab at an initial loading dose of 4 mg/kg followed by 2 mg/kg weekly; patients without progressive disease after six cycles continued to receive trastuzumab until disease progression. Overall, objective response was observed in 28 (67%) of 42 evaluable patients, including complete response in 4 (10%) and partial response in 24 (57%); stable disease was observed in 7 (17%) and progressive disease was observed in 6 (14%). Median time to treatment failure was 9+ months. Median overall survival has not yet been reached, but is estimated at approximately 27 months. Significant toxicities apart from neutropenia were uncommon. The triplet combination of gemcitabine, paclitaxel, and trastuzumab is highly active and well tolerated in patients with HER2-overexpressing metastatic breast cancer.
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PMID:Gemcitabine, paclitaxel, and trastuzumab in metastatic breast cancer. 1476 3

Despite considerable progress in the areas of epidemiology and molecular genetics, pancreatic cancer is still characterized by a dismal prognosis. The current overview attempts a critical analysis of the published data resulting in recommendations for diagnostic and therapeutic algorithms. The diagnostic work-up of suspected pancreatic cancer patients includes an initial abdominal ultrasound which in case of ambiguous results or the absence of distant metastases is followed by "one-stop-MRI" and explorative laparotomy. Locally confined tumour disease should proceed to resective surgery which however results in cure only in a minority of resected patients even in specialized centers. Adjuvant chemotherapy might be of some benefit in terms of survival. Locally advanced but irresectable disease can be considered for combined radiochemotherapy. Systemic chemotherapy with Gemcitabine -results in marginal benefit of overall survival and may offer clinical benefit to a subgroup of patients. Best supportive care still remains the mainstay of irresectable disease. This summary highlights the urgent need for the development of innovative diagnostic and therapeutic strategies.
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PMID:[Pancreatic carcinoma]. 1502 14

The purpose of this phase I study was to determine the pharmacokinetics and toxicity of gemcitabine in patients with advanced, recurrent, and/or metastatic cancer and renal impairment. Patients were entered in 4 groups estimated by EDTA-Cr plasma clearance (CLp, mL/min): > or =80; > or =60 and <80; > or =30 and <60; and > or =30 and <80 plus renal insufficiency induced by previous chemotherapy, respectively. Gemcitabine 500 to 1000 mg/m was administered intravenously on days 1, 8, and 15 every 4 weeks. Plasma concentration data were pooled and analyzed using a population pharmacokinetic program (NONMEM). Eighteen white patients (14 females, 4 males) entered the study with a median age of 55 years. Linear regression analyses revealed no significant relationship between gemcitabine CLp and indices of renal impairment (EDTA-Cr CL; p = 0.797 or beta2-microglobulin; p = 0.153). Hematologic and nonhematologic toxicities were mild. Thus, there seems to be no significant impact of mild to moderate renal insufficiency on gemcitabine pharmacokinetics in patients with advanced cancer.
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PMID:Gemcitabine in patients with solid tumors and renal impairment: a pharmacokinetic phase I study. 1517 Jan 50


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