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)

A phase I trial was performed to investigate the tolerability and efficacy of the novel nucleoside analogue gemcitabine in combination with cisplatin in the treatment of advanced non-small cell lung cancer. Both cisplatin and gemcitabine were administered as 30 min infusions weekly x 3 with a week of rest. There was one dose escalation of cisplatin from 25 mg/m2 (dose level 1) to 30 mg/m2 (in subsequent dose levels 2-5), such that the mean dose intensity for the weekly x 3 q 4 week cycle was 22.5 mg/m2/week which is close to that achieved with 100 mg/m2 bolus monthly. Gemcitabine was initiated at 1000 mg/m2 (dose levels 1 and 2) then escalated by 250 mg/m2/week to 1750 mg/m2 (dose level 5). Of 32 chemotherapy-naive patients entered (22 males, 10 females; median age 61 years, range 29-74 years), 11 had localized tumours (2 stage IIIa, 9 IIIb) and 21 had stage IV tumours with haematogenous metastases and a poor prognosis. Twenty-one patients had adenocarcinoma, 4 squamous cell carcinoma, 6 large cell undifferentiated tumors, and one had mixed squamous and adenocarcinoma. Dose-limiting toxicity was not seen in more than one patient in cycle 1 at any dose level. Grade 4 granulocytopenia and thrombocytopenia occurred more frequently with repeated dosing, necessitating dose reductions except at the lowest dose level (cisplatin 25 mg/m2, gemcitabine 1000 mg/m2). Non-haematological toxicity was mild and rapidly reversible. Cisplatin administration led to a higher frequency of nausea and vomiting than that seen with gemcitabine alone, but this was easily controlled with antiemetics. In the 28 patients evaluable, to date responses have been seen at most dose levels, with an overall response rate 35.7%. This phase I trial is ongoing and further dose escalation is intended to determine the MTD of gemcitabine.
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PMID:Phase I trial of gemcitabine and cisplatin in advanced non-small cell lung cancer: a preliminary report. 869 17

The experience with single-agent gemcitabine in advanced or metastatic breast cancer is reviewed. In all studies, gemcitabine was administered as a 30 min intravenous infusion in cycles once a week for 3 weeks followed by 1 week of rest. In the first European study (gemcitabine 800 mg/m2/week), of 40 evaluable patients, 14 were chemo-naive, 7 had received adjuvant chemotherapy, and 19 had received chemotherapy for metastatic disease. There were 3 complete responders and 7 partial responders (all independently validated by an external Oncology Review Board) for an overall response rate of 25.0% (95% CI: 12.7%-41.2%). The median time to declaration of response was 1.9 months and the median duration of survival for all 40 efficacy-evaluable patients was 11.5 months. Haematological and non-haematological toxicities were particularly mild. WHO grade 3 and 4 toxicities included leukopenia (6.8% and 2.3% of patients), neutropenia (23.3% and 7.0%), AST (6.8% and 2.3%), ALT (18.2% and 0%), infection (0% and 2.3%), nausea and vomiting (25.0% and 2.3%), alopecia (2.3% and 0%). There was no grade 3 or 4 creatinine, proteinuria or haematuria. In the smaller US study (18 evaluable patients, all but one having received prior chemotherapy for stage IV disease) there were no responders. However, the mean dose delivered was very low (577 mg/m2/injection). In an ongoing European trial, with a starting dose of 1000 mg/m2, a number of partial responders have been seen in soft tissue, lung and liver. Gemcitabine's modest toxicity profile and single-agent activity make it an attractive candidate for trial in combination therapy in advanced breast cancer where treatment is currently given to palliate symptoms and improve quality of life.
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PMID:Gemcitabine in advanced breast cancer. 871 26

There have been many recent advances in the treatment of advanced breast cancer including the introduction of novel drugs and the development of high-dose chemotherapy with peripheral blood stem cell transplantation (PBSCT). These innovations may offer significant hope for improvement in the treatment of breast cancer in the near future. Gemcitabine is a nucleoside analogue with significant antitumour activity in many human solid tumours. Conflicting results have been observed from studies evaluating gemcitabine in advanced breast cancer. Efficacy data for single-agent gemcitabine range from 25 to 46% depending on starting dose and whether patients have previously received chemotherapy for metastatic disease (as well as adjuvant use). Gemcitabine is extremely well tolerated, even in heavily pre-treated patients, and is easy to administer on an outpatient basis to both chemo-naive and previously treated patients. The most common toxicity is mild myelosuppression. Gemcitabine causes minimal nausea and vomiting, and significant hair loss is extremely uncommon. Combination chemotherapy studies with anthracyclines are underway and significant activity has been observed in combination with both doxorubicin and epirubicin. In view of its modest toxicity profile, and its novel mechanism of action, gemcitabine warrants further evaluation in breast cancer patients, both as a single agent and in combination chemotherapy schedules.
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PMID:Advanced breast cancer: investigational role of gemcitabine. 916 97

Gemcitabine has shown single-agent activity in metastatic breast cancer. Epirubicin is also widely used for the adjuvant and treatment of metastatic breast cancer. The toxicity profiles and modes of action are different which provides a good rationale for studying both drugs in combination. In a phase I study gemcitabine at a fixed dose of 1000 mg/m2 on days 1, 8, 15 of a 28 day cycle was combined with escalated weekly doses of epirubicin starting with an initial dose of 10 mg/m2. Patients had stage IV metastatic disease without previous chemotherapy except as adjuvant treatment. Nineteen patients were included in the study which defined the maximum tolerated dose (MTD) of epirubicin at 20 mg/m2. Myelosuppression was the dose limiting toxicity with leucopenia WHO grade 3 and 4 in 40.0% and 20.0%, neutropenia WHO grade 3 and 4 without neutropenic fever in 20.0% and 40.0% and thrombocytopenia WHO grade 4 in 20.0%. At the epirubicin 15 mg/m2 dose level, leucopenia (11.1% WHO grade 3) and neutropenia (12.5 and 37.5% WHO grade 3 and 4) were reported. Symptomatic toxicity was generally mild: nausea/vomiting in about 20% of patients (WHO grade 3 or 4) on both 15 and 20 mg/m2 epirubicin dose levels. Alopecia WHO grade 3 and 4 was seen in 2 patients at MTD. Four of 19 evaluable patients had a partial response. We conclude that the combination of gemcitabine and epirubicin is well tolerated and has promising activity. A phase II study is underway with gemcitabine 1000 mg/m2 and epirubicin 15 mg/m2 on days 1, 8 and 15 of a 28 day cycle.
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PMID:Gemcitabine plus dose-escalated epirubicin in advanced breast cancer: results of a phase I study. 984 77

In adults, the haemolytic-uraemic syndrome (HUS) is associated with probable causative factors in the minority of all cases. Cytotoxic drugs are one of these potential causative agents. Although metastatic cancer by itself is a recognized risk-factor for the development of HUS, therapy with mitomycin-C, with cis-platinum, and with bleomycin carries a significant, albeit extremely small, risk for the development of HUS, compared with all other cytotoxic drugs. Gemcitabine is a novel cytotoxic drug with promising activity against pancreatic adenocarcinoma. We are reporting on one patient with metastatic duodenal papillary carcinoma developing HUS while on weekly gemcitabine therapy. The presenting features in this patient were non-cardiac pulmonary oedema, renal failure, thrombocytopenia and haemolytic anaemia. The diagnosis of HUS was made on the day of admission of the patient to this institution. Upon aggressive therapy, including one single haemodialysis and five plasmaphereses, the patient recovered uneventfully, with modestly elevated creatinine-values as a remnant of the acute illness. Re-exposure to gemcitabine 6 months after the episode of HUS instituted for progressive carcinoma, thus far has not caused another episode of HUS.
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PMID:Elevated reticulocyte count--a clue to the diagnosis of haemolytic-uraemic syndrome (HUS) associated with gemcitabine therapy for metastatic duodenal papillary carcinoma: a case report. 1018

Adenocarcinoma of the pancreas is the cause of 3-4% of cancer related deaths in Italy and over 80% of all patients exhibit advanced disease. Treatment with surgery and chemio-radiotherapy may have meaningful results in resectable and locoregional tumours respectively. Chemotherapy is the treatment of choice in metastatic disease as palliative intent, although pancreatic tumour is considered resistant to treatment with conventional cytotoxicity drugs. Assessment of response of primary tumor is extremely difficult because of its anatomical location and fibrotic reaction around the tumor. Furthermore, medical problems associated with the age of patients, reduced performance status (PS), mainourished conditions, jaundice and pain, limit patients' tolerance and response to chemotherapy. 5-fluorouracil (5-FU) is the most frequently used drug in the treatment of pancreatic cancer with a RR of 28% in the trials performed in mid 1980, while more recently studies have reported a RR of 5-15%. Biochemical modulation of 5-FU by leucovorin, PALA and interferon does not appear to produce better results than 5-FU alone. 5-FU-based combination chemotherapy (FAM, SMF, etc) have shown interesting results in phase II (30-40%), but in a randomized trial the results of combination were similar to 5-FU alone (< 15%). Also, regimens containing platinum gave disappointing results just as the other combinations and cannot be recommended outside prospective clinical trials. When chemotherapy was compared to best supportive care (BSC), the results demonstrated a survival gain. Six studies, comparing chemotherapy versus BSC and 3 trials showed statistically significant difference in survival for patients treated with chemotherapy. Recently, new drugs have been introduced in the treatment of gastrointestinal tumour (gemcitabine, CPT11, raltitrexed, taxanes, etc.). Gemcitabine is a novel nucleoside analogue that has shown a very favourable toxicity profile and RR of 10-15% in advanced pancreatic cancer. Data from a phase II and randomized comparative trials suggest that gemcitabine offers an advantage over 5-FU in terms of improvement of PS and general clinical symptoms. Given the difficulty of accurate tumor measurement in this disease, some authors introduced a novel new end-point to evaluate the response: clinical benefit (CB). In a randomized trial of gemcitabine vs. 5-FU, RR using CB was 23.8 with gemcitabine and 4.8 with 5-FU, this difference was statistically significant with a median survival of 5.6 and 4.4 months, respectively. In conclusion, future studies should focus on phase III trials with gemcitabine, alone or in combination and phase II with new promising drugs. Quality of life, pharmaco-economic studies, CB should be the principal end-point of these studies. All patients with advanced pancreatic cancer should be included in clinical cooperative trials.
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PMID:[Possibilities of palliation in pancreatic cancer]. 1023 81

Chemoradiation for gastrointestinal cancers is actively under study in the Radiation Therapy Oncology Group (RTOG) and consists of external irradiation combined with simultaneously administered chemotherapy given to provide radiation sensitization and to attack micro metastatic disease. Two national protocols for the treatment of patients with pancreatic and biliary cancers are now active. RTOG 97-04 is a phase III post-operative combined modality program for patients with resected pancreatic cancer. All patients receive protracted infusional 5-fluorouracil (5-FU) combined with 50.4 Gy given in 28 fractions. Prior to and after chemoradiation all patients are randomized to receive multiple cycles of either infusional 5-FU or Gemcitabine to determine the effect on survival. In the other study (RTOG 98-12) patients with unresectable pancreatic cancer are given 50.4 Gy combined with weekly Paclitaxel (50 mg/m2) to examine the efficacy of this active combination in a phase II trial in a multi-institutional setting. Both of these trials have recently been opened to accrual. A third RTOG study for patients with biliary cancer will examine the efficacy of giving pre-operative chronomodulated infusional 5-FU chemoradiation. The background and the rationale for these studies is based on the long history of 5-FU radiation sensitization in the treatment of cancers of these anatomic sites and will be summarized. A brief review of recently published trials using chemoradiation in conjunction with new irradiation treatment techniques "3D" conformal therapy for these diseases will be discussed.
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PMID:Chemoradiation for pancreatic and biliary cancer: current status of RTOG studies. 1043 29

Gemcitabine is an active agent in the treatment of metastatic breast cancer. The phosphorylation of gemcitabine into the active gemcitabine triphosphate (dFdCTP) is catalyzed by deoxycytidine kinase. This enzyme is saturated at plasma concentrations achieved after an infusion over 30 min. Therefore accumulation of higher intracellular dFdCTP concentrations, which may result in an enhanced antineoplastic activity, cannot be achieved by higher dosage, but only by prolonged infusion time. In a previous phase I trial the maximum tolerated dose of gemcitabine given as a 6 h i.v. infusion was 250 mg/m2. The objective of this phase II trial was to determine the efficacy and safety of gemcitabine as prolonged infusion in patients with metastatic breast cancer. Twenty patients [median age 50.4 years, range 35-63 years; performance status EORTC 0 (17 patients), 1 (two patients), 2 (one patient)] with metastatic breast cancer were treated with 250 mg/m2 gemcitabine as infusion over 6 h on days 1, 8 and 15 q3 weeks for up to six courses (median 3.9 courses). Treatment was first line for four patients, second line for five patients and third line or higher for 11 patients. Metastatic sites were liver in 14 patients, bone in 12 patients, lung in eight patients and lymph nodes in nine patients. Nine patients presented two metastatic sites, three patients three and five patients four. All patients were evaluable for response and toxicity. One patient (5%) achieved a complete remission (CR) and four patients (20%) a partial remission (PR) (one patient with CR of visceral metastases but stable bone metastases), for an overall response rate of 25% (five of 20). In addition, six patients (30%) had stable disease and nine (45%) failed to respond to the treatment. Time to progression ranged from 2 to 23 months with a median of 6.3 months. Hematologic toxicity was mild with leukopenia grade 3 in only three patients (15%) and no grade 3 thrombocytopenia. Moderate elevations of liver enzymes (three patients grade 3), nausea and vomiting (two patients grade 2), and mild alopecia were observed, but only one patient had to be withdrawn due to toxicity. In conclusion gemcitabine as prolonged infusion is an effective treatment in metastatic breast cancer. Toxicity, especially myelosuppression, is surprisingly mild. Therefore, gemcitabine seems to be ideal for combination therapies.
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PMID:Phase II trial of gemcitabine as prolonged infusion in metastatic breast cancer. 1050 11

For patients having undergone complete resection for adenocarcinoma of the pancreas, combined radiochemotherapy protocols using bolus 5FU as neoadjuvant or adjuvant treatments can help control disease spread and perhaps moderately lengthen survival. As the rare controlled trials having tested these therapeutic strategies have provided conflicting data, this therapeutic attitude cannot be considered as a standard treatment. The tested protocols using combined radiochemotherapy were developed in the sixties and seventies and have been greatly improved since that time. New combinations for neoadjuvant and adjuvant radiochemotherapy protocols are currently under evaluation in controlled therapeutic trials. Systemic chemotherapy (gemcitabine, 5FU, platinum) has a palliative effect, improving the quality of life in patients with advanced-stage disease. Gemcitabine is easy to administer and has a low toxicity profile. It is widely used in standard protocols. Therapeutic trials combining gemcitabine and other cytotoxic agents are under way. Radiochemotherapy combinations using 5FU are a palliative alternative for patients with locally advanced disease, particularly those with painful symptoms. There is an urgent need for more effective treatments against metastatic disease and for better loco-regional management using a multidisciplinary approach. These patients should be treated within the framework of therapeutic trials.
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PMID:[Chemotherapy, combined radiochemotherapy and new therapeutic approaches in adenocarcinoma of the pancreas]. 1067 20

Gemcitabine has recently been compared favorably to 5-fluorouracil (5-FU) as the standard chemotherapy for advanced pancreas cancer. Based on phase I data that combining gemcitabine with 5-FU is safe and has evidence for clinical activity, a phase II trial was conducted by the Eastern Cooperative Oncology Group (ECOG). Patients with metastatic disease, good performance status and organ function were eligible and enrolled after providing informed consent. Patients were given gemcitabine (1,000 mg/m(2)) followed by 5-FU (600 mg/m(2)) weekly for 3 weeks of every 4. Of 37 patients enrolled over a 3-month period, 36 were eligible. Partial responses were seen in 5 patients (14%). Median survival was 4.4 months with a 1-year survival rate of 8.6%. A randomized trial of the combination of 5-FU and gemcitabine versus gemcitabine alone is currently accruing patients in ECOG.
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PMID:A phase II study of gemcitabine and 5-fluorouracil in metastatic pancreatic cancer: an Eastern Cooperative Oncology Group Study (E3296). 1076 23


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