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)

In order to improve survival in a disease where the majority of deaths occur from metastases, the integration of systemic chemotherapy is crucial. Research efforts must continue to focus on refining case selection criteria, improving complete response proportions, and overcoming drug resistance. The blanket recommendation of a single therapeutic strategy such as radical surgery, chemotherapy, or radiation therapy to all patients is quickly becoming an outdated approach. Refinements in the understanding of the clinical, pathologic, and molecular features of urothelial tumors will ultimately improve case selection. Evaluation of NM23 RNA levels, or DNA ploidy and T138 surface antigen expression, which have been shown to correlate with metastatic potential, may hold important therapeutic implications. The use of hematopoietic growth factors has the potential to improve both the tolerance of chemotherapy and complete response proportions, a prerequisite for cure. A recent report from Japan of granulocyte colony-stimulating factor with MVAC and other chemotherapy regimens for urothelial tumors corroborated an initial report in reducing the duration of neutropenia. However, the dose response curves for most of the known active agents are not well defined and, ultimately, new agents and strategies will be required. Gallium nitrate, when administered by continuous intravenous infusion, has significant single agent activity in cisplatin-refractory patients with 9/31 responses (29%), including 6 CRs (19%) and further studies are warranted. Drug resistance remains a major obstacle, and as the mechanisms are unravelled, more rational therapies can be designed. For example, resistance to Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) and vinblastine, two components in the MVAC regimen, are mediated in part by the MDR1 gene. Attempts are ongoing to identify prospectively those tumors with high levels of expression that may be more amenable to treatment with drugs that are not affected by this mechanism. The neoadjuvant approach allows an in vivo assessment of response to chemotherapy as well as the potential for bladder preservation. In most cases additional therapy directed at the primary is required as clinical understaging is a significant problem and pCR proportions are less than 30%. For some patients, initial surgery followed by treatment based on pathologic criteria may represent a better strategy. In these cases the recommendation for adjuvant treatment potentially limits therapy to a population of patients for whom therapy is essential. Based on available data, this would include patients with positive lymph nodes at the time of surgery. Ideally, patients with invasive bladder cancer should be entered into clinical trials designed to assess the impact of these strategies on survival.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The evolving role of chemotherapy for muscle infiltrating bladder cancer. 177 75

An ongoing phase I and pharmacokinetic trial of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in combination with carboplatin is evaluating the maximum tolerated dose (MTD) of a 3-hour paclitaxel infusion combined with fixed doses of carboplatin in previously treated and untreated patients with a variety of advanced cancers. A patient's previous treatment status determines the fixed carboplatin dose: target area under the concentration-time curves of 4.0 and 4.5 mg.min/mL in previously treated and untreated patients, respectively. Studies 1 and 2 entered previously treated patients to establish the paclitaxel MTD without and with cytokine support: study 1 established 135 mg/m2 paclitaxel as the MTD without such support. In study 2, granulocyte colony-stimulating factor is administered, and the MTD has not yet been reached with paclitaxel doses of 135 mg/m2 to 230 mg/m2 assessed thus far and 250 mg/m2 now being evaluated. Objective responses have been seen in three of five patients with squamous cell carcinoma of the head and neck and in patients with non-small cell lung cancer and metastatic cancer of unknown primary site as well. Myelosuppression has been the dose-limiting toxicity, although significant nausea and vomiting and myalgia have been documented occasionally. Paclitaxel apparently has nonlinear pharmacokinetics with a beta half-life of 6.7 hours (SD +/- 1.3 hours). Future trials of paclitaxel/carboplatin will address the management of squamous cell carcinoma of the head and neck and non-small cell carcinoma of the lung.
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PMID:Phase I study of paclitaxel and carboplatin: implications for trials in head and neck cancer. 748 55

The combination of mitozantrone, methotrexate and mitomycin (3M) gives a response rate of around 50% in patients with advanced breast cancer. The predominant toxicity is haematological. In this study, previously untreated patients were given 3M with increasing doses of mitozantrone (7-14 mg m-2) with recombinant human granulocyte colony-stimulating factor (metHuG-CSF) (filgrastim) to prevent marrow toxicity. Doses administered were 7 mg m-2 mitomycin i.v. 6 weekly, methotrexate i.v. 35 mg m-2 (maximum 50 mg) 3 weekly and mitozantrone i.v. 3 weekly as follows: 7 mg m-2, six patients (group 1); 10 mg m-2, six patients (group 2); 12 mg m-2, six patients (group 3); 14 mg m-2, six patients (group 4); all on day 1 for six cycles at the assigned dose. All patients received filgrastim (Amgen 0.3 mg ml-1) at a dose of 5 micrograms kg-1 subcutaneously daily on days 4-17 of each cycle. All treatment was given on an out-patient basis. A total of 24 patients were entered into the study. The median age was 63 years (range 48-75). ECOG performance status was 0 in ten, 1 in 11 patients and 2 in three patients. Locoregional disease alone was present in seven patients. The remainder had one or more sites of metastases. The actual dose administered to the 24 patients was as follows. The six patients in group 1 all completed six courses of treatment as per protocol. In group 2, three patients completed six courses, two stopped because of toxicity after one and four courses and one had progressive disease after one course. In group 3, three patients completed and three stopped early because of progressive disease. In group 4, two patients completed, one progressed after four courses and three responding patients stopped treatment because of toxicity. The maximum tolerated dose of mitozantrone in the 3M combination was 12 mg m-2. The use of filgrastim with increasing doses of chemotherapy prevents neutropenia, but other toxicities, namely thrombocytopenia and lethargy, then become dose limiting.
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PMID:Phase I study of mitozantrone, methotrexate and mitomycin with granulocyte colony-stimulating factor (filgrastim) in patients with advanced breast cancer. 752 7

We treated 115 patients in a phase I/II dose-escalation study of ifosfamide/carboplatin/etoposide (ICE) followed by autologous stem cell rescue. Patients treated had a variety of diagnoses, including breast cancer (high-risk stage II disease with eight or more positive nodes, stage III disease, and responsive metastatic disease), non-Hodgkin's lymphoma, Hodgkin's disease, acute leukemia in first remission, and various solid tumors that were responsive to induction therapy. Patients received autologous bone marrow stem cells or peripheral blood stem cells primed by one of several methods. The maximum tolerated dose of ICE was determined to be ifosfamide 20,100 mg/m2, carboplatin 1,800 mg/m2, and etoposide 3,000 mg/m2 when administered as a 6-day regimen. The dose-limiting toxicities included acute renal failure, severe central nervous system toxicity, and "leaky capillary syndrome" with hypoalbuminemia, profound fluid overload, and pulmonary insufficiency. Analysis of hematologic recovery based on stem cell source and influence of hematopoietic growth factor administration was undertaken. Hematopoietic growth factor use significantly reduced neutrophil engraftment time for patients receiving bone marrow stem cells, with evidence of earlier recovery times for patients receiving granulocyte colony-stimulating factor compared with granulocyte-macrophage colony-stimulating factor. Neutrophil recovery times varied based on the source of stem cells used, with the earliest engraftment times seen for patients receiving peripheral blood stem cells primed with cyclophosphamide and granulocyte colony-stimulating factor. Platelet recovery times were not statistically different for any of the subsets. In conclusion, the maximum tolerated dose of ICE has been defined, and the source of stem cells and the use of hematopoietic growth factors influence hematopoietic recovery.
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PMID:High-dose ifosfamide/carboplatin/etoposide: maximum tolerable doses, toxicities, and hematopoietic recovery after autologous stem cell reinfusion. 752 92

Twenty patients with locally advanced or metastatic breast cancer were treated with four cycles of ifosfamide/mesna 5 g m-2 and epirubicin 60 mg m-2 every 14 days with granulocyte colony-stimulating factor (G-CSF, Filgrastim). Complete remission occurred in six out of the 20 patients (30%, 95% confidence interval 12-54%) and there were 12 partial responders (60%, 95% confidence interval 37-81%), thus giving an overall response rate of 90% (95% confidence interval 63-97%). Two patients had progressive disease. The median duration of response for those patients with metastatic disease was 7.3 (1.3-20.1+) months. The median survival time for these patients was 15 (5.3-27.9+) months. Of the four patients treated with locally advanced disease three achieved a complete clinical response and one a partial response. Three out of four of these patients subsequently underwent a mastectomy, and in one of these no viable tumour was seen. Our conclusion is that this regimen is excellent palliation for metastatic disease and possibly useful neoadjuvant treatment.
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PMID:The use of granulocyte colony-stimulating factor to deliver four cycles of ifosfamide and epirubicin every 14 days in women with advanced or metastatic breast cancer. 753 18

A total of 33 patients (median age, 44 years) with high-grade, adult soft-tissue sarcoma were treated with etoposide given at 600 mg/m2 in a 72-h continuous infusion and ifosfamide given at 1500 mg/m2 per day for 3 days every 3 weeks. Dose escalation/reduction was protocolled depending on the level of hematological toxicity observed in the preceding course. Overall, 90% of patients had metastatic disease, and the most common histologies were malignant fibrous histiocytoma and leiomyosarcoma. A median of 5 (range, 1-9) courses were given. Of 30 patients who were evaluable for response, 12 (40%) obtained a partial remission, and the median time to progression was 8 (range, 4-13) months. Grade 3-4 leukopenia and thrombocytopenia were seen after 89% and 8% of the courses, respectively; neutropenic fever was seen in half of the patients (15% of courses); and 32% of courses had to be postponed by 7 days or more due to myelosuppression. Dose reduction to below the standard had to be performed in 46% of courses, and dose escalation was achieved in only 13%. The reduced toxicity seen after the addition of granulocyte colony-stimulating factor (G-CSF) in five patients indicates that growth-factor support may enhance the dose intensity of the regimen. The results indicate significant activity for this regimen in adult soft-tissue sarcoma, which may in part be a result of the escalated dose and prolonged mode of administration of the phase-specific agent etoposide. As a result of this pilot series, a phase II study with ifosfamide, etoposide, and G-CSF in advanced adult soft-tissue sarcoma has been initiated by the Scandinavian Sarcoma Group.
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PMID:Treatment of advanced, high-grade soft-tissue sarcoma with ifosfamide and continuous-infusion etoposide. 753 39

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) 250 mg/m2 by 24-hour infusion at 21-day intervals was evaluated at M.D. Anderson Cancer Center as a single agent in patients who had received one prior chemotherapy regimen either as adjuvant therapy or for metastatic disease. Of 25 patients treated, 12% had a complete remission and 44% had a partial response. The median time to progression was 9 months (range, 1 to 20 months). In the next phase of development, a phase I trial evaluated sequentially administered paclitaxel and doxorubicin as initial therapy for metastatic disease. Granulocyte colony-stimulating factor also was administered in each cycle. The dose-limiting toxicity was either stomatitis or neutropenic fever. The maximum tolerated dose (MTD) was 125 mg/m2 for paclitaxel and 48 mg/m2 for doxorubicin. Because of much lower than anticipated MTDs of both drugs in this schedule, it was hypothesized that there may be a schedule-dependent toxicity; therefore, in the second phase I study the schedule of administration was reversed (ie, doxorubicin followed by paclitaxel infusion). The MTDs of this schedule were 60 mg/m2 and 150 mg/m2 for doxorubicin and paclitaxel, respectively. Pharmacokinetic studies subsequently have confirmed that administration of paclitaxel before doxorubicin impairs the elimination of doxorubicin by some unknown mechanism. In an ongoing phase II study, paclitaxel is being evaluated in patients who have received three or more treatments with chemotherapy. Paclitaxel is administered at doses of 135 and 150 mg/m2 (for poor- and good-risk patients, respectively) without granulocyte colony-stimulating factor. Six patients (19%) have shown objective partial responses. Our initial phase II study showed significant antitumor activity for paclitaxel in patients who had received limited prior chemotherapy. Our phase I studies established that initial administration of paclitaxel alters the pharmacokinetics of doxorubicin and increases morbidity. The reverse sequence of administration was associated with better tolerance and a higher MTD. In heavily treated patients this drug also has significant antitumor activity.
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PMID:Paclitaxel in the treatment of metastatic breast cancer: M.D. Anderson Cancer Center experience. 754 Nov 51

A 67-year-old man with squamous cell bladder carcinoma showed remarkable leukocytosis (maximum 50,300 per microliter.) for 4 months while the neoplasm recurred and metastasis progressed. The patient died of systemic metastasis within 9 months after cystectomy. Enzyme immunoassay of the serum demonstrated remarkably high levels of granulocyte colony-stimulating factor (4,928 pg./ml.). Immunohistochemical examination with anti-granulocyte colony-stimulating factor monoclonal antibody demonstrated granulocyte colony-stimulating factor production in the metastatic cancer cells in the liver. The expression of the granulocyte colony-stimulating factor gene in the tumor specimens was examined by standard Northern blot analysis. Specific granulocyte colony-stimulating factor transcript was identified in the total ribonucleic acid fraction extracted from a tumor specimen of the peritoneal metastatic lesion. These results indicated that the autonomous production of granulocyte colony-stimulating factor in this bladder carcinoma induced paraneoplastic leukocytosis.
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PMID:Bladder carcinoma producing granulocyte colony-stimulating factor: a case report. 768 Nov 20

Single-agent paclitaxel (TAXOL) was administered to 79 patients with stage IV breast cancer. Twenty-eight patients had no prior chemotherapy (for metastatic disease), and 51 patients had extensive exposure to other chemotherapeutic agents before beginning the 24-hour paclitaxel infusion. Routine use of recombinant human granulocyte colony-stimulating factor helped to ameliorate neutropenia, the dose-limiting toxicity, in some cases. Other toxicity was generally mild to moderate. Paclitaxel was more active in patients whose stage IV disease had not yet been exposed to chemotherapy, but activity was seen in the patients previously treated extensively as well. There is a strong clinical suggestion of non-cross-resistance with doxorubicin. In one case, an excellent response in previously irradiated skin was seen. Paclitaxel is a very promising agent for the treatment of metastatic breast cancer.
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PMID:Preliminary experience with paclitaxel (Taxol) plus recombinant human granulocyte colony-stimulating factor in the treatment of breast cancer. 768 45

Phase II clinical trials of single-agent paclitaxel have demonstrated the drug's activity in ovarian cancer, breast cancer, and both small cell and non-small cell lung cancer. A recently completed trial in recurrent head and neck cancerpatients conducted by the Eastern Cooperative Oncology Group resulted in a 40% (12 of 30) overall (complete plus partial) response rate with a high dose of paclitaxel (250 mg/m2 by 24-hour continuous infusion) and granulocyte colony-stimulating factor support. Responses were observed in previously irradiated sites of locoregional disease as well as in distant metastases. The major toxicities were brief grade 3-4 neutropenia occurring in 91%, peripheral neuropathy in 39%, and arthralgias/myalgias in 39% of treated patients. Confirmatory single-agent trials with paclitaxel are in progress in the United States and Europe. Phase I and II trials also in progress or planned combine paclitaxel with cisplatin or carboplatin; ifosfamide; methotrexate; and cisplatin/5-fluorouracil. Lower doses (135 to 175 mg/m2) and alternative infusion schedules ranging from 3 hours to 10 days are also under evaluation in head and neck cancer and other solid tumors. Studies combining paclitaxel and radiotherapy are reviewed as well.
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PMID:Current and future trials of Taxol (paclitaxel) in head and neck cancer. 786 35


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