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)

The standard approaches of surgery or radiotherapy cure only a minority of patients with esophageal cancer. Because of these poor results and the frequent systemic pattern of recurrences, combined-modality therapy employing chemotherapy has been extensively studied. Preoperative chemotherapy, both alone and given concurrently with radiation, has not shown a significant impact on survival and remains investigational. Concurrent chemoradiation as definitive therapy is an alternative to surgery for localized disease. Paclitaxel and vinorelbine have significant activity as single agents in metastatic disease. Paclitaxel is currently under investigation in combination therapy for metastatic disease, as a radiosensitizer for locally advanced disease, and as preoperative therapy. For palliation of locally advanced esophageal cancer, a variety of endoscopic techniques are available to relieve dysphagia. Laboratory studies have identified growth factor pathways and tumor-suppressor genes as potential new pharmacologic targets.
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PMID:Management of esophageal cancer. 888 28

Sixteen patients affected by previously untreated non-small cell lung cancer stage IIIB or IV received radiotherapy and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) as radiation sensitizer in an open, nonrandomized pilot study to find the maximum tolerated dose of the drug concomitantly combined with radiation. Paclitaxel was given as a 3-hour infusion once weekly at a dose escalating by 10 mg/m2/wk for every patient cohort, starting at 40 mg/m2/wk and continuing to 80 mg/m2/wk. Conventionally fractionated (2 Gy/d for 5 d/wk for 5 weeks) radiotherapy up to 50 Gy was delivered to the primary tumor and mediastinum with a 6-mv linear accelerator. Hematologic toxicity has been very low; grade 3 World Health Organization nonhematalogic toxicities have been registered only at the 80 mg/m2/wk dose level. Seven patients achieved a major response, three patients had stable disease, and five patients progressed; three patients are still responding, whereas the others are relapsed and five of them died of disease. The median duration of response was 5 months. Paclitaxel may be safely combined with radiation at the maximum tolerated dose of 70 mg/m2/wk. Our data seem to confirm the radiosensitizing effect of the drug, independent of the dose level. Low doses of paclitaxel given as a single agent are unable to control metastatic disease.
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PMID:Paclitaxel and radiotherapy in the treatment of advanced non-small cell lung cancer. 899 95

The tolerability and efficacy of four courses of paclitaxel and ifosfamide plus cisplatin every 3 weeks was evaluated in patients with residual or refractory ovarian cancer. Additionally, supportive haematological effects of recombinant human interleukin 3 (rhIL-3) and recombinant human granulocyte colony-stimulating factor (G-CSF) were studied. Paclitaxel starting dose was 135 mg m(-2) (day 1), with ifosfamide dose 1.2 g m(-2) day(-1) (days 2-4) and cisplatin dose 30 mg m(-2) day(-1) (days 2-4). All 16 patients received 5.0 microg kg(-1) day(-1) G-CSF (days 7-16) and, in addition, eight patients were randomized to receive 10 microg kg(-1) day(-1) rhIL-3 (days 5-9). Paclitaxel and ifosfamide doses were reduced when grade IV haematological toxicity occurred. In the absence of grade IV haematological toxicity and normal recovery of haematopoiesis, paclitaxel dose was escalated. Toxicity was evaluable in 56 courses, with haematological effects in 52. Despite antiemetic treatment, nausea and vomiting (> or = grade I) occurred in 50 courses. Five patients had persisting peripheral neuropathy. Renal and liver function were not affected. Grade IV neutropenia occurred in 12 out of 52 courses, with neutropenic fever in two patients, both of whom died from fatal septicaemia. Grade IV thrombocytopenia without bleeding was observed in 15 courses. Grade IV haematological toxicity was associated with hepatic metastases and concurrent increases in alkaline phosphatase (P <0.001) and gamma-glutamyltransferase (P=0.007). No relation was found between haematological toxicity and pharmacokinetic parameters of paclitaxel. Patients treated with rhIL-3 showed a tendency to a faster platelet recovery (not affecting platelet nadir), and the cisplatin dose intensity was higher (P=0.025). Six of the nine evaluable patients had a tumour response. The overall median progression-free survival was 7 months and the overall mean survival was 13 months. In conclusion, this potentially interesting combination as second-line treatment showed a low tolerability with unexpected mortality, while rhIL-3 administration tended to induce a more rapid platelet recovery.
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PMID:Paclitaxel, ifosfamide and cisplatin with granulocyte colony-stimulating factor or recombinant human interleukin 3 and granulocyte colony-stimulating factor in ovarian cancer: a feasibility study. 904 28

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) appears to be one of the most active drugs in the treatment of advanced head and neck cancer. The maximum tolerated dose of paclitaxel in combination with carboplatin is currently being evaluated in phase I/II studies. We designed a phase II study to evaluate the activity and acute and cumulative toxicity of this combination in patients with recurrent or metastatic cancer of the head and neck. Chemotherapy consisted of paclitaxel 200 mg/m2, given as a 3-hour infusion, and carboplatin dosed to an area under the concentration-time curve of 7 mg x min/mL, administered every 28 days. Granulocyte colony-stimulating factor (5 microg/kg) also was given on days 2 to 12 of each cycle. At the time of this report, 41 patients had entered this study. Primary sites included the nasopharynx (10 patients), larynx (18), oral cavity (three), oropharynx (six), hypopharynx (three), and unknown (one). Among 25 evaluable patients with non-nasopharyngeal cancer, there were two complete responses and three partial responses, for an overall response rate of 20% (95% confidence interval, 4% to 36%). Among eight evaluable patients with nasopharyngeal cancer, four achieved a complete response and two a partial response. Grade 3 to 4 toxicities included anemia (2.5%), leukopenia (7.5%), thrombocytopenia (5%), vomiting (5%), stomatitis (2.5%), and infection (5%). These preliminary data indicate that the combination of paclitaxel and carboplatin is active against advanced head and neck cancer, particularly when used in the treatment of nasopharyngeal cancer.
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PMID:Paclitaxel and carboplatin in recurrent or metastatic head and neck cancer: a phase II study. 904 40

A phase II trial was performed to evaluate the efficacy and toxicity of the combination of paclitaxel and 5-fluorouracil (5-FU)/folinic acid in patients with advanced gastric carcinoma. Twenty-two patients (six female and 16 male) with advanced or metastatic disease were enrolled. None of them had received prior chemotherapy. Paclitaxel was administrated as a 3 h infusion of 175 mg/m2 at days 1 and 22, 5-FU 2000 mg/m2 i.v. over 24 h and folinic acid 500 mg/m2 i.v. 2 h prior to 5-FU weekly from days 1 to 36. Seven patients (32%) had partial remissions including the lungs, skin, lymph nodes and locally advanced primary tumor. The median overall survival was 11 months (range 1-17+) and the median progression-free interval was 8 months (range 1-13+). Neutropenia (WHO grade III/IV) occurred in 14% of patients. Other main toxicities were alopecia in 45%, fever/infection in 9%, and nausea/vomiting and diarrhea in 5%. In conclusion, the combination of paclitaxel and continuously infused 5-FU/folinic acid appears to be an active regimen for advanced gastric carcinoma with a remission rate comparable to ELF or FAMtx. The moderate toxicity allows treatment on an outpatient basis.
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PMID:A phase II trial of paclitaxel and weekly 24 h infusion of 5-fluorouracil/folinic acid in patients with advanced gastric cancer. 918 Mar 95

The goal of this National Cancer Institute-sponsored phase I trial is to determine the feasibility, toxicity, and pharmacokinetics of continuous-infusion (24 hr/d, 7 d/wk, 7 weeks total) intravenous paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) when combined with standard, curative-intent radiation therapy (RT) for previously untreated, locally advanced non-small cell lung cancers. Eligible patients have locally advanced (T4NXM0 or TXN2-3M0) non-small cell cancer ineligible for potentially curative surgical resection, a good performance status, adequate hematologic, hepatic, and renal functions, and no distant metastases. All patients receive a total tumor dose of 64.8 Gy megavoltage RT in 7 weeks at 1.8 Gy once daily, 5 d/wk. Paclitaxel is delivered by continuous intravenous infusion starting 48 hours before RT and continuing for its duration. The dose of paclitaxel is escalated in cohorts of three patients in a standard phase I design. To date, 16 patients have entered the trial, and 15 are evaluable for toxicity in this ongoing study. Paclitaxel dose is currently at a 6.5 mg/m2/d dose level, with no dose-limiting toxicity recorded thus far. One patient at the highest dose level has had grade 2 pneumonitis. With the exception of anemia, toxicities are those that would be expected from RT alone. A slowly progressive normocytic anemia with no renal dysfunction was found to be associated with an acquired hypoerythropoietin state. These findings indicate that this therapy is feasible and well tolerated through current dose levels, with no dose-limiting toxicity. Dose escalation is ongoing.
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PMID:Seven-week continuous-infusion paclitaxel plus concurrent radiation therapy for locally advanced non-small cell lung cancer: a phase I study. 933 Nov 30

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), the first taxane used in routine clinical practice, has aroused considerable interest for its high single-agent activity against breast cancer and for its novel mechanism of action. Epirubicin, the 4' epimer of doxorubicin, is another agent with a high activity against breast cancer and is known for its lower rate of toxic side effects, especially toxic cardiac events, compared with its mother compound. The combination of paclitaxel and doxorubicin yielded response rates between 63% and 93% in phase I/II studies. In these studies, however, the investigators reported severe cardiac toxic events. The rationale for the current study was therefore to evaluate the combination of paclitaxel/epirubicin, focusing mainly on cardiac toxicity. In two groups, 85 patients with metastatic breast cancer entered the study. Approximately 20% of the patients had primary metastatic breast cancer with large tumors at the primary site. Half of the patients had received adjuvant chemotherapy. Study medication in group A consisted of epirubicin 60 mg/m2 given intravenously over 1 hour, followed by paclitaxel 175 mg/m2 administered as a 3-hour intravenous infusion after premedication with steroids, antihistamines, and H2-blockers. In group B, epirubicin 90 mg/m2 was combined with paclitaxel 175 mg/m2, given in the same manner as in group A. Dose escalation to 225 mg/m2 paclitaxel was planned in both groups. The main toxicity in both groups was neutropenia (73% World Health Organization grade 3/4 in group A and 93% in group B). Other hematologic side effects were rare. No febrile neutropenia was reported in group A, but two episodes occurred in group B. Peripheral neuropathy, arthralgia, and myalgia were mild (only World Health Organization grades 1 and 2). Alopecia was universal. In group A, the paclitaxel dose could be escalated to 200 mg/m2 in 15 patients and to 225 mg/m2 in seven patients. Dose reduction due to severe neutropenia was necessary in 11 patients. No cardiac events were reported in group A. In group B, the paclitaxel dose could be escalated to 200 mg/m2 in only one patient, and no patient reached 225 mg/m2. Three patients needed a dose reduction. In this group, one patient had a greater than 10% decrease in the left ventricular ejection fraction with no clinical signs. In group A, 43 patients were evaluable for response; in group B, 25 patients were evaluable. Thirteen patients were out of protocol with only bone metastasis, and two patients had more than one prior chemotherapy for metastatic disease. The response rate was identical in both groups, with five complete remissions and 24 partial remissions in group A and three complete responses and 14 partial remissions in group B. The duration of response was 8.2 months in both groups. The median cumulative epirubicin dose was 420 mg/m2 in group A and 630 mg/m2 in group B. The combination of paclitaxel 175 mg/m2 and epirubicin 60 or 90 mg/m2 can be administered safely to patients with metastatic breast cancer. Although response was not the primary end point of this trial, the response data are nonetheless encouraging and suggest that further evaluation of this combination-line treatment of metastatic breast cancer is warranted.
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PMID:Phase II study of paclitaxel and epirubicin as first-line therapy in patients with metastatic breast cancer. 937 90

The goal of this National Cancer Institute-sponsored phase I trial is to determine the feasibility, toxicity, and pharmacokinetics of continuous-infusion (24 hr/d, 7 d/wk, 7-week total) intravenous paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) combined with standard curative radiotherapy (RT) for previously untreated, locally advanced head and neck squamous cell cancers. Eligible patients have squamous cell cancers of the head and neck with expected 5-year survival rates of < or =25%; a good performance status; adequate hematologic, hepatic, and renal functions; and no distant metastases. All patients receive 70 Gy megavoltage RT in 7 weeks (2 Gy/d x 5 d/wk). Paclitaxel is delivered by protracted venous infusion starting 48 hours before RT and continuing for its duration. Biopsies for cell-cycle distribution analyses and paclitaxel tissue levels are obtained, if possible, before beginning paclitaxel and after 48 hours just before RT begins. The dose of paclitaxel is escalated in cohorts of three patients. Eighteen patients are evaluable for toxicity. Treatment has been completed through the 6.5 mg/m2/d dose level and is ongoing at 10.5 mg/m2/d. There has been no dose-limiting toxicity thus far. With the exception of anemia, toxicity is commensurate with what would be expected from RT alone. A slowly progressive normocytic anemia with no renal dysfunction was found to be associated with an acquired hypoerythropoietin state. Tumor biopsies have suggested the possibility of paclitaxel-induced mitotic arrest. This therapy is feasible and has been well tolerated through current dose levels with no dose-limiting toxicity. There is a suggestion of biologic activity evidenced by the anemia and the possibility of alteration in cell-cycle distributions. Dose escalation is ongoing.
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PMID:Seven-week continuous-infusion paclitaxel with concurrent radiotherapy for locally advanced head and neck squamous cell cancer: a phase I study. 942 70

We demonstrated in an earlier trial that paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has substantial antineoplastic activity, with acceptable toxicity, in patients with advanced metastatic esophageal cancer. Preclinical and clinical data from studies in other tumors indicate substantial additive or even synergistic activity for paclitaxel/cisplatin combination chemotherapy. We encountered substantial toxicity with a cisplatin/paclitaxel/5-fluorouracil combination. To maximize paclitaxel dose, we initiated a phase II trial using cisplatin and paclitaxel alone. This report summarizes preliminary data from that trial. Paclitaxel 200 mg/m2 is given as a continuous, 24-hour infusion on day 1. On day 2, cisplatin 75 mg/m2 is given. Courses are repeated every 21 days. Dose adjustments are based on myelosuppression, neurotoxicity, and (for cisplatin) renal or auditory toxicity. All patients receive recombinant human granulocyte colony-stimulating factor to minimize the risk of neutropenic fever. The primary end point of the study is tumor regression. Secondary end points include duration of response and toxicity. Two groups of patients are being studied. Those with advanced metastatic disease receive chemotherapy alone as palliative treatment. The second group has locoregional disease that is potentially resectable. These patients receive combined-modality therapy involving induction paclitaxel/cisplatin chemotherapy followed by surgery. To date, 37 evaluable patients have been treated. Twenty had advanced metastatic disease and 17 were treated before planned surgery. Twenty-seven patients had adenocarcinoma and 10 had epidermoid carcinoma. Major objective responses were seen in 49% of all patients, with similar response rates for patients with metastatic and locoregional disease. The median duration of response for patients with metastases is 4+ months. Among 14 patients treated before surgery, one experienced a complete pathologic response, and the neoplasms of 43% were downstaged. Primary toxicity was neutropenia, which was tolerable. Surgical morbidity or mortality did not increase. Cisplatin plus paclitaxel is an active combination in the treatment of patients with advanced or locoregional esophageal cancer. Further studies with this combination both in metastatic and locally advanced disease are indicated.
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PMID:A phase II trial of paclitaxel and cisplatin in patients with locally advanced metastatic esophageal cancer: a preliminary report. 942 72

Several recent reports support administering preoperative chemotherapy and radiotherapy to improve the outcome of patients with resectable esophageal malignancies. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), 5-fluorouracil (5-FU), and cisplatin are known radiosensitizers, and paclitaxel has demonstrated single-agent activity in patients with metastatic esophageal cancer. This study sought to define the maximum tolerated dose of paclitaxel given with 5-FU, cisplatin, and 60 Gy radiotherapy before esophagectomy to patients with potentially resectable lesions. Seventeen patients so treated underwent esophagectomy. Three patients with metastatic disease, treated to obtain more information about the toxicity of the combined-modality regimen, did not undergo surgery. Over 6 weeks, 60 Gy radiation was administered in 2-Gy fractions. During radiation treatment, continuous intravenous infusions of 5-FU 225 mg/m2/d were administered, with paclitaxel given weekly as a 1-hour intravenous infusion immediately preceding a 1-hour cisplatin infusion. Surgery was performed 4 to 6 weeks after the completion of radiotherapy. The 27 patients, one of whom was a woman, had a median age of 58 years and an Eastern Cooperative Oncology Group performance status of 0 (10 patients) or 1. Three patients had a squamous cell histology, while 22 had adenocarcinoma; two had other histologies. The paclitaxel dose levels were 25 mg/m2 in four patients, 40 mg/m2 in five patients, 60 mg/m2 in nine patients, and paclitaxel 50 mg/m2 with 5-FU reduced to 200 mg/m2 in nine patients. The latter proved to be the maximum tolerated dose combination, with cisplatin held constant at 25 mg/m2. This level represents weekly dose intensities of 9.6 Gy radiation, 48 mg/m2 paclitaxel, 24 mg/m2 cisplatin, and 192 mg/m2 5-FU. Diarrhea in four patients, mucositis and dehydration in seven, electrolyte wasting in two, gram-positive catheter-related infection in three, and neuropathy in one proved dose limiting. Hematologic toxicity was relatively mild, with three episodes of nonneutropenic bacteremia, one of which was fatal. Postoperative chemotherapy consisting of four cycles of paclitaxel 175 mg/m2 over 3 hours and cisplatin 75 mg/m2 over 1 hour every 3 weeks was planned but rarely feasible due to postoperative morbidity and poor tolerability of postoperative chemotherapy. Therefore, the use of two induction cycles of this regimen given before the combined-modality study regimen is currently being investigated. Of 17 patients whose surgical specimens were assessed pathologically, three had complete remissions and 14 had partial remissions, five of which were characterized as very good, showing only microscopic foci and marked radiation effects. The median follow-up of the 17 patients who underwent surgery is 50 weeks (range, 5 to 111 weeks). Three relapses occurred at 26, 33, and 43 weeks. We conclude that this is an intense combined-modality preoperative regimen for patients with esophageal cancer. Determining the efficacy of this regimen will require further follow-up and the performance of phase II trials.
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PMID:Combined-modality therapy for esophageal cancer: phase I trial of escalating doses of paclitaxel in combination with cisplatin, 5-fluorouracil, and high-dose radiation before esophagectomy. 942 76


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