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)

Paclitaxel pharmacokinetics are nonlinear with saturable metabolism and saturable distribution to the tissues. The saturable distribution has in previous pharmacokinetic modeling been described as a saturable transport process, whereas the present study was undertaken to investigate alternative explanations. Using a sparse sampling scheme (on average 3.3 samples per profile), 101 plasma concentration-time profiles in 22 female patients with metastatic cancer of the breast or ovary were monitored. It was found that the observed data could be equally well described by saturable tissue binding as well as by capacity-limited tissue transport. The data were better described by a model where equilibrium was achieved with drug in the central rather than in the peripheral compartment. Models where the binding was assumed to be an instantaneous or a noninstantaneous process were tried, but the data did not allow resolution between these two possibilities. The value at which the saturable transport was half-maximal was 0.55 microM. The K(d) values of the binding models were 0.06 to 0.12 microM. These are close to the values reported as a threshold for drug toxicity of paclitaxel, suggesting a possible connection between the binding sites involved in the pharmacokinetics and the mechanism responsible for the toxicity. For all models, a saturable elimination of paclitaxel was included using the Michaelis-Menten model. K(m) for the elimination ranged in the different models from 2.5 to 5.6 microM.
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PMID:Pharmacokinetic models for the saturable distribution of paclitaxel. 1049 51

Anaplastic thyroid carcinoma is a rare, lethal disease with no effective systemic therapies. Preclinical studies demonstrated antineoplastic activity of paclitaxel. This prompted a prospective phase 2 clinical trial to determine activity of paclitaxel against anaplastic thyroid carcinoma in patients with persistent or metastatic disease despite surgery or local radiation therapy. Twenty patients, entered through 6 of 12 study sites, were treated with 96-hour continuous infusion paclitaxel every 3 weeks for 1 to 6 cycles; the first 7 patients received 120 mg/m2 per 96 hours and the rest received 140 mg/m2 per 96 hours. Total responses to therapy were assessed using modified criteria with response durability acceptable at 2 or more weeks, due to the exceedingly rapid growth rate of this tumor. Plasma samples were obtained for pharmacokinetic analyses. Off-protocol, data showed that 9 patients were later treated with 225 mg/m2 paclitaxel as weekly 1-hour infusions. Nineteen evaluable patients demonstrated a 53% total response rate (95% confidence interval, 29%-76%) with one complete response and nine partial responses (including one off protocol). Results of historical review off-protocol showed 2 of 7 patients, with prior partial responses to the 96-hour infusion, had subsequent partial responses to weekly treatment and 1 of 2 prior nonresponders gained a partial response to weekly therapy. No toxicities greater than grade 2 were seen with 96-hour infusions, while peripheral neuropathy (up to grade 3) was most common with postprotocol weekly infusions. Paclitaxel appears to be the only agent with significant clinical systemic activity against anaplastic thyroid carcinoma; however, it is not capable of altering the lethality of this malignancy, suggesting the need for additional therapeutic innovations. Decreased time intervals between paclitaxel infusions may be more efficacious.
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PMID:Treatment of anaplastic thyroid carcinoma with paclitaxel: phase 2 trial using ninety-six-hour infusion. Collaborative Anaplastic Thyroid Cancer Health Intervention Trials (CATCHIT) Group. 1095 11

Paclitaxel is an active agent for adenocarcinomas and squamous cell carcinomas of the esophagus and is a radiation sensitizer. We sought to investigate the toxicity and complete response rate of paclitaxel, cisplatin, and concurrent radiation for esophageal cancer. Forty-one patients with esophageal cancer were studied, 29 with adenocarcinomas and 12 with squamous cell cancers. Twelve patients had tumor extension into the proximal stomach and/or abdominal adenopathy. Patients received paclitaxel 60 mg/m2 by 3-hour intravenous (i.v.) infusion, and cisplatin 25 mg/m2 weekly on days 1, 8, 15, and 22. Radiation was administered concurrently to a total dose of 39.60 Gy, in 1.80 Gy fractions, for 22 treatments. Patients with medical or surgical contraindications to esophagectomy received 2 additional weeks of paclitaxel with a radiation boost to 50.4 Gy. Neutropenia was the most common grade 3/4 toxicity occurring in 10 patients (24%). Only 2 patients (5%) had grade 4 esophagitis requiring parenteral nutrition. Twelve patients (29%) obtained a complete response. The 2-year progression-free and overall survival rates were 40% and 42%, respectively. Esophagitis was less severe than expected and prophylactic enteral feeding tubes were not necessary. Additional effective systemic treatments are needed to reduce the development of distant metastases.
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PMID:Paclitaxel, cisplatin, and concurrent radiation for esophageal cancer. 1129 48

The methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) regimen has been the standard treatment in patients with locally advanced and metastatic urothelial cancer for the past 15 years. The minimal or moderate survival benefit-depending on prognostic features-and the severe toxicity associated with the MVAC regimen have made the search for new drugs and drug combinations of utmost importance to increase efficacy and/or decrease toxicity. In this respect, the taxanes and gemcitabine are promising new drugs. Paclitaxel and docetaxel as single agents have yielded overall response rates of 7% to 56%, depending on whether the patients have received prior chemotherapy for metastatic disease. The combination of paclitaxel and cisplatin has been explored in three studies with a total of 104 evaluable patients, a pooled overall response (OR) rate of 61%, and a complete response (CR) rate of 20%. There are two studies of docetaxel and cisplatin with a total of 91 evaluable patients, an OR rate of 54%, and a CR rate of 16%. The OR rate for paclitaxel and carboplatin in six studies was 43%, with a CR rate of 13%; however, the reported median survival was only 8.5 to 9.5 months. The OR rate for single-agent gemcitabine based on five studies was 26%, with a CR rate of 9%, which was apparently independent of whether the patients had received prior chemotherapy. The OR rate for gemcitabine and cisplatin in four phase II studies ranged from 41% to 57%, with a CR rate of 15% to 22% and a median survival of 12.5 to 14.3 months. Based on the encouraging results for the combination of gemcitabine and cisplatin (GC), a randomized phase III trial comparing GC and MVAC was begun in late 1996. This study of 405 randomized patients showed that the two regimens were associated with similar response rates, time to progression, and overall survival, whereas GC was associated with less toxicity than MVAC. On the basis of this superior risk-benefit ratio, the GC regimen should be favored as a new standard treatment in patients with locally advanced and metastatic urothelial cancer. Other promising combinations include gemcitabine and paclitaxel, with or without cisplatin, and the combination of ifosfamide, paclitaxel, and cisplatin. The triple combination of gemcitabine, paclitaxel, and cisplatin has yielded an OR rate of 78%, a CR rate of 28%, and a median survival of 24 months. An international phase III trial comparing this triple combination with GC in patients with locally advanced and metastatic urothelial cancer has now been initiated.
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PMID:Current and future perspectives in advanced bladder cancer: is there a new standard? 1189 2

To assess the activity of paclitaxel in combination with 5-fluorouracil (5-FU) and leucovorin in breast cancer, a phase II trial was conducted in women with metastatic disease. Toxicity, response rate, median survival, median duration of response, and median time to disease progression were measured. Between January 1994 and May 1996, 47 patients with metastatic breast cancer and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) < or = 2 who had previously been treated with chemotherapy received 175 mg/m2 paclitaxel over 3 hours on day 1. After paclitaxel administration, 300 mg intravenous (i.v.) leucovorin over 30 minutes was administered followed by 350 mg/m2 i.v. push 5-FU. Both 5-FU and leucovorin were given on days 1-3. Treatment was repeated every 28 days for a minimum of 6 cycles per patient. Two (4%) patients had a complete response and 21 (45%) patients had a partial response for an overall response rate of 49% (95% confidence interval: 35%-63%). The median survival was 17.7 months, median duration of response was 8.6 months, and median time to disease progression was 6.3 months. There was no statistical difference in survival or time to progression between anthracycline-naive, anthracycline-sensitive, and anthracycline-resistant patients. Nine (19%) patients had grade 3 or 4 neutropenia, and no patient required blood or platelet transfusion. The most frequently observed nonhematologic toxicities were arthralgia and myalgia. Pharmacokinetic data were obtained on 19 patients. Responders had higher peak plasma concentrations of paclitaxel than nonresponders (4.46 vs. 2.9 micrograms/mL; P = 0.02). Paclitaxel/5-fluorouracil/leucovorin is an active, well-tolerated regimen for patients with metastatic breast cancer.
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PMID:Paclitaxel, 5-fluorouracil, and leucovorin (TFL) in the treatment of metastatic breast cancer. 1189 52

A 36-year-old woman was referred to our hospital because of a right breast lump. Chest computed tomography revealed pulmonary metastases with lymphangitis carcinomatosa. Additional examination revealed liver metastases and axillary and cervical lymph node metastases. The patient was started on CA therapy (cyclophosphamide 900 mg, adriamycin 90 mg). A minor response was observed in the pulmonary metastases after two courses but new brain metastases were detected. We then tried paclitaxel administration (260 mg). A partial response was observed in the brain and pulmonary metastases. Thus, paclitaxel administration was continued on a weekly basis (120 mg) and the brain and pulmonary metastases continued to diminish. The primary breast cancer, liver metastases and axillary and cervical lymph node metastases were disappeared. Whole brain radiation was done with weekly paclitaxel administration and the brain metastases were diminished even more. Paclitaxel is as a radiosensitizer and seems to have a strong antineoplastic effect with concurrent radiation.
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PMID:[A case of effective paclitaxel therapy for adriamycin resistant metastatic breast cancer with brain metastases]. 1197 43

Paclitaxel is among the most effective agents in the treatment of breast cancer. Both as a single agent and in combinations, paclitaxel is effective as first-line therapy and as a salvage therapy in patients with locally advanced or metastatic disease. Paclitaxel also demonstrated efficacy in patients who received prior anthracyclin therapy and those with anthracyclin-resistant disease. In the adjuvant setting, data from randomized study have supported the sequential use of paclitaxel after therapy with doxorubicin / cyclophosphamide for patients with node-positive disease. The drug may be used in combination with other chemotherapeutical agents and immune stymulatory agents. Therapy on weekly and every-three-week schedules has been effective.
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PMID:[Chemotherapy of breast cancer: focus on paclitaxel] 1205 Jul 72

Paclitaxel (Taxol) is a diterpene plant product and antineoplastic agent that promotes the assembly of microtubules as well as stabilizing their formation by preventing depolymerization. Myelosuppression was found to be dose-limiting, but peripheral neurotoxicity is also a well known side-effect. Central nervous system toxicity is rare, probably because paclitaxel does not cross the blood-brain barrier. We observed three patients who presented with acute encephalopathy within 6 h after infusion of paclitaxel at normal doses. All patients had received prior whole brain irradiation (WBI) and one patient had prior brain metastasectomy. Computer tomography and magnetic resonance imaging showed no evidence of cerebral metastases. An effect from other organ toxicities was excluded in all patients. All recovered spontaneously within 4-6 h. From this we can conclude that paclitaxel can cause severe acute transient encephalopathy, which may occur more frequently after prior WBI and/or surgery due to alteration of small vessel function.
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PMID:Acute transient encephalopathy after paclitaxel infusion: report of three cases. 1205 15

Paclitaxel, a natural anticancer drug, has gained widespread acceptance as an active broad-spectrum antitumor agent, including its use in urological malignancies, particularly urothelial tract cancer and testicular cancer. The mechanism of action, based on the premature stabilization of the microtubule assembly with disruption of the cytoskeletal framework, is completely different from those of DNA-damaging agents, e.g., cisplatin and ifosfamide. As a single agent, paclitaxel is one of the most active drugs in metastatic bladder cancer, with an overall response rate of 40-50% being obtained in previously untreated patients. These promising single-agent results have prompted the use of combination regimens including, in particular, cisplatin and paclitaxel. A high degree of activity for the cisplatin-paclitaxel combination as reflected by responses in 50-80% of patients, including a substantial number of complete responses (> 30%), has been identified. The role of other agents such as vinorelbine, methotrexate, 5-fluorouracil, or ifosfamide as additions to this two-drug combination currently remains open. The combination of paclitaxel plus ifosfamide or vinorelbine in the absence of a platinum derivative has yielded rather disappointing results. Of particular interest may be the combination of paclitaxel and carboplatin. Both drugs can be given to patients with impaired renal function. Overall response rates of 45-60% have been reported in phase II studies. The so-called platelet-sparing effect of paclitaxel given in combination with carboplatin has resulted in a surprisingly low frequency of myelotoxicity, particularly thrombocytopenia. The combination of paclitaxel with carboplatin is being compared in an ongoing trial against the current standard MVAC regimen (methotrexate/vinblastine/Adriamycin/cisplatin) in patients with metastatic disease. Furthermore, the activity of paclitaxel-based combinations is currently being explored in the neoadjuvant setting in phase II studies, and the potential for the combination with the other new promising agent--gemcitabine--will be evaluated in a phase I setting. In prostate cancer, estramustine phosphate is widely used as palliative treatment for patients with hormone-refractory disease. In vitro synergistic activity has been observed between estramustine and paclitaxel in prostate-cancer cell lines, although paclitaxel has not demonstrated single-agent activity in patients with hormone-refractory prostate cancer. In clinical trials the combination of the two agents was associated with increased gastrointestinal toxicity. The addition of etoposide as a third drug has yielded prostate-specific antigen (PSA)-response rates of > 50%, but data on quality of life and survival time have not been reported for these combinations. A true clinical role for paclitaxel in prostate cancer has therefore not been established. Paclitaxel has finally demonstrated single-agent activity in relapsed and/or cisplatin-refractory testicular cancer in recent phase II trials, indicating different mechanisms of resistance to cisplatin and paclitaxel. These results have formed the rationale for the introduction of paclitaxel as part of combination chemotherapy regimens in patients with relapsed but chemosensitive testicular cancer. Preliminary results demonstrate that paclitaxel can be safely included into these conventional-dose combination regimens. When it is used prior to high-dose chemotherapy, sufficient numbers of peripheral blood stem cells (PBSCs) for high-dose therapy can be collected. The final role of paclitaxel in risk-adapted chemotherapeutic strategies in testicular cancer is not defined, but it appears that paclitaxel-based combinations can achieve a substantial response rate in patients with relapsed disease.
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PMID:Recent strategies for the use of paclitaxel in the treatment of urological malignancies. 1207 32

We treated a case of advanced gastric cancer with paclitaxel and TS-1. A 64-year-old man underwent total gastrectomy, splenectomy, and D2 + No. 16 a 2, b 1 lymph node (LN) dissection for gastric cancer. Computed tomography (CT) revealed metastases of supraclavicular and para-aortic LNs in the 4th postoperative month. Paclitaxel 90 mg was infused once a week, and TS-1 100 mg was administered daily. One course consisted of infusion of paclitaxel for 3 weeks followed by 2 weeks rest and administration of TS-1 for 4 weeks followed by 2 weeks rest. At the end of 4 courses of paclitaxel and 3 courses of TS-1, a partial response of the supraclavicular LN metastasis and a complete response of the para-aortic LN metastasis were achieved. There were no remarkable side effects for 2 years after the operation. This chemotherapy might be suitable to treat patients with LN metastases of advanced gastric cancer.
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PMID:[A case of advanced gastric cancer treated with paclitaxel and TS-1]. 1255 17


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