Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pemetrexed (Alimta; Eli Lilly and Company, Indianapolis, IN) is a new antifolate drug with activity at multiple points in folate metabolism, including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. In this way it inhibits the de novo synthesis of both purines and pyrimidines. In phase II studies, pemetrexed has shown good clinical activity as single-agent therapy in patients with advanced breast cancer with or without prior treatment, including patients with prior anthracycline and taxane treatment. Toxicities are primarily neutropenia, mucositis, and skin rash. Hematologic toxicities are markedly reduced by supplementation with vitamin B(12) and folate. Skin rash is ameliorated with prophylactic corticosteroid treatment. Pemetrexed is a promising agent in breast cancer and warrants further investigation in this setting.
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PMID:Pemetrexed (Alimta): a promising new agent for the treatment of breast cancer. 1272 17

Several agents have been evaluated for the second-line treatment of patients with non-small cell lung cancer. The TAX 317 trial found that patients treated with docetaxel (Taxotere) 75 mg/m2 had significantly longer survival than those treated with best supportive care alone. In addition, symptom control was better for patients who received chemotherapy. The TAX 320 trial found that treatment with docetaxel 75 or 100 mg/m2 resulted in significantly higher response rates than treatment with vinorelbine (Navelbine) or ifosfamide (Mitoxana), and the 1-year survival rate was also significantly better for patients treated with docetaxel 75 mg/m2. A large randomized trial compared pemetrexed (LY-231514 or Alimta) 500 mg/m2 with docetaxel 75 mg/m2. Response and survival rates were similar in the two treatment arms, however, the toxicity profile of pemetrexed was superior to that of docetaxel with significantly less Grade 3/4 neutropenia and febrile neutropenia. Fewer patients in the pemetrexed arm required hospitalization. Topotecan (Hycamtin) 2.3 mg/m2/day orally for 5 days has been compared with docetaxel 75 mg/m2 in a large 800-patient study. The results of this trial are awaited. Gemcitabine (Gemzar) and irinotecan (Campto) have been evaluated both as single agents and in combination with each other and study results do not suggest that either of these drugs is superior to docetaxel or pemetrexed. The vinca alkaloid vinorelbine has proved to be inferior to docetaxel in a randomized trial. The epidermal growth factor receptor inhibitors gefitinib (ZD1839, Iressa) and erlotinib (CP-358774, OSI 774, Tarceva) have been evaluated in Phase II trials in the second- and third-line setting. Both drugs have demonstrated interesting response rates ranging from 10 to almost 20%. The results of placebo-controlled randomized trials of this family of drugs are awaited. In summary, several studies have now found a definite role for the second-line treatment of patients with non-small cell lung cancer.
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PMID:Second-line chemotherapy for non-small cell lung cancer. 1293 56

Pemetrexed (Alimta) is a novel multitargeted antifolate that has activity against non-small-cell lung cancer (NSCLC). As a single agent, the response rate is 16%-23%. As second-line therapy, it has a 5% and 14% response rate with pemetrexed in NSCLC patients who have had prior cisplatin or nonplatinum chemotherapy, respectively. Pemetrexed combined with cisplatin has a response rate of 38.9%-44.8%, with a median survival of 8.9-10.9 months. Pemetrexed plus gemcitabine in NSCLC has a response rate of less than 25%. The major toxicity associated with pemetrexed is neutropenia, which may be reduced with vitamin B12 and folate nutritional supplement. Additional studies with pemetrexed in combination with other agents are needed for the treatment of NSCLC patients.
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PMID:Pemetrexed (Alimta): a new antifolate for non-small-cell lung cancer. 1472 Mar 51

The purpose of this report is to summarize information on pemetrexed (LY231514; MTA; Alimta; Eli Lilly and Company; Indianapolis, IN), a drug recently approved by the U.S. Food and Drug Administration (FDA). The review of the efficacy and safety of pemetrexed is summarized below. Pemetrexed is a pyrrolopyrimidine antifolate. It inhibits thymidylate synthase, glycinamide ribonucleotide formyltransferase, and dihydrofolate reductase. In a single, randomized, single-blind, multicenter phase III trial, the efficacy and safety of pemetrexed combined with cisplatin (Platinol; Bristol-Myers Squibb; Princeton, NJ) were compared with those of single-agent cisplatin in 448 patients with malignant pleural mesothelioma. Two hundred twenty-six patients were randomized to receive pemetrexed and cisplatin, while 222 patients were randomized to receive cisplatin alone. The primary study end point was survival. Median survival times were 12.1 months for the pemetrexed plus cisplatin treated arm and 9.3 months for the cisplatin alone arm. Pemetrexed causes myelosuppression. The most common adverse events were neutropenia, fatigue, leukopenia, nausea, dyspnea, and vomiting. On February 4, 2004, pemetrexed was approved by the FDA in combination with cisplatin for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. The recommended dose of pemetrexed is 500 mg/m(2) administered as an i.v. infusion over 10 minutes on day 1 of each 21-day cycle together with cisplatin at a dose of 75 mg/m(2) infused over 2 hours beginning 30 minutes after the pemetrexed infusion. Patients must receive oral folic acid and vitamin B(12) injections prior to the start of therapy and continue these during therapy to reduce severe toxicities. Patients should also receive corticosteroids with chemotherapy to reduce the risk of skin rashes. Approval was based on superior survival as a clinical benefit.
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PMID:FDA drug approval summaries: pemetrexed (Alimta). 1547 32

Pemetrexed (Alimta) is a novel antimetabolite that inhibits the folate-dependent enzymes thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Pemetrexed has demonstrated activity in clinical trials in a variety of tumor types, including lung, breast, colon, mesothelioma, pancreatic, gastric, bladder, head and neck, and cervix. Pemetrexed is rapidly metabolized into active polyglutamate forms that are potent inhibitors of several tetrahydrofolate cofactor-requiring enzymes critical to the synthesis of purines and thymidine. Functionally, pemetrexed acts as a prodrug for its polyglutamate forms. Two different transporters are known to take extracellular folates, and some antifolates, into the cell. These are the reduced folate carrier and the folate receptor. One of the many attributes that make pemetrexed unique is that methodology has been developed to eliminate and control the many of its associated clinical toxicities. Multivariate analyses demonstrated that pretreatment total plasma homocysteine levels significantly predicted severe thrombocytopenia and neutropenia, with or without associated grade 3/4 diarrhea, mucositis, or infection. Routine vitamin B12 and folic acid supplementation have resulted in decreased frequency/severity of toxicities associated with pemetrexed without affecting efficacy, making this novel antifolate a safe and efficacious anticancer agent.
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PMID:Biochemical pharmacology of pemetrexed. 1565 31

According to the updated 2004 guidelines of the American Society of Clinical Oncology (ASCO) on the treatment of advanced non-small-cell lung cancer (NSCLC), docetaxel (Taxotere) can be considered the standard second-line chemotherapy in patients relapsing after frontline therapy. This was based on two phase III trials (TAX 317 and TAX 320) that demonstrated the superiority of docetaxel at 75 mg/m2 in the parameters of survival, quality of life, and disease/symptom control when compared to best supportive care or alternative single-agent chemotherapy. The response rate was approximately 60%, with a median survival time of 7 months and a 1-year survival rate of 30%. Despite the activity demonstrated, this schedule showed an important toxicity profile, with grade 3/4 neutropenia and febrile neutropenia occurring in 70% and 11% of patients, respectively. However, the results obtained by these studies stimulated research interest in new drugs for this disease setting. Pemetrexed (Alimta), a new multitargeted antifolate, has achieved promising results in NSCLC treatment, as a single agent or in combination with other drugs. In the second-line setting, a large phase II study demonstrated good activity of pemetrexed, with an acceptable toxicity profile. This led to a phase III registration trial that compared pemetrexed at 500 mg/m2 to the standard docetaxel dose of 75 mg/m2. While results from this trial demonstrated a similar efficacy of the two regimens in response rate and survival, pemetrexed achieved a better safety profile. These results support the use of pemetrexed as a new option in the second-line treatment of NSCLC.
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PMID:Pemetrexed in second-line treatment of non-small-cell lung cancer. 1565 35

Single-agent gemcitabine (Gemzar) is the standard of chemotherapy for advanced pancreatic cancer, with no phase III trials to date having shown significantly improved survival with gemcitabine-based combinations vs single-agent treatment. The multitargeted antifolate agent pemetrexed (Alimta) shows synergistic effects in vitro in combination with gemcitabine, and activity and good tolerability when used as single-agent treatment in advanced pancreatic cancer. In a phase II trial in patients with advanced pancreatic cancer, the combination of gemcitabine at 1,250 mg/m2 on days 1 and 8 plus pemetrexed at 500 mg/m2 on day 8 after gemcitabine every 21 days resulted in a median survival of 6.5 months and a 1-year survival rate of 29%. Neutropenia was the primary toxicity, with grade 4 toxicity in 51% of patients. The promising results of this trial prompted the initiation of a phase III trial comparing gemcitabine at 1,000 mg/m2 on days 1, 8, and 15 every 28 days vs the 21-day gemcitabine/pemetrexed regimen given with vitamin supplementation in patients with pancreatic cancer. The primary outcome measure was overall survival, with secondary measures including response rate, progression-free survival, and quality of life. While an increase in response and time to progression was reported for the gemcitabine/pemetrexed combination, there were no significant differences in survival between treatment arms.
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PMID:Pemetrexed in pancreatic cancer. 1565 36

Pemetrexed (Alimta) shows single-agent activity in advanced colorectal cancer. In two phase II studies in which patients received pemetrexed at 600 mg/m2 or 500 mg/m2 as first-line treatment for metastatic disease, objective response rates were 15.4% and 17.2%. These trials were conducted prior to supplementation with folic acid and vitamin B12, which markedly decreased the frequency of hematologic toxicities of pemetrexed; routine supplementation is now included in all clinical trials of the agent. The marked improvement in toxicity and tolerance with vitamin supplementation suggests the need to reexamine optimal dosing in pemetrexed combination schedules. In a National Surgical Adjuvant Breast and Bowel Project phase II trial in 54 patients with previously untreated advanced colorectal cancer, pemetrexed at 500 mg/m2 plus oxaliplatin (Eloxatin) at 120 mg/m2 every 21 days with folic acid/vitamin B12 supplementation resulted in an objective response of 23%. Three additionalpatients (5.6%) had unconfirmed partial response (partial response at one visit), and 27 patients (50%) had stable disease. Median progression-free survival was 5.3 months and median duration of response was 5.7 months; median overall survival was approximately 11.05 months. Grade 3/4 neutropenia was observed in only 17% of patients and treatment was well tolerated. A phase I/II study is under way to identify and assess the optimal combination of pemetrexed/irinotecan in second-line treatment of advanced colorectal cancer. Planned studies include a phase I study examining the combination of pemetrexed and oxaliplatin given every 2 weeks as first-line treatment, and a phase I/II trial to identify the optimal pemetrexed/ oxaliplatin dose in a 21-day schedule and to compare pemetrexed/ oxaliplatin with FOLFOX4 in first-line treatment of metastatic disease. All of these trials include vitamin supplementation. A phase III trial comparing the every-3-week pemetrexed/oxaliplatin regimen with FOLFOX4 as first-line treatment will be initiated if the outcome of the phase II trial is encouraging.
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PMID:Pemetrexed in advanced colorectal cancer. 1565 39

Pemetrexed (Alimta) is active in a variety of solid tumors, including breast and gynecologic cancers. Phase II trials of pemetrexed at a dose of 600 mg/m2 without vitamin B12 and folic acid supplementation in largely pretreated metastatic breast cancer patients demonstrated objective response rates of 21% and 28%, with generally manageable neutropenia constituting the primary toxicity. In phase II trials using 500 mg/m2 with or without vitamin supplementation in anthracycline- and taxane-pretreated patients, response rates were lower (approximately 9%) and treatment was generally well tolerated irrespective of vitamin supplementation status. A phase II trial is currently comparing pemetrexed doses of 600 and 900 mg/m2 with vitamin B12 supplementation in patients with previously untreated advanced breast cancer. In a phase II trial in patients with advanced cervical cancer, pemetrexed at 600 mg/m2 without vitamin supplementation and 500 mg/m2 with supplementation produced similar response rates, with the frequency of neutropenia being somewhat lower among patients receiving the lower dose and vitamin supplementation. Preliminary results in an ongoing phase II trial indicate activity of the regimen of gemcitabine (Gemzar) at 1,000 mg/m2 plus pemetrexed at 500 mg/m2 with vitamin supplementation in patients with ovarian cancer. Ongoing and future studies will establish optimal dosing regimens of pemetrexed and potential benefits of vitamin supplementation in the settings of metastatic breast cancer and gynecologic malignancies.
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PMID:Phase II studies of pemetrexed in metastatic breast and gynecologic cancers. 1565 40

Pemetrexed (Alimta; Eli Lilly and Co, Indianapolis, IN) is a multitargeted antifolate that inhibits several folate-dependent enzymes that play roles in purine and pyrimidine synthesis. The principal toxicities of pemetrexed are neutropenia, diarrhea, nausea/vomiting, mucositis, and skin rash. These toxicities are more frequent in vitamin-deficient (folate and vitamin B 12 ) patients, and can be ameliorated by the co-administration of folate and vitamin B 12 . The use of prophylactic dexamethasone is also recommended to reduce the frequency of severe skin rash. Pemetrexed has significant single-agent activity in previously treated and untreated patients with non-small cell lung cancer (NSCLC). A recent phase III trial comparing pemetrexed with docetaxel in previously treated NSCLC patients showed equivalent efficacy with less bone marrow toxicity (eg, neutropenia) in the pemetrexed group. These results were pivotal in the approval of pemetrexed for the treatment of refractory NSCLC. Pemetrexed has been combined with the platinums (ie, cisplatin, carboplatin, and oxaliplatin) in NSCLC to yield clinical activity similar to that of other platinum-based doublets. A comparative phase III trial of cisplatin/pemetrexed against cisplatin/gemcitabine (Gemzar; Eli Lilly and Co) is under way. Pemetrexed has also been evaluated in combination with gemcitabine, and although the optimal dose and schedule of this combination has not been defined, clinical activity similar to other nonplatinum-based doublets has been observed. Preliminary evidence suggests that pemetrexed can be combined with thoracic radiation therapy, but more data are needed to evaluate the potential advantage(s) pemetrexed may have in this setting. Pemetrexed/platinum doublets also appear to possess activity in extensive stage small cell lung cancer. A phase II trial of single-agent pemetrexed is under way in both sensitive- and refractory-relapsed small cell lung cancer. Given the activity and excellent tolerability of pemetrexed, further studies in lung cancer are warranted.
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PMID:The evolving role of pemetrexed (Alimta) in lung cancer. 1581 33


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