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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The novel multitargeted antimetabolite pemetrexed (Alimta), recently approved by the US Food and Drug Administration for the treatment of mesothelioma when combined with cisplatin, is also active in first- and second-line non-small-cell lung cancer (NSCLC). In a phase III trial comparing single-agent pemetrexed vs docetaxel (Taxotere) as second-line therapy in advanced NSCLC, survival was shown to be comparable between these agents, but side effects were significantly less frequent and severe for patients who received pemetrexed. In the frontline setting, phase II studies have shown significant activity and a very favorable toxicity profile of the combination of pemetrexed with a platinum agent. Pemetrexed has been well tolerated at systemic doses as a radiosensitizer when given as concurrent chest radiation, and a phase I study is under way to assess its tolerability in combination with carboplatin (Paraplatin) in this setting. Pemetrexed is an important addition to the armamentarium of medicines used to treat thoracic malignancies, and merits study in combination with other drugs having novel mechanisms of action.
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PMID:Pemetrexed in advanced NSCLC: a review of the clinical data. 1533 61

Several decades of chemotherapy trials in non-small-cell lung cancer (NSCLC) have clearly shown a survival benefit for chemotherapy over best supportive care. However, only short-lived responses are attained, with an average of four cycles of chemotherapy, before tumor progression is observed. Second-line chemotherapy has been demonstrated to improve outcome, with docetaxel (Taxotere) as the predominant cytotoxic drug. A recent randomized trial in second-line NSCLC indicated that the novel drug pemetrexed (Alimta) attained the same response, time to progression, and survival as docetaxel. This finding ushers in a new age in second-line treatment that can be further invigorated by the addition of targeted agents. Accumulated evidence indicates that overexpression of epidermal growth factor receptor and HER2/neu, which occurs frequently in NSCLC, leads to the deregulation of PI3K and MAPK, activating Akt and enhancing chemoresistance. Future clinical trials in NSCLC will include tailored and multitargeted therapy and pemetrexed represents a significant step forward in this direction.
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PMID:Pemetrexed in previously treated non-small-cell lung cancer. 1533 62

Pemetrexed is a novel multitargeted antifolate with significant clinical activity against a variety of tumors. We studied the schedule-dependent cytotoxic effects of pemetrexed in combination with paclitaxel in vitro to improve our understanding of how this combination might be used clinically. Human lung cancer A549 cells, breast cancer MCF7, ovarian cancer PA1, and colon cancer WiDr cells were exposed to both pemetrexed and paclitaxel in vitro. Cell growth inhibition after 5 days was determined and the effects of drug combinations were analyzed by the isobologram method (Steel and Peckham). Simultaneous exposure to pemetrexed and paclitaxel for 24 h produced antagonistic effects in A549 and PA1 cells, additive/antagonistic effects in MCF7 cells, and additive effects in WiDr cells. Pemetrexed for 24 h followed by paclitaxel for 24 h produced synergistic effects in A549 and MCF7 cells and additive effects in PA1 and WiDr cells, while the reverse sequence produced additive effects in all four cell lines. Cell cycle analysis supported these observations. Our findings suggest that the simultaneous administration of pemetrexed and paclitaxel is suboptimal. The optimal schedule of pemetrexed in combination with paclitaxel is the sequential administration of pemetrexed followed by paclitaxel, and this schedule should be assessed in clinical trials for the treatment of solid tumors.
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PMID:Schedule-dependent synergism and antagonism between pemetrexed and paclitaxel in human carcinoma cell lines in vitro. 1534 Jul 59

Since cisplatin-based chemotherapy was proven to increase survival in advanced and metastatic NSCLC various new combinations have been tested. The third generation regimens which showed almost comparable efficacy among each other in randomised trials often proved a better response rate and time to progression combined with a remarkable reduction of toxic side effects compared to "classic" combinations, whereas most studies only noted a modest increase in survival. Two-drug regimens were more effective than monotherapy but at the expense of significantly increased toxicity, while monotherapy compared to BSC improved quality of life and survival. The novel antifolate Pemetrexed proved comparable activity to docetaxel with significantly reduced toxicities.
Lung Cancer 2004 Aug
PMID:Chemotherapy in stage-IV NSCLC. 1555 2

Pemetrexed (Alimta) possesses broad antitumor activity. It has been evaluated in non-small-cell lung cancer (NSCLC) as front-line chemotherapy in a comprehensive phase II evaluation. While various antifolates have been previously evaluated in clinical trials, drug development was stopped or delayed in light of their lack of efficacy or occurrence of life-threatening toxicities. While similar trends were observed with pemetrexed early in development, investigators instituted folic acid and vitamin B12 supplementation to minimize these toxicities without hampering drug efficacy. This article briefly summarizes the current evidence that supports the role of pemetrexed-based combinations in clinical trials for chemonaive patients with advanced NSCLC.
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PMID:Pemetrexed in front-line chemotherapy for advanced non-small-cell lung cancer. 1565 34

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

Although no overall differences in survival have been observed between the many chemotherapy combinations in non-small-cell lung cancer, the clinical application of mRNA expression levels of amplified genes may disclose many genetic influences on cytotoxic drug sensitivity and enable clinicians to tailor chemotherapy according to each individual's gene profile. Specifically, the assessment of ribonucleotide reductase subunit M1 and thymidylate synthase mRNA expression levels might select patients who benefit from gemcitabine (Gemzar) or pemetrexed (Alimta) combinations. Until recently, clinical prognostic factors such as performance status, weight loss, and lactate dehydrogenase were the only parameters used to predict chemotherapy response and survival. However, accumulated data indicate that overexpression of genes involved in cancer glycolysis pathways plays an important role, and might be an independent mechanism of chemoresistance. The dysregulation of glycolytic genes is affected by growth signals involving the PI3K/Akt pathway and downstream genes such as hypoxia-inducible factor-1-alpha. One can thus envision that substantial improvements in therapeutic outcome could benefit from the integration of tailored ribonucleotide reductase-dependent chemotherapy, ribonucleotide reductase antisense therapy, and targeted therapy.
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PMID:The promise of pharmacogenomics: gemcitabine and pemetrexed. 1565 42

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

Malignant pleural mesothelioma (MPM) is a locally invasive malignancy, but only a minority of patients can benefit by surgical resection. Among chemotherapeutic agents only vinorelbine, edatrexate, gemcitabine and raltitrexed have demonstrated response rates >20%. The largest randomised trial in MPM showed an improved median survival with cisplatin and pemetrexed versus cisplatin alone from 9.3 to 12.1 months. For the present overview about 70 requests of information were sent to the major European centres of thoracic oncology. The most widespread study treatment in Europe is an 'Extended Access Program (EAP)' evaluating pemetrexed alone or combined with cisplatin or carboplatin with about 1500 enrolled patients. Two other international randomized studies compare pemetrexed plus best supportive care (BSC) versus BSC alone, and the role of Ranpirnase (Onconase) in MPM. Important national trials are ongoing: in the UK the addressed questions were the role of radical surgery (MARS Trial), the role of chemotherapy (MS-01 trial) and the role of VATS on active treatment of pleural effusion. In Switzerland the SAKK group phase III study explores in a comparative way the value of hemithoracic radiotherapy after primary treatment with cisplatin/pemetrexed followed by surgery. In Italy, 2 phase II trials of neoadjuvant chemotherapy (pemetrexed plus cisplatin in Rome, pemetrexed plus carboplatin in Padua) followed by surgery and radiotherapy are active. With the important exception of UK, the most evident element is the overwhelming presence of pemetrexed in the ongoing and future clinical trials. Pemetrexed has influenced not only the clinical practice, but also the patient enrolment in clinical trials.
Lung Cancer 2005 Jul
PMID:Overview on ongoing or planned clinical trials in Europe. 1595 Jul 91

In February 2004, pemetrexed disodium (Alimta; Eli Lilly), an anticancer drug that targets folate-dependent reactions that are essential for cell proliferation, became the first drug to be approved by the US FDA for the treatment of the rare cancer malignant pleural mesothelioma. Its accelerated approval for the second-line treatment of non-small-cell lung cancer followed in August 2004.
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PMID:Pemetrexed disodium. 1596 27


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