vitamin-b-12 and Mesothelioma

Malignant pleural mesothelioma is an aggressive but rare malignancy with a dismal prognosis. It is traditionally resistant to chemotherapy. Antifolate agents have recently shown promising data in the treatment of this malignancy. Pemetrexed is a multitargeted antifolate inhibitor of thymidylate synthase and other folate-dependent enzymes that has emerged as one of the most active agents in this disease. Several phase I/II trials of pemetrexed as a single agent or in combination with a platinum drug have demonstrated considerable activity in mesothelioma. In a recently published phase III randomized study, pemetrexed/cisplatin showed a significant improvement in survival, response rate, and quality of life compared with single-agent cisplatin. In addition, several trials reported that folic acid and vitamin B12 supplementation significantly reduced the toxicity observed with the use of pemetrexed without affecting the efficacy of the drug.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Clinical Trials as Topic; Dietary Supplements; Folic Acid; Folic Acid Antagonists; Glutamates; Guanine; Hematinics; Humans; Mesothelioma; Pemetrexed; Pleural Neoplasms; Vitamin B 12

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.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Dietary Supplements; Folic Acid; Glutamates; Guanine; Hematinics; Humans; Lung Neoplasms; Mesothelioma; Pemetrexed; Thymidylate Synthase; Vitamin B 12

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.

Topics: Adrenal Cortex Hormones; Antineoplastic Agents; Clinical Trials, Phase III as Topic; Drug Approval; Folic Acid; Glutamates; Guanine; Humans; Infusions, Intravenous; Mesothelioma; Pemetrexed; United States; United States Food and Drug Administration; Vitamin B 12

Lung cancer is the leading cause of cancer death in the United States and throughout the world. The overall 5-year survival rate for lung cancer is dismal: 14% in the United States and even lower in other parts of the world. Recent developments in the armamentarium of chemotherapeutic agents for lung cancer have shown that two-drug combinations improve survival, relieve symptoms, and improve quality of life; however, complete response rates are still approximately 1% in stage IV disease and less than 20% of advanced stage patients survive 2 years. Therefore, improved therapeutic agents that increase efficacy are sorely needed. Most lung cancers overexpress thymidylate synthase and a variety of genes involved in cell cycle regulation. Previous studies have shown that some inhibitors of DNA synthesis (eg, gemcitabine) can improve the survival of advanced lung cancer patients, especially when combined with other agents such as cisplatin. The multitargeted antifolate, pemetrexed (Alimta; Eli Lilly and Co, Indianapolis, IN) was developed because it inhibits multiple enzymes involved in DNA synthesis including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase. The early studies of pemetrexed showed that the important dose-limiting toxicities were myelosuppression, mucositis, and diarrhea, all of which are common with any antimetabolite. Subsequent studies described in this article will show that these toxicities can be significantly reduced by the use of vitamin supplementation with folate and B12, and that pemetrexed has considerable activity in non-small cell lung cancer and mesothelioma.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cisplatin; Clinical Trials as Topic; Deoxycytidine; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Folic Acid; Gemcitabine; Glutamates; Guanine; Humans; Lung Neoplasms; Mesothelioma; Pemetrexed; Pleural Neoplasms; Thymidylate Synthase; Vitamin B 12

To understand the relationship between response and survival in malignant pleural mesothelioma (MPM).. The original clinical trial was conducted from April 1999 through March 2001. Patients with epithelioid MPM (n=305) were categorized using modified pleural Response Evaluation Criteria in Solid Tumors by whether they responded to treatment. Median progression-free survival (PFS) and overall survival (OS) were estimated and hazard ratios for responders and nonresponders were estimated and compared using the log-rank test. Multivariable Cox proportional hazards models were used to adjust for baseline prognostic factors.. Patients who responded to frontline therapy had a significantly longer OS (hazard ratio, 0.34; 95% CI, 0.24-0.49; median, 20.6 months; 95% CI, 15.3 months to not reached) than did those who did not respond (median, 9.4 months; 95% CI, 8.1-11.0 months) (P<.001). Similarly, responders had a significantly longer PFS (hazard ratio, 0.50; 95% CI, 0.39-0.64; median, 7.8 months; 95% CI, 6.5-8.5 months) than did nonresponders (median, 3.7 months; 95% CI, 2.9-4.3 months) (P<.001). These results were confirmed when adjusting for baseline prognostic factors. We also observed a survival benefit associated with disease stabilization in MPM.. Our findings indicate that reduction in tumor burden or disease stabilization determined using modified pleural Response Evaluation Criteria in Solid Tumors is strongly associated with OS and PFS in epithelioid MPM.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Female; Folic Acid; Humans; Lung Neoplasms; Male; Mesothelioma; Mesothelioma, Malignant; Middle Aged; Pemetrexed; Progression-Free Survival; Proportional Hazards Models; Tumor Burden; United States; Vitamin B 12; Vitamin B Complex

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.

Topics: Adrenal Cortex Hormones; Antineoplastic Agents; Clinical Trials, Phase III as Topic; Drug Approval; Folic Acid; Glutamates; Guanine; Humans; Infusions, Intravenous; Mesothelioma; Pemetrexed; United States; United States Food and Drug Administration; Vitamin B 12

Vitamin supplementation reduces pemetrexed toxicity. Raised plasma homocysteine reflects deficiency in vitamin B12 and folate, and is suppressed by supplementation. This observational study of 112 patients receiving pemetrexed-based chemotherapy assessed homocysteine levels after 3 weeks of vitamin supplementation, hypothesising high levels would correlate with ongoing deficiency, thus increased toxicity.. Primary endpoint was the composite of proportion of patients with treatment delay/ dose reduction/ drug change or hospitalisation during the first six weeks of chemotherapy, comparing those with normal plasma homocysteine (successfully supplemented, SS) and those with high homocysteine (unsuccessfully supplemented, USS). Secondary endpoints included toxicity and analyses for depression. Post-hoc analysis examined correlation between interval of vitamin and folate supplementation and pemetrexed on primary endpoint and grade 3-4 toxicities.. Eighty-four patients (84%) were successfully supplemented (SS group). The proportion of patients undergoing a treatment delay/ dose reduction/ drug change or hospitalisation in SS group was 44.0% (95% confidence interval [CI] 33.2%-55.3%) and in USS group was 18.8% (95% CI 4.0%-45.6%) (p = 0.09). Twelve percent of patients gave a past history of depression however 66% of patients had an on study Hospital Anxiety and Depression (HAD) score of >7. Supplementation status was not associated with depression. The median overall survival (OS) was 11.8 months (95% CI 8.6-16.5) in the SS group and 8.8 months (95% CI 6.6-16.2) in the US group (p = 0.5). The number of days (<7 or ≥ 7 days) between vitamin B12 and folate initiation and pemetrexed administration, had no effect on the primary endpoint and grade 3-4 toxicities.. On-treatment homocysteine levels were not a biomarker of toxicity or depression. Standard vitamin supplementation is adequate in the majority of patients receiving pemetrexed. High HAD score were noted in this population giving an opportunity for mental health intervention. The lead-in time for vitamin supplementation can be short.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Carcinoma, Non-Small-Cell Lung; Depression; Dietary Supplements; Female; Folic Acid; Homocysteine; Humans; Lung Neoplasms; Male; Mesothelioma; Mesothelioma, Malignant; Middle Aged; Pemetrexed; Prospective Studies; Treatment Outcome; Vitamin B 12; Vitamins

Topics: Abdominal Neoplasms; Adolescent; Adult; Aged; Breast Neoplasms; Carcinoma; Child; Cobalt Isotopes; Female; Gastric Juice; Gastrointestinal Neoplasms; Genital Neoplasms, Female; Hodgkin Disease; Humans; Intestinal Mucosa; Iodine Isotopes; Leiomyosarcoma; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Male; Mesothelioma; Methods; Middle Aged; Neuroblastoma; Pancreatic Neoplasms; Povidone; Radiation Effects; Radioisotope Teletherapy; Splenic Neoplasms; Time Factors; Triolein; Vitamin B 12