vitamin-b-12 and Carcinoma--Non-Small-Cell-Lung

Pemetrexed (ALIMTA, LY231514, MTA) is a novel antimetabolite that inhibits at least three enzymes involved in the folate pathway. These enzymes are thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Pemetrexed has demonstrated clinical activity in non-small cell lung cancer as well as in a broad array of other solid tumors, including mesothelioma, breast, colorectal, bladder, cervical, gastric and pancreatic cancer. In non-small cell lung cancer, single-agent activity has been documented in the first- and second-line settings in Phase II and Phase III trials. Promising activity has also been demonstrated when pemetrexed is combined with platinum compounds (cisplatin, carboplatin, and oxaliplatin), vinorelbine, and gemcitabine. Low level dietary supplement of folic acid and vitamin B12 has significantly decreased the mucosal and bone marrow toxicity of pemetrexed without compromising its antitumor effect.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Folic Acid; Glutamates; Guanine; Humans; Lung Neoplasms; Neoplasms; Pemetrexed; Platinum Compounds; Thymidylate Synthase; Vitamin B 12

Pemetrexed (Alimta , LY231514) is a new multitargeted antifolate that inhibits several enzymes involved in the folate pathway. Pemetrexed is a potent inhibitor of thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Pemetrexed has demonstrated clinical activity in non-small-cell lung cancer (NSCLC) as well as in a broad array of other solid tumors including mesothelioma and breast, colorectal, bladder, cervical, gastric, and pancreatic cancer. In NSCLC, single-agent activity has been documented in the first- and second-line settings. Promising activity has also been demonstrated when pemetrexed is combined with cisplatin, vinorelbine, oxaliplatin, carboplatin, and gemcitabine. Low-level dietary supplement of folic acid and vitamin B12 has significantly improved the safety profile of pemetrexed without compromising its antitumor effect. In this review, the pharmacology and clinical activity of pemetrexed in NSCLC cancer is discussed.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Glutamates; Guanine; Humans; Lung Neoplasms; Pemetrexed; 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

Pemetrexed is the preferred chemotherapeutic drug for nonsquamous, non-small-cell lung cancer patients whenever the predictive molecular biomarkers for targeted therapy have either not been assessed or are absent. As per manufacturers' instructions, supplementation with folic acid (FA; folate) at a dose of 350 to 1000 μg daily should be started seven days before the first dose of pemetrexed-based chemotherapy and continued during therapy and for 21 days after therapy cessation. Vitamin B

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Dietary Supplements; Female; Folic Acid; Humans; Lung Neoplasms; Male; Middle Aged; Patient Selection; Pemetrexed; Prospective Studies; Research Design; Treatment Outcome; Vitamin B 12; Young Adult

A vitamin B12 supplement is required in pemetrexed single agent therapy. Intramuscular administration is the method of choice; however, oral administration is simpler and easier and may be sufficiently effective. We conducted a Phase II study to evaluate the safety of oral administration of vitamin B12 in patients with advanced non-small cell lung cancer who received pemetrexed single agent therapy.. Folic acid and vitamin B12 were given orally for ˃ 1 week before pemetrexed administration. The primary end-point was onset of a grade ≥ 3 neutropenia ratio (50% of threshold expression ratios; an expectation expression ratio of 21%; α, 0.05; β, 0.1). Blood concentration of folic acid and homocysteine which are markers of vitamin B12 deficiency were also examined (UMIN000003180).. A total of 25 cases were registered from February 2010 to July 2014. The ratio of grade ≥ 3 neutropenia was 36% (95% CI 22-52 %). Grade ≥ 3 non-hematologic toxicity and hematologic toxicity were seen in 20% (5 cases) and 44% (11 cases) of patients, respectively. In addition, the homocysteine blood concentration just before the first cycle dosage of pemetrexed was significantly elevated relative to the 2-3 cycle.. This study failed to meet its primary endpoint. We could not demonstrate the safety and efficacy of the 1-week vitamin B12 oral administration protocol as compared with intramuscular administration.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Female; Folic Acid; Homocysteine; Humans; Lung Neoplasms; Male; Middle Aged; Pemetrexed; Vitamin B 12; Vitamin B 12 Deficiency; Vitamin B Complex

Prior supplementation with folic acid and vitamin B12 is required to reduce pemetrexed therapy toxicity; the recommended lead-in time is at least 7 days. On the basis of previous pharmacokinetic and clinical studies, we hypothesized that the lead-in time could be shortened to 24 hours, enabling earlier commencement of standard chemotherapy; thus, we planned the first prospective trial of this regimen.. Patients with advanced nonsquamous non-small cell lung cancer who had not previously received cytotoxic chemotherapy were enrolled. After measurement of homocysteine concentrations, the patients received 1,000 μg of vitamin B12 by intramuscular injection and began taking 350-500 μg of oral folic acid daily. Starting 24-48 hours after the vitamin B12 injection, the patients received intravenous 500 mg/m(2) pemetrexed and 75 mg/m(2) cisplatin for 4 cycles at 3 weekly intervals. The primary endpoint was the proportion of patients who developed neutropenia grade ≥3.. Thirty patients received chemotherapy starting within 48 hours of the vitamin B12 injection. No treatment-related deaths or grade 4 toxicity occurred. Neutropenia grade ≥3, other laboratory toxicities grade ≥3, and nonlaboratory toxicities grade ≥3 occurred in 6.7%, 13%, and 13% of patients, respectively. The baseline homocysteine concentrations were not higher in patients with grade ≥3 toxicities than in the remainder of the cohort (mean values, 8.6 and 10.7 μmol/L, respectively). The response rate to chemotherapy was 43%.. The shortened vitamin supplementation was well tolerated and retained antitumor efficacy. Analysis of baseline homocysteine concentrations confirmed the efficacy of short-term vitamin supplementation.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Female; Folic Acid; Glutamates; Guanine; Humans; Lung Neoplasms; Male; Middle Aged; Neutropenia; Pemetrexed; Prospective Studies; Treatment Outcome; Vitamin B 12

Pralatrexate is an antifolate designed for preferential tumor cell uptake and accumulation and received accelerated Food and Drug Administration approval in relapsed/refractory peripheral T-cell lymphoma. Pralatrexate 135 to 150 mg/m(2) every 2 weeks without vitamin supplementation was active in non-small cell lung cancer (NSCLC) although mucositis was dose limiting. This phase 1 study evaluated the safety of higher pralatrexate doses with vitamin supplementation to minimize toxicities.. Patients with stage IIIB/IV NSCLC received pralatrexate 150 to 325 mg/m(2) every 2 weeks with folic acid and vitamin B12 supplementation. Outcomes measured included adverse events (AEs), pharmacokinetics, and radiologic response.. Thirty-nine patients were treated for a median of two cycles (range 1-16+). Common treatment-related grade 3 and 4 AEs by dose (≤190 mg/m(2) and >190 mg/m(2)) included mucositis (33 and 40%) and fatigue (11 and 17%). Treatment-related serious AE (SAE) rates for doses ≤190 and >190 mg/m(2) were 0 and 20%, respectively. The response rate was 10% (95% confidence interval: 1-20%), including two patients with complete response (26+ and 32+ months) and two with partial response. Serum pralatrexate concentrations increased dose dependently up to 230 mg/m(2).. Pralatrexate with vitamin supplementation was safely administered to patients with previously treated NSCLC, and durable responses were observed. The recommended starting dose for phase 2 is 190 mg/m(2). A similar safety profile was observed in patients treated at 230 mg/m(2), although a higher serious AE rate was evident. Mucositis remains the dose-limiting toxicity of pralatrexate, and this study failed to demonstrate that vitamin supplementation prevents mucositis and failed to identify clinical predictors of mucositis. Individualized dose-modification strategies and prospective mucositis management will be necessary in future trials.

Topics: Adenocarcinoma; Aged; Aminopterin; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Dietary Supplements; Female; Folic Acid; Folic Acid Antagonists; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Prognosis; Tissue Distribution; Vitamin B 12; Vitamin B Complex

We examined the efficacy of enzastaurin plus pemetrexed as second-line therapy in patients with advanced (stage IIIA/B or IV) non-small cell lung cancer in a double-blinded, randomized, phase II study.. Patients received pemetrexed 500 mg/m intravenously on day 1 of 21-day cycles (day 8 in cycle 1) plus oral enzastaurin (250 mg two times per day; combination arm) or placebo (pemetrexed arm). Both arms received supplementation with vitamin B12, folic acid, and dexamethasone. An interim analysis was conducted to determine whether efficacy would warrant a phase III study.. The interim analysis showed no evidence of improved progression-free survival with enzastaurin. At final analysis (N = 160, 80 in each arm), baseline characteristics were well balanced. There was no significant difference in progression-free survival (3.0 months, p = 0.544) or overall survival (9.6 months in combination arm and 7.4 months in pemetrexed arm, p = 0.171). Drug-related serious adverse events included cerebrovascular accident, palpitations, and renal failure (n = 1, each) in combination arm and neutropenic sepsis, thrombocytopenia, and panniculitis (n = 1, each) in pemetrexed arm. Nonhematologic drug-related grade 3/4 toxicities were similar in both arms. Grade 3/4 hematologic toxicities were higher with the combination, specifically leukopenia (6.3% versus 0%), neutropenia (15.2% versus 5.0%), and thrombocytopenia (8.9% versus 1.3%). Of the 26 deaths reported on-study or within 30 days of discontinuation (10 in combination arm and 16 in pemetrexed arm), none were drug related.. The combination regimen of enzastaurin and pemetrexed is well tolerated but does not improve efficacy over pemetrexed and placebo as second-line treatment of unselected patients with advanced non-small cell lung cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Double-Blind Method; Female; Folic Acid; Glutamates; Guanine; Humans; Indoles; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Pemetrexed; Prognosis; Salvage Therapy; Survival Rate; Vitamin B 12

Pemetrexed is a multitargeted folate pathway inhibitor with documented activity in non-small cell lung cancer (NSCLC). The presumed maximum tolerated dose is 500 mg/m2 every 3 weeks, but pemetrexed-related toxicity is ameliorated when folate and B12 supplementation is provided and therefore a higher dose intensity may be tolerated. The current exploratory study assessed the feasibility of administration of pemetrexed at a fixed dose of 1000 mg every 2 weeks in patients with relapsed or refractory NSCLC.. The first cohort of 12 patients received pemetrexed monotherapy. No dose-limiting grade 4 toxicity was noted after 4 cycles, so the subsequent cohort of 14 patients received additional anticancer agents (bevacizumab, erlotinib, carboplatin, docetaxel, vinorelbine) given along with dose-dense pemetrexed.. Toxicity overall was reversible and manageable. Among 19 patients who received pemetrexed either alone or with non-myelosuppressive targeted agents, there were only 2 instances of grade 4 neutropenia after prolonged treatment. Grade 3-4 hematologic toxicity was eventually noted in 11 of the 26 patients (42%; 95% confidence interval, 23% to 61%) after a median of 4 cycles (range, 2-14 cycles). There was no significant additional toxicity nor any treatment-related deaths.. Our preliminary observations indicate that dose-dense pemetrexed every 2 weeks is feasible and this regimen can be used as monotherapy. These data may serve as a scaffold for combination studies.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Dose-Response Relationship, Drug; Drug Combinations; Feasibility Studies; Female; Folic Acid Antagonists; Glutamates; Guanine; Hematologic Diseases; Humans; Male; Neutropenia; Pemetrexed; Vitamin B 12

The objective of this study was to evaluate the efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B(12) in pretreated Japanese patients with advanced non-small cell lung cancer (NSCLC).. Patients with an Eastern Cooperative Oncology Group performance status 0 to 2, stage III or IV, and who received previously one or two chemotherapy regimens were randomized to receive 500 mg/m(2) pemetrexed (P500) or 1,000 mg/m(2) pemetrexed (P1000) on day 1 every 3 weeks. The primary endpoint was response rate.. Of the 216 patients evaluable for efficacy (108 in each arm), response rates were 18.5% (90% confidence interval, 12.6-25.8%) and 14.8% (90% confidence interval, 9.5-21.6%), median survival times were 16.0 and 12.6 months, 1-year survival rates were 59.2% and 53.7%, and median progression-free survival were 3.0 and 2.5 months for the P500 and P1000, respectively. Cox multiple regression analysis indicated that pemetrexed dose was not a significant prognostic factor. Drug-related toxicity was generally tolerable for both doses; however, the safety profile of P500 showed generally milder toxicity. Main adverse drug reactions of severity grade 3 or 4 were neutrophil count decreased (20.2%) and alanine aminotransferase (glutamine pyruvic transaminase) increased (15.8%) in P500 and neutrophil count decreased (24.3%), WBC count decreased (20.7%), and lymphocyte count decreased (18.0%) in P1000. One drug-related death from interstitial lung disease occurred in the P500.. P500 and P1000 are similarly active with promising efficacy and acceptable safety outcomes in pretreated patients with NSCLC. These results support the use of P500 as a second- and third-line treatment of NSCLC.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Carcinoma, Non-Small-Cell Lung; Female; Folic Acid; Glutamates; Guanine; Humans; Lung Neoplasms; Male; Middle Aged; Pemetrexed; Regression Analysis; Safety; Treatment Outcome; Vitamin B 12

The purpose of this study was to investigate the utility of plasma pharmacokinetic and pharmacodynamic measures including plasma deoxynucleosides, homocysteine and methylmalonic acid concentrations in understanding the time course and extent of the inhibition of thymidylate synthase (TS) by pemetrexed in the context of a phase I/II combination study with vinorelbine. Eighteen patients received supplementation with folic acid and Vitamin B(12) 1 week before beginning treatment with pemetrexed and vinorelbine administered in a dose-escalating manner on a 21-day cycle. Heparinised blood samples were collected from consenting patients in the first cycle for pharmacokinetic analyses and in the first two cycles for determination of plasma thymidine, deoxyuridine, homocysteine and methylmalonic acid concentrations. These values were correlated with response and toxicity. Plasma deoxyuridine was used as a measure of TS inhibition, and concentrations of deoxyuridine were significantly elevated relative to baseline on days 1 (P<0.01), 2 (P<0.001) and 3 (P<0.05) after treatment at all pemetrexed dose levels (400-700 mg m(-2)). The magnitude of deoxyuridine elevation correlated with pemetrexed area under the plasma concentration-time curve (AUC) (r(2)=0.23, P<0.05). However, deoxyuridine concentrations returned to baseline between 8 and 15 days after treatment with pemetrexed, suggesting that inhibition of TS was not durable. Pemetrexed AUC correlated with the percentage decline (relative to baseline) in both platelets (r(2)=0.58, P<0.001) and leucocytes (r(2)=0.26, P<0.05) at day 8. Baseline homocysteine was also significantly correlated with these measures of haematological toxicity (r(2)=0.37, P<0.01 and r(2)=0.39, P<0.01, respectively). In addition, there was a significant reduction of plasma homocysteine on days 8 (P<0.005) and 15 (P<0.05) in cycle 1 compared to baseline values. The results suggest that the TS inhibitory effects of pemetrexed are short-lived and make the case for a more frequent schedule of administration such as every 2 weeks. The lack of protracted TS inhibition may be due to concomitant vitamin administration, and this may be the mechanism by which vitamins prevent life-threatening toxicity from pemetrexed. Baseline homocysteine concentration remains a predictive marker for haematological toxicity even following folate supplementation.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Carcinoma, Non-Small-Cell Lung; Deoxyuridine; Dietary Supplements; Dose-Response Relationship, Drug; Female; Folic Acid; Glutamates; Guanine; Homocysteine; Humans; Lung Neoplasms; Male; Methylmalonic Acid; Middle Aged; Pemetrexed; Thymidine; Thymidylate Synthase; Vinblastine; Vinorelbine; Vitamin B 12

Pemetrexed and vinorelbine are active antineoplastic agents in non-small cell lung cancer (NSCLC). Phase I objectives include maximum tolerated dose (MTD) and recommended phase II dose determination, and pharmacokinetics of the pemetrexed-vinorelbine doublet in locally advanced or metastatic solid tumor patients (pts). Phase II objectives include tumor response evaluation, efficacy, and toxicity for first-line treatment of advanced NSCLC.. Phase I pts received pemetrexed (day 1, 300-700 mg/m2) and vinorelbine (days 1 and 8, 15-30 mg/m2) every 21 days. Pharmacokinetics determined at cycle 1. Beginning with dose-level 3, folic acid and Vitamin B12 supplementation were given.. Thirty-one phase I pts were enrolled. MTD was pemetrexed 700 mg/m2 and vinorelbine 30 mg/m2; and recommended phase II dose was pemetrexed 500 mg/m2 and vinorelbine 30 mg/m2. When administered in combination, pemetrexed and vinorelbine pharmacokinetics were consistent with single-agent administration. Thirty-seven (36 chemonaive) phase II NSCLC pts received pemetrexed-vinorelbine. Evaluable tumor response was 40%, with intent-to-treat 38%. One drug-related death occurred from febrile neutropenia with Staphylococcal infection. Grade 3/4 hematologic toxicities were neutropenia (65%) and febrile neutropenia (11%), while prevalent grade 3/4 non-hematologic toxicity was fatigue (27%).. The pemetrexed-vinorelbine combination is well tolerated and shows activity as first-line treatment in advanced NSCLC patients.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Creatinine; Dietary Supplements; Female; Glutamates; Guanine; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Pemetrexed; Time Factors; Treatment Outcome; Vinblastine; Vinorelbine; Vitamin B 12

High cobalamin levels have previously been associated with short-term cancer risk, including lung cancer. We explored whether levels of cobalamin and/or its binding proteins are useful as a diagnostic tool in patients suspected of non-small cell lung cancer. We included 889 patients referred for fast-track diagnosis of lung cancer to Aarhus University Hospital, Denmark. We analyzed plasma concentrations of cobalamin, transcobalamin, holotranscobalamin and haptocorrin. Information on lung cancer diagnosis was retrieved from a national database. The study cohort showed levels above reference intervals for cobalamin 12%, holotranscobalamin 25%, transcobalamin 9% and haptocorrin 36% (all

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Odds Ratio; ROC Curve; Transcobalamins; Vitamin B 12; Young Adult

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

The administration of pemetrexed requires routine supplementation with vitamin B12 and folate, even if blood concentrations are normal, in order to mitigate its hematologic toxicity. Emerging data suggest that such premedication can be initiated less than 1 week before starting chemotherapy. The current available data on later administration of vitamin B12 in patients with thoracic tumors are placed into a general context, and the possible role of such strategy in the era of immunooncology is discussed.

Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Pemetrexed; Thoracic Neoplasms; Vitamin B 12

Administration of vitamin B12 and folic acid for 7 days prior to the administration of the first dose of pemetrexed is recommended. However, vitamin supplementation rarely is initiated less than 7 days prior to the first dose of pemetrexed. Therefore, we analyzed the safety of pemetrexed with vitamin supplementation for less than 7 days prior to the first dose of pemetrexed.. Patients were classified into 2 groups according to the duration of vitamin supplementation prior to the first dose of pemetrexed: group A received vitamin supplementation for 7 days or more, and group B received vitamin supplementation for less than 7 days. We analyzed adverse effects, such as myelosuppression, rash, and diarrhea, after 1 cycle of pemetrexed therapy.. A total of 70 patients were administered pemetrexed; 40 patients were men and 30 were women with a median age of 64.5 years(range, 43-86 years). A total of 57 patients were classified into group A and 13 into group B; 33 patients were administered pemetrexed as a first-line treatment. Neutropenia of Grade 3 or more was observed in 4/49(8.2%)patients in group A and 2/13(15.4%)patients in group B(p=0.60). There were no significant differences in the rates of occurrence of neutropenia, rash, and diarrhea.. This retrospective study indicated that patients could be safely treated with pemetrexed if vitamin supplementation is initiated for less than 7 days prior to the first administration of pemetrexed. However, further studies are needed because of a lack of statistical power and adjustment for confounding factors.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Carcinoma, Non-Small-Cell Lung; Diarrhea; Dietary Supplements; Drug Combinations; Exanthema; Female; Folic Acid; Glutamates; Guanine; Humans; Lung Neoplasms; Male; Middle Aged; Neutropenia; Pemetrexed; Retrospective Studies; Vitamin B 12

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Female; Folic Acid; Humans; Lung Neoplasms; Male; Vitamin B 12

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Female; Folic Acid; Humans; Lung Neoplasms; Male; Vitamin B 12

Pemetrexed (MTA) is a multitargeted antifolate drug approved for lung cancer therapy. Clinically, supplementation with high doses of folic acid (FA) and vitamin B12 (VB12) lowers MTA cytotoxicities. An antagonistic effect of FA/VB12 on MTA efficacy has been proposed. However, patients who receive FA/VB12 show better tolerance to MTA with improved survival. The aims of this study are to investigate the modulation of FA and VB12 on MTA drug efficacy in human nonsmall cell lung cancer (NSCLC) cell lines. The sensitivities of cells, apoptosis, and MTA-regulated proteins were characterized to determine the possible effects of high doses of FA and VB12 on MTA efficacy. MTA has the lowest efficacy under 10% serum conditions. However, supplementation with FA and VB12 individually and additively reversed the insensitivity of NSCLC cells to MTA treatment with 10% serum. The enhanced sensitivities of cells following FA/VB12 treatment were correlated with increasing apoptosis and were specific to MTA but not to 5-fluorouracil (5-FU). Enhanced sensitivity was also associated with p21(WAF1/Cip1) expression level. Our results revealed no antagonistic effect of high doses of FA/VB12 on MTA efficacy in cancer cells grown in nutrient medium. Furthermore, these data may partially explain why supplementation of FA and VB12 resulted in better survival in MTA-treated patients.

Topics: Antimetabolites, Antineoplastic; Apoptosis; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Dietary Supplements; Drug Screening Assays, Antitumor; Fluorouracil; Folic Acid; Folic Acid Antagonists; G1 Phase; Glutamates; Guanine; Humans; Lung Neoplasms; Neoplasm Proteins; Pemetrexed; Protein Stability; Serum; Treatment Outcome; Vitamin B 12

Pemetrexed is a multitargeted antifolate initially approved as a single agent for the second-line treatment of locally advanced or metastatic non-small cell lung cancer and more recently in the first-line setting combined with cisplatin. The combination of pemetrexed with carboplatin has been tested in several phase II clinical trials showing interesting antitumour activity with mild toxicity. Supplementation with folic acid and vitamin B12 during treatment with pemetrexed is recommended to reduce potential haematological and gastrointestinal adverse events.. A patient experienced cutaneous lesions including widespread erythema, epidermal detachment, and skin denudation, associated with deterioration of his general condition after the second cycle of this chemotherapy combination, which was clinically and histologically compatible with toxic epidermal necrolysis (Lyell's syndrome). Treatment with systemic steroids, antihistamines, and antibiotics led to resolution of the skin lesions and improvement of his general condition.. To our knowledge, this is the second case reported in the literature of this type of suspected adverse drug reaction associated with a pemetrexed-based chemotherapy combination.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Folic Acid; Glutamates; Guanine; Humans; Lung Neoplasms; Male; Middle Aged; Pemetrexed; Stevens-Johnson Syndrome; Vitamin B 12

The main objective of this study was to evaluate the safety of second-line pemetrexed in Stage IIIB or IV NSCLC.. Overall, 95 patients received pemetrexed 500 mg/m2 i.v. over Day 1 of a 21-day cycle. Patients also received oral dexamethasone, oral folic acid and i.m. vitamin B12 supplementation to reduce toxicity. NCI CTC 2.0 was used to rate toxicity. All the adverse events were graded in terms of severity and relation to study treatment. Dose was reduced in case of toxicity and treatment was delayed for up to 42 days from Day 1 of any cycle to allow recovering from study drug-related toxicities. Tumor response was measured using the RECIST criteria.. Patients received a median number of 4 cycles and 97.8% of the planned dose. Overall, 75 patients (78.9% of treated) reported at least one adverse event: 34 (35.8%) had grade 3 as worst grade and only 5 (5.2%) had grade 4. Drug-related events occurred in 57.9% of patients. Neutropenia (8.4%) and leukopenia (6.3 %) were the most common grade 3/4 hematological toxicities. Grade 3 anemia and thrombocytopenia were reported in 3.2% and 2.1% of patients, respectively. Diarrhea (6.3%), fatigue (3.2%) and dyspnea (3.2%) were the most common grade 3/4 non-hematological toxicities. The most common drug-related toxicities (any grade) were pyrexia (11.6%), vomiting, nausea, diarrhea and asthenia (9.5%) and fatigue (8.4%). Tumor Response Rate (CR/PR) in treated patients was 9.2%. The survival at 4.5 months (median follow-up) was 79% and the median PFS was 3.1 months. Twenty patients (21.1%) died mainly because of disease progression.. Patients with locally advanced or metastatic NSCLC could benefit from second-line pemetrexed, with a low incidence of hematological and non-hematological toxicities.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Dexamethasone; Female; Folic Acid; Glutamates; Guanine; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pemetrexed; Vitamin B 12

Treatment with third-generation chemotherapy agents improves survival and quality of life of patients with non-small-cell lung cancer (NSCLC). Despite these favorable outcomes, most patients receiving front-line therapy experience disease progression. The availability of many new novel agents with activity in NSCLC has prompted investigators to explore second-line chemotherapy options. For many years, docetaxel was the only approved agent for the second-line treatment of NSCLC. More recently, the multi-targeted antifolate pemetrexed has demonstrated activity in patients previously treated with chemotherapy with locally advanced or metastatic NSCLC. The findings of a phase III trial comparing pemetrexed to docetaxel led to the regulatory approval of pemetrexed as monotherapy for the second-line treatment of NSCLC. Several other novel therapies, including molecular targeting agents such as erlotinib, are under development in clinical trials in patients with NSCLC. One of these trials has subsequently led to the approval of erlotinib as second- or third-line therapy in advanced NSCLC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Docetaxel; Folic Acid Antagonists; Glutamates; Guanine; Humans; Lung Neoplasms; Pemetrexed; Salvage Therapy; Survival Analysis; Taxoids; Vitamin B 12

Pemetrexed is a new cytotoxic agent that is a standard of care for the second-line treatment of non-small-cell lung cancer (NSCLC) and treatment of malignant pleural mesothelioma. It is currently in clinical development for the first-line treatment of NSCLC. In untreated advanced NSCLC, single-agent activity has been demonstrated in phase II trials. Pemetrexed has encouraging response rates and a favorable toxicity profile. Pemetrexed also has promising activity and acceptable toxicity when combined with platinum compounds or gemcitabine. Dietary supplementation with low-dose folic acid and vitamin B(12) significantly reduces the incidence and severity of toxicities without compromising the antitumor activity of pemetrexed. With its innovative mode of action, proven efficacy, favorable toxicity profile and convenient administration, pemetrexed represents a new therapeutic option for the treatment of advanced NSCLC.

Topics: Antimetabolites, Antineoplastic; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase III as Topic; Dietary Supplements; Folic Acid; Folic Acid Antagonists; Glutamates; Guanine; Humans; Lung Neoplasms; Pemetrexed; Vitamin B 12