-
International Journal of Molecular... Oct 2022Malignant pleural mesothelioma (MPM) is a rare but aggressive thoracic malignancy with limited treatment options. One of the standard treatments for MPM is chemotherapy,...
Malignant pleural mesothelioma (MPM) is a rare but aggressive thoracic malignancy with limited treatment options. One of the standard treatments for MPM is chemotherapy, which consists of concurrent treatment with pemetrexed and cisplatin. Pemetrexed limits tumor growth by inhibiting critical metabolic enzymes involved in nucleotide synthesis. Cisplatin causes direct DNA damage, such as intra-strand and inter-strand cross-links, which are repaired by the nucleotide excision repair pathway, which depends on relatively high nucleotide levels. We hypothesized that prolonged pretreatment with pemetrexed might deplete nucleotide pools, thereby sensitizing cancer cells to subsequent cisplatin treatment. The MPM cell lines ACC-MESO-1 and NCI-H28 were treated for 72 h with pemetrexed. Three treatment schedules were evaluated by initiating 24 h of cisplatin treatment at 0 h (concomitant), 24 h, and 48 h relative to pemetrexed treatment, resulting in either concomitant administration or pemetrexed pretreatment for 24 h or 48 h, respectively. Multicolor flow cytometry was performed to detect γH2AX (phosphorylation of histone H2AX), a surrogate marker for the activation of the DNA damage response pathway. DAPI staining of DNA was used to analyze cell cycle distribution. Forward and side scatter intensity was used to distinguish subpopulations based on cellular size and granularity, respectively. Our study revealed that prolonged pemetrexed pretreatment for 48 h prior to cisplatin significantly reduced long-term cell growth. Specifically, pretreatment for 48 h with pemetrexed induced a cell cycle arrest, mainly in the G2/M phase, accumulation of persistent DNA damage, and induction of a senescence phenotype. The present study demonstrates that optimizing the treatment schedule by pretreatment with pemetrexed increases the efficacy of the pemetrexed-cisplatin combination therapy in MPM. We show that the observed benefits are associated with the persistence of treatment-induced DNA damage. Our study suggests that an adjustment of the treatment schedule could improve the efficacy of the standard chemotherapy regimen for MPM and might improve patient outcomes.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Histones; Humans; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Nucleotides; Pemetrexed; Pleural Neoplasms
PubMed: 36233258
DOI: 10.3390/ijms231911949 -
Clinical Lung Cancer May 2022Before immune checkpoint blockade therapy, chemotherapy with pemetrexed maintenance was the standard of care for patients with advanced nonsquamous non-small-cell lung... (Meta-Analysis)
Meta-Analysis
Overall Survival and Safety With Pemetrexed/Platinum ± Anti-VEGF Followed by Pemetrexed ± Anti-VEGF Maintenance in Advanced Nonsquamous Non-Small-Cell Lung Cancer: A Pooled Analysis of 4 Randomized Studies.
BACKGROUND
Before immune checkpoint blockade therapy, chemotherapy with pemetrexed maintenance was the standard of care for patients with advanced nonsquamous non-small-cell lung cancer (NSQ-NSCLC) and remains such where immunotherapy is not applicable. This pooled analysis aimed to characterize overall survival (OS) and safety of pemetrexed ± anti-VEGF maintenance, by treatment duration.
PATIENTS AND METHODS
Data from 4 randomized clinical trials (PARAMOUNT, PRONOUNCE, PointBreak, JVBL) of patients with NSQ-NSCLC receiving pemetrexed ± anti-VEGF maintenance therapy were pooled as 2 groups (Group A: pemetrexed-only maintenance, n = 486; and Group B: pemetrexed + anti-VEGF maintenance, n = 329). OS and treatment-emergent adverse events (TEAEs) were analyzed in both groups by treatment duration.
RESULTS
Baseline characteristics were well balanced between both groups. Median OS did not significantly differ between Group A (16.1 months) and Group B (18.4 months; hazard ratio: 1.17, P= .1417). A correlation between median OS and treatment duration was numerically stronger in Group A (r = 0.72) versus B (r = 0.62). Across treatment groups, TEAEs were largely grade 1 to 2 and, with few exceptions, did not increase with increased treatment duration.
CONCLUSION
There was no significant OS difference between pemetrexed-only and pemetrexed ± anti-VEGF maintenance in patients with NSQ-NSCLC. Patients receiving pemetrexed + anti-VEGF experienced a slightly less favorable safety profile with more reported TEAEs compared to pemetrexed monotherapy. Pemetrexed ± anti-VEGF maintenance therapy may be considered in NSQ-NSCLC, based on an individualized patient approach, particularly where immunotherapy is not clinically indicated.
Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Pemetrexed; Platinum
PubMed: 34852947
DOI: 10.1016/j.cllc.2021.10.010 -
Journal of Comparative Effectiveness... Feb 2023In the absence of head-to-head trials comparing immunotherapies for advanced nonsquamous non-small-cell lung cancer (NsqNSCLC), a network meta-analysis (NMA) was... (Meta-Analysis)
Meta-Analysis Review
In the absence of head-to-head trials comparing immunotherapies for advanced nonsquamous non-small-cell lung cancer (NsqNSCLC), a network meta-analysis (NMA) was conducted to compare the relative efficacy of these treatments. A systematic literature review of randomized controlled trials evaluating first-line-to-progression and second-line treatments for advanced NsqNSCLC informed Bayesian NMAs for overall survival (OS) and progression-free survival (PFS) end points. Among first-line-to-progression treatments, pembrolizumab + pemetrexed + platinum showed the greatest OS benefit versus other regimens and a PFS benefit versus all but three regimens. Among second-line treatments, an OS benefit was seen for atezolizumab, nivolumab and pembrolizumab versus docetaxel. Pembrolizumab + pemetrexed + platinum showed the maximum OS benefit in the first-line setting. In the second-line setting, anti-PD-1/anti-PD-L1 monotherapies were better than docetaxel.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Docetaxel; Pemetrexed; Network Meta-Analysis; Platinum; Bayes Theorem; Immunotherapy; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36621905
DOI: 10.2217/cer-2022-0016 -
Clinical Lung Cancer Mar 2023Leptomeningeal metastasis (LM) is a highly fatal and debilitating complication of lung adenocarcinoma (LUAD) with limited therapeutic options. This study aimed to...
Safety, Pharmacokinetic and Clinical Activity of Intrathecal Chemotherapy With Pemetrexed via the Ommaya Reservoir for Leptomeningeal Metastases From Lung Adenocarcinoma: A Prospective Phase I Study.
INTRODUCTION
Leptomeningeal metastasis (LM) is a highly fatal and debilitating complication of lung adenocarcinoma (LUAD) with limited therapeutic options. This study aimed to evaluate the efficacy and toxicities of intrathecal chemotherapy (IC) with pemetrexed via Ommaya reservoir in LUAD with refractory LM.
METHODS
In this prospective, single-arm, phase I trial (ChiCTR2000028936), LUAD-LM patients who had progressed after at least two prior treatments were recruited. Pemetrexed from 30 mg to 50 mg was administered on Days 1 and 8 every 3 weeks via Ommaya reservoir. Serial samples of cerebrospinal fluid (CSF) and plasma were obtained for pharmacokinetic studies. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and therapeutic toxicities.
RESULTS
Twenty-three patients were enrolled and analyzed, revealing an ORR of 43.5% (95% CI, 23.2%-63.8%) and DCR of 82.6% (95% CI, 61.2%-95.0%). The median PFS and OS were 6.3 and 9.5 months, respectively. Dose-limiting toxicity was only observed in 2 patients (2/23, 8.7%), and 30 mg pemetrexed was considered as the recommended dose for IC. Pharmacokinetic analysis showed that using Ommaya reservoirs, higher pemetrexed concentrations and prolonged half-lives were achieved in the CSF compared with lumbar puncture (LP).
CONCLUSIONS
Intrathecal pemetrexed at a dose of 30 mg via Ommaya reservoirs on Days 1 and 8 every 21 days achieved promising disease control and satisfactory survival with moderate toxicities in resistant LUAD-LM, providing a feasible and effective option, especially for the patients who cannot tolerate LP.
Topics: Humans; Pemetrexed; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Prospective Studies; Adenocarcinoma of Lung; Meningeal Carcinomatosis; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36588048
DOI: 10.1016/j.cllc.2022.11.011 -
Cancer Genomics & Proteomics 2021Cisplatin combined with pemetrexed disodium heptahydrate (pemetrexed) is considered the standard treatment for patients with advanced, non-squamous, non-small-cell lung...
BACKGROUND/AIM
Cisplatin combined with pemetrexed disodium heptahydrate (pemetrexed) is considered the standard treatment for patients with advanced, non-squamous, non-small-cell lung cancer. However, its growth-inhibitory effects on KRAS-dependent lung cancer as monotherapy and combination therapy are not well understood. The aim of this study was to compare the effects of cisplatin and pemetrexed on A549 cells as mono- and combination therapies and elucidate the underlying mechanisms.
MATERIALS AND METHODS
For in vitro studies, A549 cells were exposed to cisplatin with/without pemetrexed for 72 h. The results were then evaluated by cell viability, apoptosis, reactive oxygen species, terminal deoxynucleotidyl transferase dUTP nick-end labeling, and western blotting assays.
RESULTS
Our results revealed that cisplatin monotherapy was most cytotoxic to A549 cells, while cisplatin plus pemetrexed combination had an intermediate effect, and pemetrexed monotherapy induced a minimal cytotoxic effect on A549 cells. This effect was evidenced by cell viability results, inhibition of KRAS proto-oncogene, GTPase (KRAS)/Raf proto-oncogene, serine/threonine kinase/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathways and apoptosis induction triggered by reactive oxygen species-mediated DNA damage. The immunoblotting result of conversion of microtubule-associated protein 1 light chain 3 alpha (LC3)-I to -II indicated that the greatest inducer of autophagy was combined treatment with cisplatin plus pemetrexed, while pemetrexed monotherapy had the lowest effect on autophagy induction, with cisplatin monotherapy having an intermediate effect. We found that the AKT serine/threonine kinase 1/mechanistic target of rapamycin kinase (mTOR) and AMP-activated protein kinase/mTOR signaling pathways were associated with autophagy activation. Interestingly, combination therapy with cisplatin plus pemetrexed was the primary eliminator of cellular senescence; cisplatin monotherapy had an intermediate effect, while pemetrexed monotherapy increased cellular senescence of A549 cells, as assessed by the expression of β-galactosidase protein.
CONCLUSION
Cisplatin monotherapy may be more effective than pemetrexed monotherapy or cisplatin plus pemetrexed combination therapy against KRAS-dependent lung cancer.
Topics: A549 Cells; Antineoplastic Agents; Apoptosis; Autophagy; Cell Survival; Cellular Senescence; Cisplatin; DNA Damage; Extracellular Signal-Regulated MAP Kinases; Humans; Lung Neoplasms; Mitogen-Activated Protein Kinase Kinases; Pemetrexed; Proto-Oncogene Mas; Proto-Oncogene Proteins c-raf; Proto-Oncogene Proteins p21(ras); Reactive Oxygen Species; Signal Transduction
PubMed: 34183390
DOI: 10.21873/cgp.20282 -
Therapeutic Advances in Respiratory... Jun 2016Malignant pleural mesothelioma (MPM) represents a significant diagnostic and therapeutic challenge and is almost always a fatal disease. Imaging abnormalities are... (Review)
Review
Malignant pleural mesothelioma (MPM) represents a significant diagnostic and therapeutic challenge and is almost always a fatal disease. Imaging abnormalities are common, but have a limited role in distinguishing mesothelioma from metastatic pleural disease. Similarly, minimally invasive biomarkers have shown promise but also have limitations in the diagnosis of mesothelioma. In experienced centers, cytology and immunohistochemistry are now sufficient to diagnose the epithelioid subtype of mesothelioma, which can reduce the need for more invasive diagnostic investigations. Prognosis of MPM is modestly impacted by oncological treatments. Chemotherapy with cisplatin and pemetrexed is considered the standard of care, though the addition of bevacizumab to the platinum doublet may be the new standard of care. New targeted therapies have demonstrated some promise and are being addressed in clinical trials. This review focuses on the current data on the diagnostic and therapeutic issues of MPM.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Cisplatin; Humans; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Molecular Targeted Therapy; Pemetrexed; Pleural Neoplasms; Prognosis
PubMed: 26873306
DOI: 10.1177/1753465816628800 -
British Journal of Clinical Pharmacology Feb 2022Pemetrexed is a cytotoxic drug for first-line treatment of lung cancer. It is often combined with other anticancer drugs such as cisplatin or carboplatin. In clinical...
Pemetrexed is a cytotoxic drug for first-line treatment of lung cancer. It is often combined with other anticancer drugs such as cisplatin or carboplatin. In clinical practice, hyperhydration regimens are applied to overcome cisplatin-related nephrotoxicity. As pemetrexed is almost completely eliminated from the body by the kidneys, hyperhydration can result in augmented clearance. Furthermore, administration of large quantities of fluid may increase the volume of distribution of pemetrexed. Pharmacokinetics and, thus, efficacy and toxicity may be influenced by hyperhydration. This has not yet been properly studied. We performed a population pharmacokinetic analysis to assess hyperhydration as a covariate for pemetrexed clearance and for volume of distribution A relevant change was defined as >25% increase in clearance or volume of distribution. In our extensive dataset of 133 individuals, we found that hyperhydration did not significantly or relevantly explain variability in pemetrexed clearance (unchanged, P = .196) or volume of distribution (+7% change, P = .002), despite a power of >99% to detect a relevant change. Therefore, dose adjustments of pemetrexed are not required during hyperhydration with cisplatin.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cisplatin; Humans; Lung Neoplasms; Pemetrexed
PubMed: 34374116
DOI: 10.1111/bcp.15031 -
Journal of Thoracic Oncology : Official... Jan 2020
Topics: Biomarkers; ErbB Receptors; Gefitinib; Humans; Lung Neoplasms; Mutation; Pemetrexed
PubMed: 31864546
DOI: 10.1016/j.jtho.2019.10.017 -
Journal of Analytical Methods in... 2019Combination therapy is opted as a potential therapeutic strategy for cancer treatment. combined with pemetrexed disodium or gemcitabine could reinforce the overall...
Combination therapy is opted as a potential therapeutic strategy for cancer treatment. combined with pemetrexed disodium or gemcitabine could reinforce the overall effects and alleviate the adverse effects. To investigate the effects of on the pharmacokinetics of pemetrexed disodium and gemcitabine, a HPLC method for simultaneous determination of pemetrexed disodium and gemcitabine in rat plasma was developed and validated. Chromatographic separation was achieved on a C18 column using a gradient mode containing water (containing 20 mM NaHPO and 0.1% FA) and methanol at a flow rate of 0.8 mL/min. The specificity, linearity, recovery, stability, precision, and accuracy of the HPLC method were all validated. The rats were pretreated with extract at the dosage of 3 g/kg for 20 consecutive days until we commence studying the pharmacokinetics of pemetrexed disodium or gemcitabine. There were no significant differences in pharmacokinetic parameters of pemetrexed disodium between the extract treatment group and the control group. However, AUC, MRT, and Cl of gemcitabine were changed dramatically after treating with extract ( < 0.05). The AUC, AUC, and MRT of gemcitabine decreased from 15747.12 ± 497.11 to 12312.41 ± 594.21 mg/L·min, 15976.18 ± 511.33 to 12489.59 ± 682.01 mg/L·min, and 97.83 ± 5.82 to 84.37 ± 2.79 min, respectively. The Cl of gemcitabine increased from 0.019 ± 0.0067 to 0.024 ± 0.0013 L/min/kg. The results showed that the pretreatment of extract could exert an influence on the pharmacokinetic characteristics of gemcitabine in rats.
PubMed: 31183244
DOI: 10.1155/2019/3162426 -
European Journal of Hospital Pharmacy :... Mar 2023The aim of this study was to assess the stability of pemetrexed disodium (Alimta), reconstituted in 100 mL sodium chloride 0.9% w/v intravenous infusion bags (Baxter...
OBJECTIVES
The aim of this study was to assess the stability of pemetrexed disodium (Alimta), reconstituted in 100 mL sodium chloride 0.9% w/v intravenous infusion bags (Baxter Viaflo) at two target bag concentrations (2.0 and 13.5 mg/mL) during storage at 2-8°C for 28 days (protected from light), followed by 24 hours at 25±2°C with 60±5% relative humidity (RH) (protected from light). This study was commissioned by NHS England and NHS Improvement to generate data to aid shelf life extensions for aseptic products compounded in National Health Service (NHS) hospital aseptic facilities.
METHODS
A high performance liquid chromatography (HPLC) assay was developed and validated to monitor pemetrexed concentration and related substance levels in accordance with NHS yellow cover document requirements. This assay and analysis of related substances was used alongside visual inspection, pH monitoring and sub-visible particle count analysis to monitor stability. The stability of three preparations of each concentration of pemetrexed disodium in Viaflo saline bags (0.9% w/v) was assessed at various time points.
RESULTS
Pemetrexed assay concentrations remained >97.0% of initial concentration at all points during the study (including the period at elevated temperature). Appearance remained consistent with the Summary of Product Characteristics, particle count data remained within the British Pharmacopoeia limits, and pH remained within 0.43 units of T=0 at all times. The increases in related substance levels during the study were found to be the limiting factor for shelf life assignment.
CONCLUSION
The data for appearance, pH, sub-visible particle count analysis and pemetrexed assay would support a shelf life of 28 days stored at 2-8°C (protected from light) followed by 24 hours at 25±2°C with 60±5% RH (protected from light). However, given the increase in related substance levels, a shelf life of 21 days stored at 2-8°C (protected from light) was deemed to be appropriate.
Topics: Pemetrexed; Infusions, Intravenous; Sodium Chloride; State Medicine; Drug Stability; Drug Packaging; Saline Solution
PubMed: 34272213
DOI: 10.1136/ejhpharm-2021-002823