ABSTRACT
Aim: The objective of this study was to compare adverse event (AE) management costs for fruquintinib, regorafenib, trifluridine/tipiracil (T/T) and trifluridine/tipiracil+bevacizumab (T/T+bev) for patients with metastatic colorectal cancer (mCRC) previously treated with at least two prior lines of therapy from the US commercial and Medicare payer perspectives. Materials & methods: A cost-consequence model was developed to calculate the per-patient and per-patient-per-month (PPPM) AE costs using rates of grade 3/4 AEs with incidence ≥5% in clinical trials, event-specific management costs and duration treatment. Anchored comparisons of AE costs were calculated using a difference-in-differences approach with best supportive care (BSC) as a common reference. AE rates and treatment duration were obtained from clinical trials: FRESCO and FRESCO-2 (fruquintinib), RECOURSE (T/T), CORRECT (regorafenib) and SUNLIGHT (T/T, T/T+bev). AE management costs for the commercial and Medicare perspectives were obtained from publicly available sources. Results: From the commercial perspective, the AE costs (presented as per-patient, PPPM) were: $4015, $1091 for fruquintinib (FRESCO); $4253, $1390 for fruquintinib (FRESCO-2); $17,110, $11,104 for T/T (RECOURSE); $9851, $4691 for T/T (SUNLIGHT); $8199, $4823 for regorafenib; and $11,620, $2324 for T/T+bev. These results were consistent in anchored comparisons: the difference-in-difference for fruquintinib based on FRESCO was -$1929 versus regorafenib and -$11,427 versus T/T; for fruquintinib based on FRESCO-2 was -$2257 versus regorafenib and -$11,756 versus T/T. Across all analyses, results were consistent from the Medicare perspective. Conclusion: Fruquintinib was associated with lower AE management costs compared with regorafenib, T/T and T/T+bev for patients with previously treated mCRC. This evidence has direct implications for treatment, formulary and pathways decision-making in this patient population.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Benzofurans , Bevacizumab , Colorectal Neoplasms , Phenylurea Compounds , Pyridines , Thymine , Trifluridine , Humans , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/economics , United States , Pyridines/economics , Pyridines/therapeutic use , Pyridines/adverse effects , Thymine/therapeutic use , Trifluridine/therapeutic use , Trifluridine/economics , Antineoplastic Combined Chemotherapy Protocols/economics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab/economics , Bevacizumab/therapeutic use , Bevacizumab/adverse effects , Phenylurea Compounds/therapeutic use , Phenylurea Compounds/economics , Phenylurea Compounds/adverse effects , Benzofurans/economics , Benzofurans/therapeutic use , Benzofurans/adverse effects , Irinotecan/therapeutic use , Irinotecan/economics , Drug Combinations , Pyrrolidines/therapeutic use , Pyrrolidines/economics , Oxaliplatin/economics , Oxaliplatin/therapeutic use , Oxaliplatin/adverse effects , Medicare/economics , Camptothecin/analogs & derivatives , Camptothecin/therapeutic use , Camptothecin/economics , Camptothecin/adverse effects , Quinazolines/economics , Quinazolines/therapeutic use , Quinazolines/adverse effects , Organoplatinum Compounds/economics , Organoplatinum Compounds/therapeutic use , Organoplatinum Compounds/adverse effects , Uracil/analogs & derivatives , Uracil/therapeutic use , Uracil/economics , Uracil/adverse effects , Fluorouracil/therapeutic use , Fluorouracil/economics , Fluorouracil/adverse effects , Models, Economic , Biological Products/economicsABSTRACT
BACKGROUND: The liver is the most frequent site of metastases in colorectal cancer (CRC). This study aimed to assess the response rate and survival outcomes in metastatic CRC patients with non-liver metastases (NLM) compared to those with liver metastases (LM) across different lines of treatment. METHODS: A total of 17,924 mCRC patients included in 26 trials from the ARCAD CRC database were analyzed. The analysis was conducted based on the presence or absence of LM across different treatment groups: chemotherapy (CT) alone, CT + anti-VEGF, CT + anti-EGFR in KRAS wild-type tumors, within the first-line (1 L) and second-line (2 L), and patients enrolled in third-line (≥3 L) trials treated with trifluridine/tipiracil or regorafenib or placebo. The endpoints were overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). RESULTS: Out of the 17,924 patients, 14,066 had LM (30.6 % with only liver involvement and 69.4 % with liver and other metastatic sites), while 3858 patients had NLM. In the CT alone and CT + anti-VEGF subgroups, NLM patients showed better OS and PFS in the 1 L and 2 L settings. However, in the CT + anti-EGFR 1 L and 2 L subgroups, there was no significant difference in OS and PFS between NLM and LM patients. In the ≥ 3 L subgroups, better OS and PFS were observed in NLM patients. ORRs were higher in LM patients than in NLM patients across all cohorts treated in the 1 L and only in the anti-EGFR cohort in the 2 L. CONCLUSION: LM is a poor prognostic factor for mCRC increasing from 1 L to ≥ 3 L except for patients in 1 L and 2 L receiving CT+anti-EGFR. These data justify using LM as a stratification factor in future trials for patients with unresectable mCRC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Colorectal Neoplasms , Liver Neoplasms , Humans , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Colorectal Neoplasms/mortality , Liver Neoplasms/secondary , Liver Neoplasms/drug therapy , Liver Neoplasms/mortality , Male , Female , Middle Aged , Prognosis , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Progression-Free Survival , Pyridines/therapeutic use , Adult , Trifluridine/therapeutic use , Phenylurea Compounds/therapeutic use , Thymine/therapeutic use , Drug Combinations , PyrrolidinesABSTRACT
The systemic treatment options for patients with metastatic colorectal cancer have recently expanded with the US Food and Drug Administration approval of fruquintinib being added to previously approved trifluridine/tipiracil with or without bevacizumab and regorafenib. These therapies are recommended for use based on the initial clinical trials that focused on their safety and efficacy in extending overall survival of patients with refractory metastatic disease, as well as later studies, including the ReDOS study that confirmed the dose-escalation strategy of regorafenib to be key in optimizing duration of therapy and preventing side effects. Although more research is needed on how to sequence third-line therapies, data from real-world studies showed that switching from regorafenib to trifluridine/tipiracil with or without bevacizumab allowed patients to have a chemotherapy-free break and led to improved survival, suggesting that there may be a benefit for using regorafenib first. Current treatment guidelines state that each therapy can be given before or after the others. Generally, sequencing considerations in the refractory setting include multiple variables such as tumor characteristics, toxicities, factors that are important to the patient, response to prior lines of therapy, and extent of disease.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Colorectal Neoplasms , Neoplasm Metastasis , Patient Selection , Phenylurea Compounds , Pyridines , Trifluridine , Humans , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Colorectal Neoplasms/mortality , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Pyridines/therapeutic use , Trifluridine/therapeutic use , Phenylurea Compounds/therapeutic use , Thymine/therapeutic use , Bevacizumab/therapeutic use , Pyrrolidines/therapeutic use , Drug Combinations , Uracil/analogs & derivatives , Uracil/therapeutic useABSTRACT
BACKGROUND: There are few molecular markers driving treatment selection in later lines of treatment for advanced colorectal cancer patients. The vast majority of patients who progress after first- and second-line therapy undergo chemotherapy regardless of molecular data. OBJECTIVE: We aimed to assess the prognostic and predictive effects of specific RAS mutations on overall survival of patients receiving regorafenib (rego), trifluridine/tipiracil (TFD/TPI), or both. PATIENTS AND METHODS: This was a retrospective observational study based on data from a previous study of our research network, involving nine Italian institutions over a 10-year timeframe (2012-2022). Extended RAS analysis, involving KRAS exon 2-4 and NRAS exon 2-4, and BRAF were the main criteria for inclusion in this retrospective evaluation. Patients with BRAF mutation were excluded. Patients were classified according to treatment (rego- or TFD/TPI-treated) and RAS mutational status (wild-type [WT], KRAS codon 12 mutations, KRAS codon 13 mutations, KRAS rare mutations and NRAS mutations, KRAS G12C mutation and KRAS G12D mutation). RESULTS: Overall, 582 patients were included in the present analysis. Overall survival did not significantly differ in rego-treated patients according to RAS extended analysis, although a trend toward a better median survival in patients carrying G12D mutation (12.0 months), Codon 13 mutation (8.0 months), and Codon 12 mutation (7.0 months) has been observed, when compared with WT patients (6.0 months). Overall survival did not significantly differ in TFD/TPI-treated patients according to RAS extended analysis, although a trend toward a better median survival in WT patients had been observed (9.0 months) in comparison with the entire population (7.0 months). Patients receiving both drugs displayed a longer survival when compared with the population of patients receiving rego alone (p = 0.005) as well as the population receiving TFD/TPI alone (p < 0.001), suggesting a group enriched for favorable prognostic factors. However, when each group was analyzed separately, the addition of TFD/TPI therapy to the rego-treated group improved survival only in all-RAS WT patients (p = 0.003). Differently, the addition of rego therapy to TFD/TPI-treated patients significantly improved OS in the Codon 12 group (p = 0.0004), G12D group (p = 0.003), and the rare mutations group (p = 0.02), in addition to all-RAS WT patients (p = 0.002). The rego-TFD/TPI sequence, compared with the reverse sequence, significantly improved OS only in the KRAS codon 12 group (p = 0.003). CONCLUSIONS: Our data demonstrate that RAS mutations do not affect outcome in rego-treated patients as well as TFD/TPI-treated patients. Nevertheless, a trend toward a higher efficacy of rego in RAS-mutated (in particular codon 12, rare RAS mutations, and G12D) patients has been recorded. The rego-TFD/TPI sequence seems to be superior to the reverse sequence in patients carrying an RAS codon 12 mutation, although the impact of other factors as disease burden or performance status cannot be excluded.
Subject(s)
Colorectal Neoplasms , Phenylurea Compounds , Pyridines , Pyrrolidines , Trifluridine , Humans , Retrospective Studies , Male , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Female , Trifluridine/therapeutic use , Trifluridine/pharmacology , Pyridines/therapeutic use , Pyridines/pharmacology , Phenylurea Compounds/therapeutic use , Phenylurea Compounds/pharmacology , Pyrrolidines/therapeutic use , Pyrrolidines/pharmacology , Aged , Middle Aged , Thymine/pharmacology , Thymine/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Drug Combinations , Neoplasm Metastasis , Adult , Mutation , Aged, 80 and over , Uracil/therapeutic use , Uracil/analogs & derivatives , Uracil/pharmacologyABSTRACT
We performed a systematic literature review to identify and summarize data from studies reporting clinical efficacy and safety outcomes for trifluridine/tipiracil (FTD/TPI) combined with other antineoplastic agents in advanced cancers, including metastatic colorectal cancer (mCRC). We conducted a systematic search on May 29, 2021, for studies reporting one or more efficacy or safety outcome with FTD/TPI-containing combinations. Our search yielded 1378 publications, with 38 records meeting selection criteria: 35 studies of FTD/TPI-containing combinations in mCRC (31 studies second line or later) and 3 studies in other tumor types. FTD/TPI plus bevacizumab was extensively studied, including 19 studies in chemorefractory mCRC. Median overall survival ranged 8.6-14.4 months and median progression-free survival 3.7-6.8 months with FTD/TPI plus bevacizumab in refractory mCRC. Based on one randomized and several retrospective studies, FTD/TPI plus bevacizumab was associated with improved outcomes compared with FTD/TPI monotherapy. FTD/TPI combinations with chemotherapy or other targeted agents were reported in small early-phase studies; preliminary data indicated higher antitumor activity for certain combinations. Overall, no safety concerns existed with FTD/TPI combinations; most common gradeâ ≥â 3 adverse event was neutropenia, ranging 5%-100% across all studies. In studies comparing FTD/TPI combinations with monotherapy, gradeâ ≥â 3 neutropenia appeared more frequently with combinations (29%-67%) vs. monotherapy (5%-41%). Discontinuation rates due to adverse events ranged 0%-11% for FTD/TPI plus bevacizumab and 0%-17% with other combinations. This systematic review supports feasibility and safety of FTD/TPI plus bevacizumab in refractory mCRC. Data on non-bevacizumab FTD/TPI combinations remain preliminary and need further validation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Colorectal Neoplasms , Drug Combinations , Pyrrolidines , Thymine , Trifluridine , Humans , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab/therapeutic use , Bevacizumab/pharmacology , Bevacizumab/adverse effects , Bevacizumab/administration & dosage , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Pyrrolidines/therapeutic use , Pyrrolidines/adverse effects , Thymine/therapeutic use , Thymine/pharmacology , Trifluridine/therapeutic use , Trifluridine/adverse effects , Trifluridine/administration & dosage , Trifluridine/pharmacologyABSTRACT
PURPOSE: The optimal drug regimen and sequence are still unknown for patients with metastatic colorectal cancer (mCRC) who are candidates for third-line (3L) or subsequent treatment. The aim of this study is to know the opinion of experts on the most appropriate treatment options for mCRC in 3L and to clarify certain clinical decisions in Spain. METHODS: Using a modified Delphi method, a group of experts discussed the treatment in 3L of patients with mCRC and developed a questionnaire with 21 items divided into 5 sections. RESULTS: After 2 rounds, the 67 panelists consulted agreed on 17 items (81%). They considered that the main objective of 3L is to equally increase survival and improve patients' quality of life (QoL), but preferably the QoL. It was agreed that patients with mCRC in 3L prefer to receive active versus symptomatic treatment. Panelists considered trifluridine/tipiracil (FTD/TPI) to be the best oral treatment available to them in 3L. In patients with MSI-H or dMMR and BRAF V600E, the panelists mostly prefer targeted treatments. Panelists agreed the use of a therapeutic sequence that not only increases outcomes but also allows patients to be treated later. Finally, it was agreed that FTD/TPI has a mechanism of action that allows it to be used in patients refractory to previous treatment with 5-fluorouracil. CONCLUSION: The experts agreed with most of the proposed items on 3L treatment of mCRC, prioritizing therapeutic options that increase survival and preserve QoL, while facilitating the possibility that patients can continue to be treated later.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Colorectal Neoplasms , Delphi Technique , Quality of Life , Humans , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Consensus , Pyrrolidines/therapeutic use , Trifluridine/therapeutic use , Thymine/therapeutic use , Surveys and Questionnaires , Neoplasm Metastasis , Proto-Oncogene Proteins B-raf/genetics , SpainABSTRACT
2', 3'-cGAMP (CDN) as cGAS-STING pathway agonist is extensively used in tumor treatment. However, due to its negatively charged nature (containing two phosphate groups) and high hydrophilicity, CDN faces challenges in crossing cell membranes, resulting in reduced efficiency of its use. Additionally, CDN is susceptible to inactivation through phosphodiesterase hydrolysis. Therefore, the development of a new drug delivery system for CDN is necessary to prevent hydrolysis and enhance targeted accumulation in tumors, as well as improve cellular uptake for STING activation. In this study, we have developed peptide-polymer nanofibers (PEG-Q11) that incorporate thymine (T) and arginine (R) residues to facilitate complexation with CDN through the principles of Watson-Crick base pairing with thymine and favorable electrostatic interactions and bidentate hydrogen bonding with arginine side chains. The entrapment efficiency (EE) of PEG-Q11T3R4@CDN was found to be 51% higher than that of PEG-Q11@CDN. Due to its favorable biocompatibility, PEG-Q11T3R4@CDN was employed for immunotherapy in mouse CT26 tumors. In local tumor treatment, the administration of PEG-Q11T3R4@CDN at a low dose and through a single injection exhibited inhibitory effects. Furthermore, the local injection of PEG-Q11T3R4@CDN resulted in systemic therapeutic responses, effectively suppressing tumor metastasis by activating CD8 + T cells to target distant tumors. This research not only underscores the potential of PEG-Q11T3R4@CDN as an efficient therapeutic agent but also highlights its ability to achieve long-lasting systemic therapeutic outcomes following local treatment. Consequently, PEG-Q11T3R4@CDN represents a promising strategy for immunization.
Subject(s)
Nanofibers , Neoplasms , Mice , Animals , Thymine/therapeutic use , Neoplasms/drug therapy , Immunotherapy , ArginineABSTRACT
Renal impairment may be associated with an increased risk of hematologic events (AEs) in patients undergoing treatment with trifluridine/tipiracil (FTD/TPI). This study aimed to investigate the specific types of AEs linked to renal impairment in patients with metastatic colorectal cancer (mCRC) receiving FTD/TPI, using real-world data. Among the patients included in the REGOTAS study (a retrospective study of FTD/TPI versus regorafenib), those treated with FTD/TPI were evaluated. Creatinine clearance values of < 30, 30-60, 60-90, and > 90 mL/min were defined as severe, moderate, mild renal impairment, and normal renal function, respectively. Renal impairment was analyzed as a risk factor for grade 3 or higher AEs using a logistic regression model. Overall survival (OS) and progression-free survival (PFS) based on renal impairment were evaluated. A total of 309 patients were included in the analysis, with 124, 130, and 55 patients divided into the normal, mild, and moderate-to-severe groups, respectively. The risk of grade 3 or higher neutropenia was significantly higher in the moderate-to-severe group (odds ratio 3.47; 95% confidence interval 1.45-8.30; P = 0.005), but there was no significant increase in the risk of non-hematologic AEs in any of the groups. The OS and PFS of patients in the mild and moderate-to-severe groups were comparable to those in the normal group. Patients with mCRC and moderate/severe renal impairment receiving FTD/TPI therapy may develop severe neutropenia; however, FTD/TPI remains a viable treatment option due to its clinical benefit.
Subject(s)
Colonic Neoplasms , Colorectal Neoplasms , Frontotemporal Dementia , Neutropenia , Rectal Neoplasms , Humans , Uracil/therapeutic use , Retrospective Studies , Trifluridine/adverse effects , Frontotemporal Dementia/drug therapy , Colorectal Neoplasms/pathology , Thymine/therapeutic use , Pyrrolidines/adverse effects , Colonic Neoplasms/drug therapy , Rectal Neoplasms/drug therapy , Drug Combinations , Risk Factors , Neutropenia/chemically induced , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
Background: The current work was designed to estimate the cost-effectiveness of trifluridine/tipiracil (T/T) versus best supportive care (BSC) for patients with advanced stage or metastatic gastroesophageal cancer (mGC) from a UK perspective. Materials & methods: A partitioned survival analysis was undertaken using data from the phase III TAGS trial. A jointly fitted lognormal model was selected for overall survival and individual generalized gamma models were chosen for progression-free survival and time-to-treatment-discontinuation. The primary outcome was the cost per quality-adjusted life year (QALY) gained. Sensitivity analyses were undertaken to investigate uncertainty. Results: Compared with BSC, T/T was associated with a cost per QALY gained of £37,907. Conclusion: T/T provides a cost-effective treatment option for mGC in the UK setting.
Subject(s)
Colorectal Neoplasms , Esophageal Neoplasms , Neoplasms, Second Primary , Stomach Neoplasms , Humans , Trifluridine/therapeutic use , Uracil/therapeutic use , Cost-Effectiveness Analysis , Cost-Benefit Analysis , Thymine/therapeutic use , Stomach Neoplasms/drug therapy , Stomach Neoplasms/secondary , Pyrrolidines/therapeutic use , Esophageal Neoplasms/drug therapy , United Kingdom/epidemiology , Colorectal Neoplasms/pathology , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
BACKGROUND: This open-label, multicentre, phase II/III trial assessed the noninferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab vs. fluoropyrimidine and irinotecan plus bevacizumab (control) as second-line treatment for metastatic colorectal cancer (mCRC). METHODS: Patients were randomised (1:1) to receive FTD/TPI (35 mg/m2 twice daily, days 1-5 and days 8-12, 28-day cycle) plus bevacizumab (5 mg/kg, days 1 and 15) or control. The primary endpoint was overall survival (OS). The noninferiority margin of the hazard ratio (HR) was set to 1.33. RESULTS: Overall, 397 patients were enrolled. Baseline characteristics were similar between the groups. Median OS was 14.8 vs. 18.1 months (FTD/TPI plus bevacizumab vs. control; HR 1.38; 95% confidence interval [CI] 0.99-1.93; Pnoninferiority = 0.5920). In patients with a baseline sum of the diameter of target lesions of <60 mm (n = 216, post hoc analyses), the adjusted median OS was similar between groups (FTD/TPI plus bevacizumab vs. control, 21.4 vs. 20.7 months; HR 0.92; 95% CI 0.55-1.55). Grade ≥3 adverse events (FTD/TPI plus bevacizumab vs. control) included neutropenia (65.8% vs. 41.6%) and diarrhoea (1.5% vs. 7.1%). CONCLUSIONS: FTD/TPI plus bevacizumab did not demonstrate noninferiority to fluoropyrimidine and irinotecan plus bevacizumab as second-line treatment for mCRC. CLINICAL TRIAL REGISTRATION: JapicCTI-173618, jRCTs031180122.
Subject(s)
Colonic Neoplasms , Colorectal Neoplasms , Frontotemporal Dementia , Rectal Neoplasms , Humans , Bevacizumab , Colorectal Neoplasms/pathology , Irinotecan , Trifluridine/adverse effects , Frontotemporal Dementia/chemically induced , Frontotemporal Dementia/drug therapy , Thymine/therapeutic use , Pyrrolidines , Colonic Neoplasms/drug therapy , Rectal Neoplasms/chemically induced , Drug Combinations , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
Regorafenib is a standard salvage line therapy used for advanced colorectal cancer (CRC). Recently, trifluridine/tipiracil (TFTD) plus bevacizumab also showed promising efficacy as a salvage line therapy for advanced CRC. However, the efficacy and safety of regorafenib for patients with advanced CRC who have previously received TFTD plus bevacizumab is unclear. We retrospectively collected clinicopathologic data from patients with advanced CRC who received regorafenib after TFTD plus bevacizumab in multiple institutions between April 2017 and June 2020.Thirty-four advanced CRC patients who received regorafenib were analyzed. The median age was 66.5 (range 43-81 years), 11 patients were male, and all had an ECOG performance status(PS) of 0 or 1. Twenty-two patients had left-sided tumors, 18 patients had RAS mutants, and 1 patient had a BRAF V600E mutation. The response rate was 0%, and the disease control rate was 31%. The median progression-free survival was 70 days (95% CI: 56-91), and the overall survival was 233 days (95% CI: 188-324). Treatment was discontinued in 32 patients, and 28 (82%) discontinued treatment due to progressive disease. The major grade 3 and4 toxicities were proteinurea (29%), hypertension (26%), hand-foot syndrome(15%), and platelet decrease (6%). Regorafenib after TFTD plus bevacizumab showed efficacy similar to that of the previous study, and no new adverse events were observed.
Subject(s)
Colorectal Neoplasms , Trifluridine , Humans , Male , Adult , Middle Aged , Aged , Aged, 80 and over , Female , Bevacizumab/adverse effects , Retrospective Studies , Trifluridine/therapeutic use , Uracil/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Thymine/therapeutic use , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Phenylurea Compounds/adverse effects , Pyrrolidines/therapeutic use , Drug CombinationsABSTRACT
Manganese oxide nanomaterials (MONs) are emerging as a type of highly promising nanomaterials for diseases diagnosis, and surface modification is the basis for colloidal stability and targeting delivery of the nanomaterials. Here, we report the in-situ functionalization of MnO2 with DNA through a biomineralization process. Using adsorption-oxidation method, DNA templated Mn2+ precursor to biomineralize into nano-cubic seed, followed by the growth of MnO2 to form cube/nanosheet hybrid nanostructure. Among four types of DNA homopolymers, poly-thymine (poly-T) was found to stably attach on MnO2 surface to resist various biological displacements (phosphate, serum, and complementary DNA). Capitalized on this finding, a di-block DNA was rationally designed, in which the poly-T block stably anchored on MnO2 surface, while the AS1411 aptamer block was not only an active ligand for tumor targeting delivery, but also a carrier for photosensitizer (Ce6) loading. Upon targeting delivery into tumor cells, the MnO2 acted as catalase-mimic nanozyme for oxygenation to sensitize photodynamic therapy, and the released Mn2+ triggered chemodynamic therapy via Fenton-like reaction, achieving synergistic anti-tumor effect with full biocompatibility. This work provides a simple yet robust strategy to functionalize metal oxides nanomaterials for biological applications via DNA-templated biomineralization.
Subject(s)
Nanoparticles , Neoplasms , Photochemotherapy , Humans , Oxides/chemistry , Thymine/therapeutic use , Manganese Compounds/pharmacology , Manganese Compounds/chemistry , Biomineralization , Neoplasms/drug therapy , DNA/chemistry , Nanoparticles/chemistryABSTRACT
BACKGROUND: The emergence of multidrug-resistant tuberculosis (MDR-TB) has complicated the situation due to the decline in potency of second-line anti-tubercular drugs. This limits the treatment option for extensively drug-resistant tuberculosis (XDR-TB). The aim of this study was to determine and compare the minimum inhibitory concentration (MIC) by agar dilution and resazurin microtiter assay (REMA) along with the detection of mutations against linezolid and clofazimine in confirmed XDR-TB clinical isolates. RESULTS: A total of 169 isolates were found positive for Mycobacterium tuberculosis complex (MTBC). The MIC was determined by agar dilution and REMA methods. The isolates which showed non-susceptibility were further subjected to mutation detection by targeting rplC gene (linezolid) and Rv0678 gene (clofazimine). The MIC for linezolid ranged from 0.125 µg/ml to > 2 µg/ml and for clofazimine from 0.25 µg/ml to > 4 µg/ml. The MIC50 and MIC90 for linezolid were 0.5 µg/ml and 1 µg/ml respectively while for clofazimine both were 1 µg/ml. The essential and categorical agreement for linezolid was 97.63% and 95.26% and for clofazimine, both were 100%. The sequencing result of the rplC gene revealed a point mutation at position 460 bp, where thymine (T) was substituted for cytosine (C) while seven mutations were noted between 46 to 220 bp in Rv0678 gene. CONCLUSION: REMA method has been found to be more suitable in comparison to the agar dilution method due to lesser turnaround time. Mutations in rplC and Rv0678 genes were reasons for drug resistance against linezolid and clofazimine respectively.
Subject(s)
Extensively Drug-Resistant Tuberculosis , Mycobacterium tuberculosis , Tuberculosis, Multidrug-Resistant , Agar , Antitubercular Agents/pharmacology , Clofazimine/pharmacology , Clofazimine/therapeutic use , Cytosine/therapeutic use , Drug Resistance, Multiple, Bacterial/genetics , Extensively Drug-Resistant Tuberculosis/drug therapy , Extensively Drug-Resistant Tuberculosis/microbiology , Humans , Linezolid/pharmacology , Linezolid/therapeutic use , Microbial Sensitivity Tests , Mutation , Thymine/therapeutic use , Tuberculosis, Multidrug-Resistant/microbiologyABSTRACT
Background: The efficacy and safety of trifluridine/tipiracil (FTD/TPI) for third-line treatment of metastatic colorectal cancer have been demonstrated. The authors present the Turkish post hoc analysis of the PRECONNECT study. Methods: An international, multicenter, single-arm, open-label, phase IIIb trial evaluating FTD/TPI in patients with ≥2 previous lines of chemotherapy for metastatic colorectal cancer was conducted. The primary end point was safety. Results: In this Turkish cohort (n = 100; eight centers), the most frequent treatment-emergent adverse event was neutropenia (48%). Median progression-free survival was 3.0 months; disease control rate was 36%; quality of life remained stable. Conclusion: Outcomes with FTD/TPI in Turkey are consistent with previous studies and confirm the efficacy and safety of FTD/TPI treatment in the third-line setting. Clinical Trial Registration: NCT03306394 (ClinicalTrials.gov).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Colorectal Neoplasms , Humans , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Drug Combinations , Pyrrolidines/therapeutic use , Quality of Life , Thymine/therapeutic use , Trifluridine/therapeutic use , TurkeyABSTRACT
Understanding the immunological effects of chemotherapy is of great importance, especially now that we have entered an era where ever-increasing pre-clinical and clinical efforts are put into combining chemotherapy and immunotherapy to combat cancer. Single-cell RNA sequencing (scRNA-seq) has proved to be a powerful technique with a broad range of applications, studies evaluating drug effects in co-cultures of tumor and immune cells are however scarce. We treated a co-culture comprised of human colorectal cancer (CRC) cells and peripheral blood mononuclear cells (PBMCs) with the nucleoside analogue trifluridine (FTD) and used scRNA-seq to analyze posttreatment gene expression profiles in thousands of individual cancer and immune cells concurrently. ScRNA-seq recapitulated major mechanisms of action previously described for FTD and provided new insight into possible treatment-induced effects on T-cell mediated antitumor responses.
Subject(s)
Colorectal Neoplasms , Frontotemporal Dementia , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Frontotemporal Dementia/drug therapy , Humans , Leukocytes, Mononuclear/metabolism , Pyrrolidines/pharmacology , Single-Cell Analysis , Thymine/pharmacology , Thymine/therapeutic use , Trifluridine/pharmacology , Trifluridine/therapeutic useABSTRACT
TAS-102 is approved for treatment of refractory metastatic gastroesophageal carcinoma (mGEC). This study sought to determine whether the combination of TAS-102 with irinotecan (TASIRI) was safe and effective in previously treated mGEC. This was a single-arm phase 1b study for patients (pts) with mGEC previously treated with at least one line of fluoropyrimidine and platinum-containing regimen. TAS-102 was given at 25 mg/m2 twice daily on days 1 to 5 with irinotecan 180 mg/m2 on day 1 of a 14-day cycle. The primary endpoint was progression-free survival at 6 months ≥ 35% (PFS-6). 20 Pts were enrolled. The study met its primary endpoint. PFS-6 is 40% (95% CI 19.3-60.0). Median PFS and overall survival are 5.3 months and not reached, respectively. 17 of 20 pts had measurable disease by RECIST criteria. Of the 17, 13 had stable disease and 4 had progressive disease as best response (8 pts had tumor shrinkage < 30%). The disease control rate was 75%. In exploratory analyses, mutations in homologous recombination deficiency genes were associated with inferior PFS (P < 0.03). The most common any grade (G) treatment-related adverse events (TRAE) were nausea (n = 14, 70%), diarrhea (n = 9, 45%), and fatigue (n = 8, 40%). G3-4 TRAE in > 5% of pts were anemia (20%) and neutropenia (10%). 2 serious TRAE were reported: G4 febrile neutropenia (n = 1) and G3 hypotension (n = 1). There was no G5 TRAE. The combination of TASIRI showed encouraging clinical activity with a meaningful improvement in PFS-6 compared to historic controls.
Subject(s)
Adenocarcinoma , Esophageal Neoplasms , Irinotecan , Stomach Neoplasms , Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols , Drug Combinations , Esophageal Neoplasms/drug therapy , Humans , Irinotecan/therapeutic use , Platinum/therapeutic use , Pyrrolidines/therapeutic use , Stomach Neoplasms/drug therapy , Thymine/therapeutic use , Trifluridine/therapeutic useABSTRACT
Cancer response to chemotherapeutic agents and its side effects remain a challenge for the development of new anticancer compounds. Dates are consumed worldwide due to their high nutritional value. We investigated the cytotoxicity and expression of the proapoptotic BAX gene in human hepatocellular carcinoma (HepG2) cells treated with Ruthana date ethanolic extract (RDE). The RDE ingredients analyzed by GC/MS and HepG2 cells were treated with different concentrations of RDE for 24, 48, and 72 h. Cytotoxicity, cell viability, DNA fragmentation, and BAX expression were determined. The GC/MS analysis of RDE showed its high content of quercetin, myricetin kaempferol, thymine, and catechol as the most active ingredients. HepG2 treated with RDE showed a significant change in morphological characteristics related to cell death. The antiproliferative activity determined by WST-1 demonstrated that RDE significantly reduced cell viability. Cells treated with RDE (10-60 mg) showed gradual DNA fragmentation in a dose-dependent manner. Gene expression analysis showed upregulation of BAX at 30 mg/ml of RDE (p < 0.001). However, it showed downregulation at (40-60 mg/ml) as compared to control. Our findings indicated that RDE exert cytotoxicity against HepG2 cells due to its high content of flavonoids. This effect through DNA fragmentation and activation of the proapoptotic BAX gene.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Apoptosis , Catechols , Cell Proliferation , Flavonoids/pharmacology , Hep G2 Cells , Humans , Kaempferols/pharmacology , Kaempferols/therapeutic use , Quercetin/pharmacology , Thymine/pharmacology , Thymine/therapeutic use , bcl-2-Associated X Protein/geneticsABSTRACT
Trifluridine/tipiracil is a compound drug, approved in 2015 by the US FDA, and in 2016 by the EMA, for the treatment of chemorefractory metastatic colorectal cancers, after the phase III RECOURSE trial demonstrated significant benefit. Another phase III trial (TAGS) showed significant improvement of overall survival and progression-free survival in refractory gastric cancer and gastroesophageal junction cancer, leading to further approval from the FDA on February 2019, followed by Japan in August 2019 and the EU in September 2019. As promising results have already been observed in the chemorefractory gastric and gastroesophageal-junction cancers, ongoing trials are assessing the use of trifluridine/tipiracil with other standard of care agents, aiming to further improve the survival rate of these patients.
Subject(s)
Pyrrolidines , Stomach Neoplasms , Thymine , Trifluridine , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Clinical Trials, Phase III as Topic , Drug Combinations , Humans , Pyrrolidines/therapeutic use , Stomach Neoplasms/drug therapy , Thymine/therapeutic use , Trifluridine/therapeutic useABSTRACT
For patients with refractory metastatic colorectal cancer (mCRC) treatment with Trifluridine/Tipiracil, also known as TAS-102, improves overall survival. This study aims to investigate the efficacy and safety of TAS-102 in a real-world population from Victoria, Australia. A retrospective analysis of prospectively collected data from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry was undertaken. The characteristics and outcomes of patients receiving TAS-102 were assessed and compared to those enrolled in the registration study (RECOURSE). Across 13 sites, 107 patients were treated with TAS-102. The median age was 60 years (range: 31-83), compared to 63 for RECOURSE. Comparing registry TAS-102-treated and RECOURSE patients, 75% vs 100% were ECOG performance status 0-1, 74% vs 79% had initiated treatment more than 18 months from diagnosis of metastatic disease and 36% vs 49% were RAS wild-type. Median time on treatment was 10.4 weeks (range: 1.7-32). Median progression-free survival (PFS) was 3.3 months compared to 2 months in RECOURSE, while median overall survival was the same at 7.1 months. Two patients (2.3%) had febrile neutropenia and there were no treatment-related deaths, where TAS-102 dose at treatment initiation was at clinician discretion.TRACC registry patients treated with TAS-102 were younger than those from the RECOURSE trial, with similar overall survival observed. Less strict application of RECIST criteria and less frequent imaging may have contributed to an apparently longer PFS.