ma-1 and Colorectal-Neoplasms

Colorectal cancer is a disease of older patients, but few guidelines directly address age in their recommendations. Older patients may present comorbidities that affect the choice of chemotherapy, and care must be taken when choosing the best approach. This narrative review aimed to describe the literature regarding approved oral agents for third-line treatment in older patients with refractory metastatic colorectal cancer, regorafenib, and trifluridine/tipiracil (FTD/TPI).

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; Frontotemporal Dementia; Humans; Rectal Neoplasms; Trifluridine; Uracil

Colorectal cancer is the most prevalent gastrointestinal neoplasm. When metastatic, the disease has limited systemic treatment options. Novel targeted therapies have expanded these options for subsets with specific molecular alterations, such as microsatellite instability (MSI)-high cancers, but additional treatments and combinations are in urgent need to improve outcomes and improve survival of this incurable disease. The fluoropyrimidine-derivative trifluridine, in combination with tipiracil, has been introduced as a third-line treatment, and more recently, it was studied in combination with bevacizumab. This meta-analysis reports on studies with this combination in clinical practice outside clinical trials.. A literature search in the Medline/PubMed and Embase databases was executed for finding series of trifluridine/tipiracil with bevacizumab in metastatic colorectal cancer. Criteria for inclusion in the meta-analysis were English or French language of the report, inclusion of twenty or more patients with metastatic colorectal cancer treated with trifluridine/tipiracil in combination with bevacizumab outside of a trial and containing information regarding response rates, progression-free survival (PFS), and overall survival (OS). Information on the demographics of the patients and on adverse effects of treatment was also collected.. Eight series with a total of 437 patients were eligible for the meta-analysis. The performed meta-analysis discovered a summary response rate (RR) of 2.71% (95% confidence interval (CI): 1.11-4.32%) and a disease control rate (DCR) of 59.63% (95% CI: 52.06-67.21%). Summary PFS was 4.56 months (95% CI: 3.57-5.55 months), and summary OS was 11.17 months (95% CI: 10.15-12.19 months). Common adverse effects identified mirrored the adverse-effect profile of the two components of the combination.. The current systematic review and meta-analysis reports the efficacy of trifluridine/tipiracil with bevacizumab in advanced lines of therapy for metastatic colorectal cancer in the setting of clinical practice outside clinical trials. Discovery of predictive biomarkers of response to trifluridine/tipiracil with bevacizumab will promote the tailoring of this treatment to individual patients to maximize clinical benefit.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Colorectal Neoplasms; Humans; Rectal Neoplasms; Trifluridine; Uracil

COVID-19 as a viral disease has brought up the need to exercise more than before due to its physiological effects on health. Therefore, this study investigates the effect of 12-week of aerobic exercise on female students' hormone levels and lipid profile with polycystic ovary syndrome (PCOS) during the COVID-19 pandemic.. Using a 12-week quasi-experimental with pretest, posttest research design among 40 Iranian female students aged 18-14 with PCOS, we randomly allocated the participants to either an experimental (they performed aerobic exercises three 60-minute sessions per week at home using content production) or a control condition. Their anthropometric and blood samples (e.g., testosterone, estrogen, prolactin, and lipid profile) were taken in two stages before and after the training protocol.. Findings demonstrated that performing aerobic exercises is an effective and non-invasive method that could have a positive effect on young girls' PCOS during COVID-19 pandemic.. La pandémie de COVID-19, en tant que maladie virale, a fait ressortir la nécessité de faire de l’exercice plus que jamais en raison de ses effets physiologiques sur la santé. Par conséquent, cette étude examine l’effet de 12 semaines d’exercice aérobique sur les niveaux hormonaux et le profil lipidique d’étudiantes atteintes du syndrome d’ovaires polykystiques (SOPK) pendant la pandémie de COVID-19.. En utilisant un modèle de recherche quasi-expérimental de 12 semaines avec pré-test, post-test auprès de 40 étudiantes iraniennes âgées de 18 à 14 ans atteintes du SOPK, nous avons réparti au hasard les participantes entre une série expérimentale (elles ont effectué des exercices aérobiques à raison de trois séances de 60 minutes par semaine à la maison) et une série contrôle. Les échantillons anthropométriques et sanguins (testostérone, œstrogène, prolactine et profil lipidique) ont été prélevés en deux étapes, avant et après le protocole d’entraînement.. Les résultats ont démontré que la pratique d’exercices d’aérobic est une méthode efficace et non invasive qui pourrait avoir un effet positif sur le SOPK des jeunes filles pendant la pandémie de COVID-19.. Our research showed that even less than 5 GBq irradiation could induce a transient testicular dysfunction in the first 3 months of therapy, but it was mostly reversible after 12 months.. The online version contains supplementary material available at 10.1007/s13204-023-02822-5.. Embelin is predicted to have a high probability of immunotoxicity potential and affect drug metabolism by inhibiting CYP2D6. In addition, it affects food intake, weight gain, and the number of implantations in pregnant rats. Therefore, it is highly recommended not to take embelin and embelin-rich plants during pregnancy. Further. The online version contains supplementary material available at 10.1007/s42965-023-00306-9.. The online version contains supplementary material available at 10.1007/s11696-023-02771-x.. The online version contains supplementary material available at 10.1007/s00477-023-02476-3.. This study ascribes for a new immunomodulatory role for IL11 during tumor development that is amenable to anti-cytokine based therapy of colon cancer.. Inflammation response do not seem to be enough to explain all the Essure-related adverse outcomes, suggesting the involvement of other biological mechanisms.. NCT03281564.. Inflammation and fibrosis are found in the surrounding tubal tissue around the Essure. Adult patients with BED with co-occurring obesity who have good responses to acute treatment with naltrexone/bupropion should be offered maintenance treatment with naltrexone/bupropion.. dp/dtmax in PiCCO parameter can be used as a bedside indicator to evaluate cardiac function in SIC patients due to its simplicity and ease of operation. Esmolol control of heart rate in SIC patients can improve cardiac function and reduce short-term mortality.. Inverted microscopy showed that compared with the NC group, the OGD/R group had poor cell status, swollen cytosol, visible cell lysis fragments and significantly lower cell activity [(49.1±2.7)% vs. (100.0±9.7)%, P < 0.01]; compared with the OGD/R group, the HW group had improved cell status and remarkably higher cell activity [(63.3±1.8)% vs. (49.1±2.7)%, P < 0.01]. Transmission electron microscopy showed that the neuronal nuclear membrane of cells in the OGD/R group was lysed and a higher number of autophagic lysosomes were visible compared with the NC group; compared with the OGD/R group, the neuronal damage of cells in the HW group was reduced and the number of autophagic lysosomes was notably decreased. The results of immunofluorescence assay showed that the expressions of LC3 and Beclin-1 were outstandingly enhanced in the OGD/R group compared with the NC group, and the expressions of LC3 and Beclin-1 were markedly weakened in the HW group compared with the OGD/R group. Western blotting assay showed that the expressions were prominently higher in both LC3II/I and Beclin-1 in the OGD/R group compared with the NC group (LC3II/I: 1.44±0.05 vs. 0.37±0.03, Beclin-1/β-actin: 1.00±0.02 vs. 0.64±0.01, both P < 0.01); compared with the OGD/R group, the protein expression of both LC3II/I and Beclin-1 in the HW group cells were notably lower (LC3II/I: 0.54±0.02 vs. 1.44±0.05, Beclin-1/β-actin: 0.83±0.07 vs. 1.00±0.02, both P < 0.01).. Hydrogen-rich water has a significant protective effect on OGD/R-causing HT22 cell injury, and the mechanism may be related to the inhibition of autophagy.. The prevalence of delirium in ICU patients is over 50%, with hypoactive delirium being the most common. Age, APACHE score at ICU admission, neurological disease, sepsis and duration of mechanical ventilation were all independent risk factors for the development of delirium in ICU patients. More than half of patients with delirium were still delirious when they discharged from the ICU.. For individuals ≥75 years, plasma Aβ42 and P-tau181 might not be associated with cognitive impairment, and MRI parameters, including PVWMH, LVBI and cortical atrophy, are related to CI. The cognitive statuses of people over 75 years old were used as the endpoint event in this study. Therefore, it can be considered that these MRI markers might have more important clinical significance for early assessment and dynamic observation, but more studies are still needed to verify this hypothesis.. We recommend using the Art/Zn complex owing to its moderate inhibitory and antiviral effects against the SARS-CoV-2 with a low cytotoxic effect on host (Vero E6) cells. We suggest conducting further prospective studies to investigate the biological effects of Art/Zn in animal models at different concentrations for testing its clinical efficacy and safety in inhibiting SARS-CoV-2 activities.. The R/T sequence resulted in a significantly longer OS and PFS and improved disease control compared with the reverse sequence. R and T given not sequentially have similar impacts on survival. More data are needed to define the best sequence and to explore the efficacy of sequential (T/R or R/T) treatment combined with molecular-targeted drugs.

Topics: Actin Cytoskeleton; Actins; Adaptor Proteins, Signal Transducing; Adenocarcinoma; Adenosine Triphosphate; Adsorption; Adult; Africa, Eastern; Aged; Air Pollutants; Air Pollution; Air Pollution, Indoor; Alcohol Drinking; Allergens; Alzheimer Disease; Amyotrophic Lateral Sclerosis; Animals; Anti-Bacterial Agents; Antibodies; Antibodies, Immobilized; Antigen Presentation; Antigens, CD; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Apoptosis; Aptamers, Nucleotide; Asthma; Asthma, Exercise-Induced; Atrophy; Autophagy; Azoospermia; Bacillus cereus; Bacterial Infections; Beclin-1; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biofouling; Biological Monitoring; Biomarkers; Biomarkers, Tumor; Biosensing Techniques; Blastocyst; Bone Neoplasms; Bone Regeneration; Bronchoconstriction; Burkitt Lymphoma; C9orf72 Protein; Campylobacter; Campylobacter Infections; Campylobacter jejuni; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Pancreatic Ductal; Carcinoma, Squamous Cell; Cardiomyopathies; Caregivers; Carmine; Case-Control Studies; Catalysis; Cattle; Cause of Death; CCAAT-Enhancer-Binding Protein-alpha; CD8-Positive T-Lymphocytes; Cefepime; Cell Differentiation; Cell Line, Tumor; Cell Nucleus; Cell Transdifferentiation; Chelating Agents; Chemical and Drug Induced Liver Injury, Chronic; Chemoradiotherapy, Adjuvant; Child; Child, Preschool; China; Chlorquinaldol; Cholangiocarcinoma; Cholera; Chromatin; Clinical Trials as Topic; Cognitive Dysfunction; Cohort Studies; Colonic Neoplasms; Colorectal Neoplasms; Colorimetry; Cooking; Coordination Complexes; COVID-19; Creatinine; CRISPR-Cas Systems; Critical Care; Critical Illness; Cross-Sectional Studies; Cryopreservation; Cryoprotective Agents; Cysteine; Cytokines; Device Removal; Diet; Diet, High-Fat; Diet, Mediterranean; Dietary Supplements; Dimethyl Sulfoxide; Dipeptides; Disease Models, Animal; Dithiothreitol; DNA; DNA Repeat Expansion; DNA, Bacterial; DNA, Complementary; Dopamine; Electrochemical Techniques; Electrodes; Endocannabinoids; Environmental Exposure; Environmental Monitoring; Environmental Pollutants; Enzyme-Linked Immunosorbent Assay; Erlotinib Hydrochloride; Escherichia coli; Escherichia coli O157; Esophageal Neoplasms; Esophagitis, Peptic; Ethylene Glycol; Europium; Exanthema; Fallopian Tubes; Feces; Female; Fertilization in Vitro; Fluoresceins; Fluorescent Dyes; Follicle Stimulating Hormone; Follow-Up Studies; Food Microbiology; Forced Expiratory Volume; Forkhead Transcription Factors; Frontotemporal Dementia; G-Quadruplexes; Galactose; Gastroenteritis; Gastrointestinal Diseases; Gastrointestinal Microbiome; Gastrointestinal Neoplasms; Gastrointestinal Tract; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genital Neoplasms, Female; Genome-Wide Association Study; Genome, Viral; Genomics; Genotype; Glucose; Glutathione; Glycerol; Gold; Graphite; GTPase-Activating Proteins; Heat-Shock Proteins; Heme Oxygenase-1; Hepacivirus; Hepatitis C; Hepatocytes; Histamine; Histocompatibility Antigens Class II; Hoarseness; Hospice and Palliative Care Nursing; Humans; Hydrogen; Hydrogen Peroxide; Hydrogen Sulfide; Hydroxybenzoates; Hydroxyl Radical; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperthermia, Induced; Hysteroscopy; Immunoassay; Indigo Carmine; Inflammation; Inflammatory Bowel Diseases; Insulin Resistance; Intensive Care Units; Interleukin-11; Interleukin-6; Interleukins; Iodine Radioisotopes; Iran; Iridium; Islets of Langerhans; Kinetics; Lactation; Lactobacillus; Lactobacillus plantarum; Lamins; Latin America; Lead; Lectins; Leukopenia; Ligands; Limit of Detection; Lipopolysaccharides; Lipoprotein Lipase; Liver; Liver Cirrhosis; Liver Neoplasms; Lolium; Luminescent Measurements; Luminol; Lung; Luteinizing Hormone; Macrophages; Magnetic Phenomena; Magnetic Resonance Imaging; Male; Malnutrition; Maltose; Manganese Compounds; Maternal Nutritional Physiological Phenomena; Melatonin; Metabolic Engineering; Metal Nanoparticles; Metallocenes; Metaplasia; Methicillin-Resistant Staphylococcus aureus; Methylation; Mevalonic Acid; Mexico; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microbial Sensitivity Tests; Microbiota; MicroRNAs; Milk; Mitomycin; Molecular Diagnostic Techniques; Molecular Docking Simulation; Monte Carlo Method; Moringa oleifera; Multiple Sclerosis; Muscle Strength; Muscle, Skeletal; Nanocomposites; Nanotubes, Carbon; Neoadjuvant Therapy; Neoplasms; Neurodegenerative Diseases; Neurotransmitter Agents; NF-E2-Related Factor 2; Nickel; Nitrogen Dioxide; Non-alcoholic Fatty Liver Disease; Nucleic Acid Amplification Techniques; Nucleic Acid Hybridization; Nucleocapsid Proteins; Nutritional Status; Obesity; Osteogenesis; Osteosarcoma; Oxidation-Reduction; Oxides; Oxygen; Oxyquinoline; Pain; Palliative Care; Pancreatic Neoplasms; Pandemics; Particulate Matter; Peroxidase; Peroxidases; Phagocytosis; Phaseolus; Photothermal Therapy; Point-of-Care Systems; Polyethyleneimine; Polymers; Polymorphism, Single Nucleotide; Polysomnography; Postoperative Complications; Pregnancy; Pregnant Women; Prenatal Exposure Delayed Effects; Prevalence; Printing, Three-Dimensional; Probability; Probiotics; Prognosis; Prophages; Prospective Studies; Proteomics; Proto-Oncogene Proteins; Pseudomonas aeruginosa; Pseudomonas putida; Pulmonary Disease, Chronic Obstructive; Pulmonary Embolism; Pyridines; Pyrroles; Quality of Life; Quinolones; Rabbits; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; Receptors, Histamine; Receptors, Histamine H2; Recombinases; Rectal Neoplasms; Reperfusion Injury; Respiration; Respiratory Function Tests; Respiratory Rate; Respiratory Sounds; Retrospective Studies; rho GTP-Binding Proteins; Risk Assessment; Risk Factors; RNA; RNA, Messenger; RNA, Ribosomal, 16S; Robotic Surgical Procedures; Running; Rural Population; Saccharomyces cerevisiae; Salpingectomy; Sarcopenia; SARS-CoV-2; Seeds; Semen; Sensitivity and Specificity; Sepsis; Shock, Septic; Signal Transduction; Silicon Dioxide; Silver; Sirtuin 1; Skin Neoplasms; Sleep Apnea, Obstructive; Soil; Spain; Spectrum Analysis, Raman; Sperm Retrieval; Spermatozoa; Spirometry; Staphylococcus aureus; STAT3 Transcription Factor; Stereoisomerism; Sterilization, Tubal; Stroke Volume; Sulfadiazine; Sulfites; Superoxide Dismutase; Surface Plasmon Resonance; tau Proteins; Testis; Testosterone; Thioredoxin-Disulfide Reductase; Thyroid Neoplasms; Thyroidectomy; Trans-Activators; Transcription Factor AP-1; Treatment Outcome; Triazoles; Triclosan; Trifluridine; Tumor Microenvironment; Tumor Necrosis Factor-alpha; United States; Uracil; Vagina; Vegetables; Ventricular Function, Left; Ventricular Pressure; Vibrio cholerae; Vietnam; Virulence; Vital Capacity; Vitrification; Walking; Water; Water Pollutants, Radioactive; Whole Genome Sequencing; Wind; YAP-Signaling Proteins; Zeolites; Zinc Oxide

KRAS gene mutations can predict prognosis and treatment response in patients with metastatic colorectal cancer (mCRC).. We undertook a meta-analysis of three randomized, placebo-controlled trials (RECOURSE, TERRA and J003) to investigate the impact of KRAS mutations in codons 12 or 13 on overall survival (OS) and progression-free survival in patients receiving trifluridine/tipiracil (FTD/TPI) for refractory mCRC.. A total of 1375 patients were included, of whom 478 had a KRAS codon 12 mutation and 130 had a KRAS codon 13 mutation. In univariate analyses, the absence of a KRAS codon 12 mutation was found to significantly increase the OS benefit of FTD/TPI relative to placebo compared with the presence of the mutation {hazard ratio (HR), 0.62 [95% confidence interval (CI): 0.53-0.72] versus 0.86 (0.70-1.05), respectively; interaction P = 0.0206}. Multivariate analyses showed that taking confounding factors into account reduced the difference in treatment effect between the presence and the absence of KRAS codon 12 mutations, confirming that treatment benefit was maintained in patients with [HR, 0.73 (95% CI: 0.59-0.89)] and without [HR, 0.63 (95% CI: 0.54-0.74)] codon 12 mutations (interaction P = 0.2939). KRAS mutations in codon 13 did not reduce the OS benefit of FTD/TPI relative to placebo, and, furthermore, KRAS mutations at either codon 12 or codon 13 did not affect the progression-free survival benefit.. Treatment with FTD/TPI produced a survival benefit, relative to placebo, regardless of KRAS codon 12 or 13 mutation status in patients with previously treated mCRC.

Topics: Codon; Colonic Neoplasms; Colorectal Neoplasms; Frontotemporal Dementia; Humans; Mutation; Proto-Oncogene Proteins p21(ras); Pyrrolidines; Randomized Controlled Trials as Topic; Thymine; Trifluridine; Uracil

Trifluridine/tipiracil (Lonsurf(®)) is a novel, orally active, antimetabolite agent comprised of trifluridine, a thymidine-based nucleoside analogue, and tipiracil, a potent thymidine phosphorylase inhibitor. Trifluridine is incorporated into DNA via phosphorylation, ultimately inhibiting cell proliferation. Tipiracil increases systemic exposure of trifluridine when coadministered. Trifluridine/tipiracil has recently been approved for the treatment of adult patients with metastatic colorectal cancer (mCRC) who are refractory to or are not considered candidates for, current standard chemotherapy and biological therapy in the EU and USA and in unresectable advanced or recurrent CRC in Japan. The approved regimen of oral twice-daily trifluridine/tipiracil (35 mg/m(2) twice daily on days 1-5 and 8-12 of each 28-day cycle) significantly improved overall survival and progression-free survival and was associated with a significantly higher disease control rate than placebo when added to best supportive care in the multinational, pivotal phase III trial (RECOURSE) and a phase II Japanese trial. Trifluridine/tipiracil was associated with an acceptable tolerability profile, with adverse events generally being managed with dose reductions, temporary interruptions in treatment or administration of granulocyte-colony stimulating factor. The most common grade 3-4 adverse events (≥10 %) were anaemia, neutropenia, thrombocytopenia and leukopenia. In conclusion, trifluridine/tipiracil is a useful additional treatment option for the management of mCRC in patients who are refractory to, or are not considered candidates for, currently available therapies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Disease-Free Survival; Humans; Pyrrolidines; Thymine; Trifluridine

CA102N is a covalently bound conjugate of modified nimesulide (Nim) and NaHA, the sodium salt of hyaluronic acid (HA). HA is a natural ligand of cluster of differentiation 44 (CD44), which is over-expressed in colorectal cancer (CRC). CA102N is designed to deliver nimesulide directly to the tumor via the interaction of HA and CD44. A Phase 1, 2-part (dose escalation, dose expansion), non-randomized, open-label, first-in-human study of CA102N, as monotherapy and in combination with trifluridine-tipiracil, was conducted in patients with locally advanced or metastatic solid tumors. The CA102N doses evaluated were 0.36 mg/kg, 0.54 mg/kg, and 0.72 mg/kg Nim equivalent. The primary endpoints were dose-limiting toxicities (DLTs) in Cycle 1 as well as serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs) throughout the study; secondary endpoints were pharmacodynamics parameters, objective tumor response, and urinary pharmacodynamics markers of target inhibition. Between April 2019 and October 2021, 37 patients were enrolled in 3 US centers. No DLTs were observed in Part 1, and 0.72 mg/kg Nim equivalent was the dose selected for Part 2. In total, 52 TEAEs in 18 patients were CA102N-related; 4 (in 3 patients) were ≥ Grade 3. Exploratory analysis in the dose expansion cohort revealed a median progression-free survival of 3.7 (1.0, 6.77) months. Based on this study, CA102N as monotherapy or in combination with trifluridine-tipiracil, was safe and well-tolerated at the recommended Phase 2 dose of 0.72 mg/kg Nim equivalent in patients with locally advanced or metastatic solid tumors. Preliminary evidence of antitumor activity in CRC warrants further clinical development. (ClinicalTrials.gov registration number: NCT03616574. Registration date: August 6, 2018).

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Cyclooxygenase 2 Inhibitors; Drug Combinations; Humans; Hyaluronic Acid; Sulfonamides; Trifluridine

Trifluridine-tipiracil plus bevacizumab has shown efficacy in previous phase 2 studies including patients with unresectable metastatic colorectal cancer. We aimed to investigate first-line trifluridine-tipiracil plus bevacizumab versus capecitabine plus bevacizumab in patients with unresectable metastatic colorectal cancer ineligible for intensive treatment.. In this open-label, randomised, phase 3 study, we enrolled patients aged 18 years and older with histologically confirmed metastatic colorectal cancer, ineligible for full-dose doublet or triplet chemotherapy and curative resection across 25 countries and regions. Participants were randomly allocated (1:1) to trifluridine-tipiracil plus bevacizumab or capecitabine plus bevacizumab until disease progression or unacceptable toxicity using an interactive web response system, stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1 vs 2), primary tumour location (right vs left colon), and the main reason for not being a candidate for intensive therapy (clinical condition vs non-clinical condition). The primary endpoint was investigator-assessed progression-free survival, defined as the time from randomisation to radiological progression or death from any cause, in the intention-to-treat population. Safety was assessed in all patients having taken at least one dose of the study drug. The trial is ongoing, findings presented here are those of the primary analysis of progression-free survival, conducted after 629 events had occurred. This study is registered with ClinicalTrials.gov, NCT03869892.. Between March 21, 2019, and Sept 14, 2020, 856 patients (54% male, 46% female) were randomly assigned to trifluridine-tipiracil plus bevacizumab (n=426) or capecitabine plus bevacizumab (n=430). After a median follow-up of 16·6 months (95% CI 16·5-17·1), the hazard ratio for progression-free survival for trifluridine-tipiracil plus bevacizumab versus capecitabine plus bevacizumab was 0·87 (0·75-1·02; p=0·0464; protocol-defined significance level of p=0·021 not met). Investigator-assessed median progression-free survival was 9·4 months (95% CI 9·1-10·9) with trifluridine-tipiracil plus bevacizumab versus 9·3 months (8·9-9·8) with capecitabine plus bevacizumab. The most common grade 3 and higher treatment-emergent adverse events were neutropenia (220 [52%] of 423 patients in the trifluridine-tipiracil plus bevacizumab group vs six [1%] of 427 in the capecitabine plus bevacizumab group), decreased neutrophil count (78 [18%] vs four [<1%]), anaemia (60 [14%] vs 16 [4%]), and hand-foot syndrome (none vs 61 [15%]). Nine deaths (five in the trifluridine-tipiracil plus bevacizumab group and four in the capecitabine plus bevacizumab group) were treatment related.. First-line trifluridine-tipiracil plus bevacizumab was not superior to capecitabine plus bevacizumab in this population. As expected, the safety profile differed between the two treatments, but there were no new safety concerns. Trifluridine-tipiracil plus bevacizumab represents a feasible alternative to capecitabine plus bevacizumab in this population.. Servier International Research Institute, Suresnes, France.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Colonic Neoplasms; Colorectal Neoplasms; Female; Humans; Male; Rectal Neoplasms; Trifluridine

PRECONNECT was an international, phase IIIb trial evaluating the safety and efficacy of trifluridine/tipiracil (FTD/TPI) for metastatic colorectal cancer (mCRC).. Patients with mCRC received FTD/TPI 35 mg/m. safety and time to deterioration of Eastern Cooperative Oncology Group performance status [ECOG PS] to ≥2). Secondary endpoints included progression-free survival (PFS). Potential prognostic factors for PFS were explored.. Of 914 patients, 69% completed 0-3, 24% completed 4-7, and 7% completed ≥8 cycles of FTD/TPI. Drug-related grade ≥ 3 adverse events included neutropenia (38.1%), anaemia (7.2%) and asthenia (3.4%). Median [95% CI] time to ECOG PS deterioration was 8.7 [8.1-not calculable] months and increased with duration of treatment (DoT). Median PFS was 2.8 [2.7-3.0] months and increased with duration of treatment DoT. Prognostic factors associated with longer PFS included time since diagnosis of first metastasis, number of metastatic sites, baseline ECOG PS, presence/absence of liver metastasis or previous regorafenib treatment, and laboratory variables.. No new safety concerns for FTD/TPI were identified and PFS increased with DoT. These data provide confidence for the use of FTD/TPI, including the use of multiple cycles, in routine practice.. EudraCT Number: 2016-002311-18; registered 19/09/2016. https://clinicaltrials.gov/ct2/show/NCT03306394 ; registered 11/10/2017.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Combinations; Duration of Therapy; Humans; Trifluridine

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).. FTD/TPI plus bevacizumab did not demonstrate noninferiority to fluoropyrimidine and irinotecan plus bevacizumab as second-line treatment for mCRC.. JapicCTI-173618, jRCTs031180122.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Colorectal Neoplasms; Drug Combinations; Frontotemporal Dementia; Humans; Irinotecan; Pyrrolidines; Rectal Neoplasms; Thymine; Trifluridine

In a previous phase 3 trial, treatment with trifluridine-tipiracil (FTD-TPI) prolonged overall survival among patients with metastatic colorectal cancer. Preliminary data from single-group and randomized phase 2 trials suggest that treatment with FTD-TPI in addition to bevacizumab has the potential to extend survival.. We randomly assigned, in a 1:1 ratio, adult patients who had received no more than two previous chemotherapy regimens for the treatment of advanced colorectal cancer to receive FTD-TPI plus bevacizumab (combination group) or FTD-TPI alone (FTD-TPI group). The primary end point was overall survival. Secondary end points were progression-free survival and safety, including the time to worsening of the Eastern Cooperative Oncology Group (ECOG) performance-status score from 0 or 1 to 2 or more (on a scale from 0 to 5, with higher scores indicating greater disability).. A total of 246 patients were assigned to each group. The median overall survival was 10.8 months in the combination group and 7.5 months in the FTD-TPI group (hazard ratio for death, 0.61; 95% confidence interval [CI], 0.49 to 0.77; P<0.001). The median progression-free survival was 5.6 months in the combination group and 2.4 months in the FTD-TPI group (hazard ratio for disease progression or death, 0.44; 95% CI, 0.36 to 0.54; P<0.001). The most common adverse events in both groups were neutropenia, nausea, and anemia. No treatment-related deaths were reported. The median time to worsening of the ECOG performance-status score from 0 or 1 to 2 or more was 9.3 months in the combination group and 6.3 months in the FTD-TPI group (hazard ratio, 0.54; 95% CI, 0.43 to 0.67).. Among patients with refractory metastatic colorectal cancer, treatment with FTD-TPI plus bevacizumab resulted in longer overall survival than FTD-TPI alone. (Funded by Servier and Taiho Oncology; SUNLIGHT ClinicalTrials.gov number, NCT04737187; EudraCT number, 2020-001976-14.).

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Colorectal Neoplasms; Drug Combinations; Humans; Pyrrolidines; Rectal Neoplasms; Trifluridine; Uracil

Current third-line therapies for patients with metastatic colorectal cancer (MCRC) have limited efficacy. Rechallenge with epidermal growth factor receptor (EGFR) inhibitors for RAS wild-type (WT) MCRC may be valuable for these patients.. To compare the anti-EGFR monoclonal antibody panitumumab plus standard-of-care trifluridine-tipiracil with trifluridine-tipiracil alone as third-line therapy for RAS WT MCRC.. This phase 2 randomized clinical trial (RCT) was conducted in 7 Italian centers from June 2019 to April 2022. Patients with refractory RAS WT MCRC who had a partial or complete response to first-line chemotherapy plus an anti-EGFR monoclonal antibody and an anti-EGFR drug-free interval of 4 or more months during second-line therapy were included.. Patients were randomized 1:1 to receive panitumumab plus trifluridine-tipiracil or trifluridine-tipiracil alone.. The primary end point was progression-free survival (PFS). Circulating tumor DNA (ctDNA) extended sequence variation analysis was performed in a subgroup of patients.. Of 62 included patients, 31 received panitumumab plus trifluridine-tipiracil (19 [61.3%] male; median age, 65 years [range, 39-81 years]) and 31 received trifluridine-tipiracil alone (17 [54.8%] male; median age, 66 years [range, 32-82 years]). The primary end point was met. Median PFS was 4.0 months (95% CI, 2.8-5.3 months) in the panitumumab plus trifluridine-tipiracil arm vs 2.5 months (95% CI, 1.4-3.6 months) in the trifluridine-tipiracil only (hazard ratio [HR], 0.48; 95% CI, 0.28-0.82; P = .007). Pretreatment plasma RAS/BRAF WT ctDNA identified patients obtaining prolonged clinical benefit with panitumumab plus trifluridine-tipiracil compared with trifluridine-tipiracil, with PFS rates at 6 months of 38.5% vs 13.0% and at 12 months of 15.4% vs 0%. A ctDNA liquid-biopsy extended mutation analysis by FoundationOne Liquid CDx (profiling 324 genes) was performed in a subgroup of patients with baseline plasma RAS/BRAF WT ctDNA; in 15 of 23 patients (65.2%) whose tumors were WT for KRAS, NRAS, BRAFV600E, EGFR, ERBB2, MAP2K1, and PIK3CA, median PFS was 6.4 months (95% CI, 3.7-9.2 months). Within this group of 15 patients, 2 (13.3%) had partial response, 11 (73.3%) had stable disease, and 2 (13.3%) had disease progression as best response.. In this RCT, third-line treatment with the anti-EGFR monoclonal antibody panitumumab plus the standard-of-care trifluridine-tipiracil resulted in improved PFS compared with treatment with trifluridine-tipiracil alone among patients with refractory RAS WT MCRC. The findings support the clinical utility of liquid biopsy-guided anti-EGFR rechallenge therapy for refractory RAS WT MCRC.. ClinicalTrials.gov Identifier: NCT05468892.

Topics: Aged; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Humans; Male; Panitumumab; Proto-Oncogene Proteins B-raf; Trifluridine

In the phase III TAGS trial, trifluridine/tipiracil showed survival benefit versus placebo in patients with metastatic gastric/gastroesophageal junction cancer and ≥ 2 prior chemotherapies. This post hoc exploratory analysis assessed the impact of prior therapy type on outcomes.. Based on prior treatment, patients in TAGS (N = 507) were categorized into overlapping subgroups: ramucirumab ± other agents (n = 169), no ramucirumab (n = 338), paclitaxel but no ramucirumab (n = 136), ramucirumab + paclitaxel sequentially or in combination (n = 154), neither paclitaxel nor ramucirumab (n = 202), irinotecan (n = 281), and no irinotecan (n = 226). Overall and progression-free survival, time to Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 2, and safety were assessed.. Baseline characteristics and prior therapy patterns were generally well balanced between trifluridine/tipiracil and placebo arms across subgroups. Trifluridine/tipiracil was associated with survival benefits versus placebo regardless of prior treatment: across subgroups, median overall survival was 4.6-6.1 versus 3.0-3.8 months (hazard ratios, 0.47-0.88), median progression-free survival was 1.9-2.3 versus 1.7-1.8 months (hazard ratios, 0.49-0.67), and median time to ECOG PS ≥ 2 was 4.0-4.7 versus 1.9-2.5 months (hazard ratios, 0.56-0.88). Among trifluridine/tipiracil-randomized patients, median overall and progression-free survival trended longer in those who had not received ramucirumab, paclitaxel and ramucirumab, or irinotecan (6.0-6.1 and 2.1-2.3 months, respectively) than in those who previously received these agents (4.6-5.7 and 1.9 months). The trifluridine/tipiracil safety profile was consistent across subgroups, with similar overall incidences of grade ≥ 3 adverse events. Minor variations in hematologic toxicities were noted.. In TAGS, third- or later-line trifluridine/tipiracil treatment demonstrated overall and progression-free survival and functioning benefits versus placebo and a consistent safety profile in patients with metastatic gastric/gastroesophageal junction cancer, regardless of prior treatment type.. clinicaltrials.gov NCT02500043.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Combinations; Esophagogastric Junction; Humans; Irinotecan; Paclitaxel; Pyrrolidines; Stomach Neoplasms; Trifluridine

The prognosis of patients with advanced biliary tract cancer (BTC) who have progressed on gemcitabine plus cisplatin is dismal. Trifluridine/tipiracil (FTD/TPI) and irinotecan have proven efficacy in different gastrointestinal malignancies. We therefore hypothesized that this combination might improve the therapeutic outcome in patients with BTC after failure of first line treatment.. TRITICC is an interventional, prospective, open-label, non-randomised, exploratory, multicentre, single-arm phase IIA clinical trial done in 6 sites with expertise in managing biliary tract cancer across Germany. A total of 28 adult patients (aged ≥ 18 years) with histologically verified locally advanced or metastatic biliary tract cancer (including cholangiocarcinoma and gallbladder or ampullary carcinoma) with documented radiological disease progression to first-line gemcitabine based chemotherapy will be included to receive a combination of FTD/TPI plus irinotecan according to previously published protocols. Study treatment will be continued until disease progression according to RECIST 1.1 criteria or occurrence of unacceptable toxicity. The effect of FTD/TPI plus irinotecan on progression-free survival will be analyzed as primary endpoint. Safety (according to NCI-CTCAE), response rates and overall survival are secondary endpoints. In addition, a comprehensive translational research program is part of the study and might provide findings about predictive markers with regard to response, survival periods and resistance to treatment.. The aim of TRITICC is to evaluate the safety and efficacy of FTD/TPI plus irinotecan in patients with biliary tract cancer refractory to previous Gemcitabine based treatment.. EudraCT 2018-002936-26; NCT04059562.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biliary Tract Neoplasms; Cholangiocarcinoma; Cisplatin; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Deoxycytidine; Disease Progression; Frontotemporal Dementia; Gemcitabine; Humans; Irinotecan; Prospective Studies; Trifluridine

In this phase Ib study MODURATE, we optimized the dosing schedule and tested the efficacy and safety of trifluridine/tipiracil, irinotecan, and bevacizumab in patients with metastatic colorectal cancer with fluoropyrimidine and oxaliplatin treatment failure.. We included a dose escalation (3 + 3 design) and an expansion cohort. Patients were administered trifluridine/tipiracil (25-35 mg/m2 twice daily, days 1-5), irinotecan (150-180 mg/m2, day 1), and bevacizumab (5 mg/kg, day 1) every 2 weeks. The recommended phase II dose (RP2D) in the dose escalation cohort was administered to at least 15 patients in both cohorts combined.. Twenty-eight patients were enrolled. Five dose-limiting toxicities were observed. RP2D was defined as trifluridine/tipiracil 35 mg/m2, irinotecan 150 mg/m2, and bevacizumab 5 mg/kg. Of 16 patients who received RP2D, 86% (14/16) experienced grade ≥3 neutropenia without febrile neutropenia. Dose reduction, delay, and discontinuation occurred in 94%, 94%, and 6% of patients, respectively. Three patients (19%) showed partial response and 5 had stable disease for >4 months, with a median progression-free and overall survival of 7.1 and 21.7 months, respectively.. Biweekly trifluridine/tipiracil, irinotecan, and bevacizumab administration may have moderate antitumor activity with high risk of severe myelotoxicity in previously treated patients with metastatic colorectal cancer [UMIN Clinical Trials Registry (UMIN000019828) and Japan Registry of Clinical Trials (jRCTs041180028)].

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Colorectal Neoplasms; Drug Combinations; Humans; Irinotecan; Rectal Neoplasms; Trifluridine; Uracil

COVID-19 as a viral disease has brought up the need to exercise more than before due to its physiological effects on health. Therefore, this study investigates the effect of 12-week of aerobic exercise on female students' hormone levels and lipid profile with polycystic ovary syndrome (PCOS) during the COVID-19 pandemic.. Using a 12-week quasi-experimental with pretest, posttest research design among 40 Iranian female students aged 18-14 with PCOS, we randomly allocated the participants to either an experimental (they performed aerobic exercises three 60-minute sessions per week at home using content production) or a control condition. Their anthropometric and blood samples (e.g., testosterone, estrogen, prolactin, and lipid profile) were taken in two stages before and after the training protocol.. Findings demonstrated that performing aerobic exercises is an effective and non-invasive method that could have a positive effect on young girls' PCOS during COVID-19 pandemic.. La pandémie de COVID-19, en tant que maladie virale, a fait ressortir la nécessité de faire de l’exercice plus que jamais en raison de ses effets physiologiques sur la santé. Par conséquent, cette étude examine l’effet de 12 semaines d’exercice aérobique sur les niveaux hormonaux et le profil lipidique d’étudiantes atteintes du syndrome d’ovaires polykystiques (SOPK) pendant la pandémie de COVID-19.. En utilisant un modèle de recherche quasi-expérimental de 12 semaines avec pré-test, post-test auprès de 40 étudiantes iraniennes âgées de 18 à 14 ans atteintes du SOPK, nous avons réparti au hasard les participantes entre une série expérimentale (elles ont effectué des exercices aérobiques à raison de trois séances de 60 minutes par semaine à la maison) et une série contrôle. Les échantillons anthropométriques et sanguins (testostérone, œstrogène, prolactine et profil lipidique) ont été prélevés en deux étapes, avant et après le protocole d’entraînement.. Les résultats ont démontré que la pratique d’exercices d’aérobic est une méthode efficace et non invasive qui pourrait avoir un effet positif sur le SOPK des jeunes filles pendant la pandémie de COVID-19.. Our research showed that even less than 5 GBq irradiation could induce a transient testicular dysfunction in the first 3 months of therapy, but it was mostly reversible after 12 months.. The online version contains supplementary material available at 10.1007/s13204-023-02822-5.. Embelin is predicted to have a high probability of immunotoxicity potential and affect drug metabolism by inhibiting CYP2D6. In addition, it affects food intake, weight gain, and the number of implantations in pregnant rats. Therefore, it is highly recommended not to take embelin and embelin-rich plants during pregnancy. Further. The online version contains supplementary material available at 10.1007/s42965-023-00306-9.. The online version contains supplementary material available at 10.1007/s11696-023-02771-x.. The online version contains supplementary material available at 10.1007/s00477-023-02476-3.. This study ascribes for a new immunomodulatory role for IL11 during tumor development that is amenable to anti-cytokine based therapy of colon cancer.. Inflammation response do not seem to be enough to explain all the Essure-related adverse outcomes, suggesting the involvement of other biological mechanisms.. NCT03281564.. Inflammation and fibrosis are found in the surrounding tubal tissue around the Essure. Adult patients with BED with co-occurring obesity who have good responses to acute treatment with naltrexone/bupropion should be offered maintenance treatment with naltrexone/bupropion.. dp/dtmax in PiCCO parameter can be used as a bedside indicator to evaluate cardiac function in SIC patients due to its simplicity and ease of operation. Esmolol control of heart rate in SIC patients can improve cardiac function and reduce short-term mortality.. Inverted microscopy showed that compared with the NC group, the OGD/R group had poor cell status, swollen cytosol, visible cell lysis fragments and significantly lower cell activity [(49.1±2.7)% vs. (100.0±9.7)%, P < 0.01]; compared with the OGD/R group, the HW group had improved cell status and remarkably higher cell activity [(63.3±1.8)% vs. (49.1±2.7)%, P < 0.01]. Transmission electron microscopy showed that the neuronal nuclear membrane of cells in the OGD/R group was lysed and a higher number of autophagic lysosomes were visible compared with the NC group; compared with the OGD/R group, the neuronal damage of cells in the HW group was reduced and the number of autophagic lysosomes was notably decreased. The results of immunofluorescence assay showed that the expressions of LC3 and Beclin-1 were outstandingly enhanced in the OGD/R group compared with the NC group, and the expressions of LC3 and Beclin-1 were markedly weakened in the HW group compared with the OGD/R group. Western blotting assay showed that the expressions were prominently higher in both LC3II/I and Beclin-1 in the OGD/R group compared with the NC group (LC3II/I: 1.44±0.05 vs. 0.37±0.03, Beclin-1/β-actin: 1.00±0.02 vs. 0.64±0.01, both P < 0.01); compared with the OGD/R group, the protein expression of both LC3II/I and Beclin-1 in the HW group cells were notably lower (LC3II/I: 0.54±0.02 vs. 1.44±0.05, Beclin-1/β-actin: 0.83±0.07 vs. 1.00±0.02, both P < 0.01).. Hydrogen-rich water has a significant protective effect on OGD/R-causing HT22 cell injury, and the mechanism may be related to the inhibition of autophagy.. The prevalence of delirium in ICU patients is over 50%, with hypoactive delirium being the most common. Age, APACHE score at ICU admission, neurological disease, sepsis and duration of mechanical ventilation were all independent risk factors for the development of delirium in ICU patients. More than half of patients with delirium were still delirious when they discharged from the ICU.. For individuals ≥75 years, plasma Aβ42 and P-tau181 might not be associated with cognitive impairment, and MRI parameters, including PVWMH, LVBI and cortical atrophy, are related to CI. The cognitive statuses of people over 75 years old were used as the endpoint event in this study. Therefore, it can be considered that these MRI markers might have more important clinical significance for early assessment and dynamic observation, but more studies are still needed to verify this hypothesis.. We recommend using the Art/Zn complex owing to its moderate inhibitory and antiviral effects against the SARS-CoV-2 with a low cytotoxic effect on host (Vero E6) cells. We suggest conducting further prospective studies to investigate the biological effects of Art/Zn in animal models at different concentrations for testing its clinical efficacy and safety in inhibiting SARS-CoV-2 activities.. The R/T sequence resulted in a significantly longer OS and PFS and improved disease control compared with the reverse sequence. R and T given not sequentially have similar impacts on survival. More data are needed to define the best sequence and to explore the efficacy of sequential (T/R or R/T) treatment combined with molecular-targeted drugs.

Topics: Actin Cytoskeleton; Actins; Adaptor Proteins, Signal Transducing; Adenocarcinoma; Adenosine Triphosphate; Adsorption; Adult; Africa, Eastern; Aged; Air Pollutants; Air Pollution; Air Pollution, Indoor; Alcohol Drinking; Allergens; Alzheimer Disease; Amyotrophic Lateral Sclerosis; Animals; Anti-Bacterial Agents; Antibodies; Antibodies, Immobilized; Antigen Presentation; Antigens, CD; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Apoptosis; Aptamers, Nucleotide; Asthma; Asthma, Exercise-Induced; Atrophy; Autophagy; Azoospermia; Bacillus cereus; Bacterial Infections; Beclin-1; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biofouling; Biological Monitoring; Biomarkers; Biomarkers, Tumor; Biosensing Techniques; Blastocyst; Bone Neoplasms; Bone Regeneration; Bronchoconstriction; Burkitt Lymphoma; C9orf72 Protein; Campylobacter; Campylobacter Infections; Campylobacter jejuni; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Pancreatic Ductal; Carcinoma, Squamous Cell; Cardiomyopathies; Caregivers; Carmine; Case-Control Studies; Catalysis; Cattle; Cause of Death; CCAAT-Enhancer-Binding Protein-alpha; CD8-Positive T-Lymphocytes; Cefepime; Cell Differentiation; Cell Line, Tumor; Cell Nucleus; Cell Transdifferentiation; Chelating Agents; Chemical and Drug Induced Liver Injury, Chronic; Chemoradiotherapy, Adjuvant; Child; Child, Preschool; China; Chlorquinaldol; Cholangiocarcinoma; Cholera; Chromatin; Clinical Trials as Topic; Cognitive Dysfunction; Cohort Studies; Colonic Neoplasms; Colorectal Neoplasms; Colorimetry; Cooking; Coordination Complexes; COVID-19; Creatinine; CRISPR-Cas Systems; Critical Care; Critical Illness; Cross-Sectional Studies; Cryopreservation; Cryoprotective Agents; Cysteine; Cytokines; Device Removal; Diet; Diet, High-Fat; Diet, Mediterranean; Dietary Supplements; Dimethyl Sulfoxide; Dipeptides; Disease Models, Animal; Dithiothreitol; DNA; DNA Repeat Expansion; DNA, Bacterial; DNA, Complementary; Dopamine; Electrochemical Techniques; Electrodes; Endocannabinoids; Environmental Exposure; Environmental Monitoring; Environmental Pollutants; Enzyme-Linked Immunosorbent Assay; Erlotinib Hydrochloride; Escherichia coli; Escherichia coli O157; Esophageal Neoplasms; Esophagitis, Peptic; Ethylene Glycol; Europium; Exanthema; Fallopian Tubes; Feces; Female; Fertilization in Vitro; Fluoresceins; Fluorescent Dyes; Follicle Stimulating Hormone; Follow-Up Studies; Food Microbiology; Forced Expiratory Volume; Forkhead Transcription Factors; Frontotemporal Dementia; G-Quadruplexes; Galactose; Gastroenteritis; Gastrointestinal Diseases; Gastrointestinal Microbiome; Gastrointestinal Neoplasms; Gastrointestinal Tract; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genital Neoplasms, Female; Genome-Wide Association Study; Genome, Viral; Genomics; Genotype; Glucose; Glutathione; Glycerol; Gold; Graphite; GTPase-Activating Proteins; Heat-Shock Proteins; Heme Oxygenase-1; Hepacivirus; Hepatitis C; Hepatocytes; Histamine; Histocompatibility Antigens Class II; Hoarseness; Hospice and Palliative Care Nursing; Humans; Hydrogen; Hydrogen Peroxide; Hydrogen Sulfide; Hydroxybenzoates; Hydroxyl Radical; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperthermia, Induced; Hysteroscopy; Immunoassay; Indigo Carmine; Inflammation; Inflammatory Bowel Diseases; Insulin Resistance; Intensive Care Units; Interleukin-11; Interleukin-6; Interleukins; Iodine Radioisotopes; Iran; Iridium; Islets of Langerhans; Kinetics; Lactation; Lactobacillus; Lactobacillus plantarum; Lamins; Latin America; Lead; Lectins; Leukopenia; Ligands; Limit of Detection; Lipopolysaccharides; Lipoprotein Lipase; Liver; Liver Cirrhosis; Liver Neoplasms; Lolium; Luminescent Measurements; Luminol; Lung; Luteinizing Hormone; Macrophages; Magnetic Phenomena; Magnetic Resonance Imaging; Male; Malnutrition; Maltose; Manganese Compounds; Maternal Nutritional Physiological Phenomena; Melatonin; Metabolic Engineering; Metal Nanoparticles; Metallocenes; Metaplasia; Methicillin-Resistant Staphylococcus aureus; Methylation; Mevalonic Acid; Mexico; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microbial Sensitivity Tests; Microbiota; MicroRNAs; Milk; Mitomycin; Molecular Diagnostic Techniques; Molecular Docking Simulation; Monte Carlo Method; Moringa oleifera; Multiple Sclerosis; Muscle Strength; Muscle, Skeletal; Nanocomposites; Nanotubes, Carbon; Neoadjuvant Therapy; Neoplasms; Neurodegenerative Diseases; Neurotransmitter Agents; NF-E2-Related Factor 2; Nickel; Nitrogen Dioxide; Non-alcoholic Fatty Liver Disease; Nucleic Acid Amplification Techniques; Nucleic Acid Hybridization; Nucleocapsid Proteins; Nutritional Status; Obesity; Osteogenesis; Osteosarcoma; Oxidation-Reduction; Oxides; Oxygen; Oxyquinoline; Pain; Palliative Care; Pancreatic Neoplasms; Pandemics; Particulate Matter; Peroxidase; Peroxidases; Phagocytosis; Phaseolus; Photothermal Therapy; Point-of-Care Systems; Polyethyleneimine; Polymers; Polymorphism, Single Nucleotide; Polysomnography; Postoperative Complications; Pregnancy; Pregnant Women; Prenatal Exposure Delayed Effects; Prevalence; Printing, Three-Dimensional; Probability; Probiotics; Prognosis; Prophages; Prospective Studies; Proteomics; Proto-Oncogene Proteins; Pseudomonas aeruginosa; Pseudomonas putida; Pulmonary Disease, Chronic Obstructive; Pulmonary Embolism; Pyridines; Pyrroles; Quality of Life; Quinolones; Rabbits; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; Receptors, Histamine; Receptors, Histamine H2; Recombinases; Rectal Neoplasms; Reperfusion Injury; Respiration; Respiratory Function Tests; Respiratory Rate; Respiratory Sounds; Retrospective Studies; rho GTP-Binding Proteins; Risk Assessment; Risk Factors; RNA; RNA, Messenger; RNA, Ribosomal, 16S; Robotic Surgical Procedures; Running; Rural Population; Saccharomyces cerevisiae; Salpingectomy; Sarcopenia; SARS-CoV-2; Seeds; Semen; Sensitivity and Specificity; Sepsis; Shock, Septic; Signal Transduction; Silicon Dioxide; Silver; Sirtuin 1; Skin Neoplasms; Sleep Apnea, Obstructive; Soil; Spain; Spectrum Analysis, Raman; Sperm Retrieval; Spermatozoa; Spirometry; Staphylococcus aureus; STAT3 Transcription Factor; Stereoisomerism; Sterilization, Tubal; Stroke Volume; Sulfadiazine; Sulfites; Superoxide Dismutase; Surface Plasmon Resonance; tau Proteins; Testis; Testosterone; Thioredoxin-Disulfide Reductase; Thyroid Neoplasms; Thyroidectomy; Trans-Activators; Transcription Factor AP-1; Treatment Outcome; Triazoles; Triclosan; Trifluridine; Tumor Microenvironment; Tumor Necrosis Factor-alpha; United States; Uracil; Vagina; Vegetables; Ventricular Function, Left; Ventricular Pressure; Vibrio cholerae; Vietnam; Virulence; Vital Capacity; Vitrification; Walking; Water; Water Pollutants, Radioactive; Whole Genome Sequencing; Wind; YAP-Signaling Proteins; Zeolites; Zinc Oxide

The randomized phase II VELO trial showed that the addition of panitumumab to trifluridine/tipiracil significantly improves progression-free survival (PFS) as compared to trifluridine/tipiracil in third-line therapy in patients with refractory RAS wild-type (WT) metastatic colorectal cancer (mCRC). With longer follow-up, final overall survival results and posttreatment subgroup analysis are presented. Sixty-two patients with refractory RAS WT mCRC were randomly assigned to receive, as third-line therapy, trifluridine/tipiracil alone (arm A) or in combination with panitumumab (arm B). Primary endpoint was PFS; secondary endpoints included overall survival (OS) and overall response rate (ORR). Median OS was 13.1 months (95% CI 9.5-16.7) in arm A compared to 11.6 months (95% CI 6.3-17.0) in arm B (HR: 0.96, 95% CI 0.54-1.71, P = .9). To evaluate the impact of subsequent lines of treatment, subgroup analysis was performed for the 24/30 patients in arm A, that received fourth-line therapy after disease progression. Median PFS was 4.1 months (95% CI 1.44-6.83) for 17 patients treated with anti-EGFR rechallenge as compared to 3.0 months (95% CI 1.61-4.31) for seven patients that received other therapies (HR: 0.29, 95% CI 0.10-0.85, P = .024). Median OS from the start of fourth-line treatment was 13.6 months (95% CI 7.2-20), and 5.1 months (95% CI 1.8-8.3) for patients treated with anti-EGFR rechallenge vs other therapies, respectively (HR: 0.30, 95% CI 0.11-0.81, P = .019). Final results of the VELO trial support the role of anti-EGFR rechallenge in the continuum of care of patients with RAS/BRAF WT mCRC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; Humans; Panitumumab; Rectal Neoplasms; Trifluridine

Trifluridine/tipiracil (FTD/TPI) prolongs survival in the third- or later-line treatment for advanced gastric cancer (GC), esophagogastric junction (EGJ) adenocarcinoma, and colorectal cancer. While single-arm phase II trials showed promising outcomes of FTD/TPI plus ramucirumab (RAM) as third- or later-line treatments for advanced GC or EGJ cancer, there have been no clinical trials to directly compare FTD/TPI plus RAM with FTD/TPI monotherapy. Therefore, we have started a randomised phase II trial to evaluate the efficacy and safety of FTD/TPI plus RAM compared with FTD/TPI monotherapy as third- or later-line treatments in patients with advanced GC and EGJ adenocarcinoma.. This study will clarify the additional effect of RAM continuation beyond disease progression on FTD/TPI in the third- or later-line setting for patients with advanced GC or EGJ cancer.. jRCTs041220120.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Combinations; Esophagogastric Junction; Frontotemporal Dementia; Humans; Prospective Studies; Ramucirumab; Stomach Neoplasms; Trifluridine; Young Adult

Trifluridine and tipiracil (FTD/TPI) demonstrated survival benefit vs placebo and manageable safety in previously treated patients with metastatic gastric/gastroesophageal junction cancer (mGC/GEJC) in the randomized, placebo-controlled, phase 3 TAGS study. This subgroup analysis of TAGS examined efficacy/safety outcomes by age.. In TAGS, patients with mGC/GEJC and ≥ 2 prior therapies were randomized (2:1) to receive FTD/TPI 35 mg/m. Among 507 randomized patients (n = 337 FTD/TPI; n = 170 placebo), 55%, 45%, and 14% were aged < 65, ≥ 65, and ≥ 75 years, respectively. Overall survival hazard ratios for FTD/TPI vs placebo were 0.67 (95% CI 0.51-0.89), 0.73 (95% CI 0.52-1.02), and 0.67 (95% CI 0.33-1.37) in patients aged < 65, ≥ 65, and ≥ 75 years, respectively. Regardless of age, patients receiving FTD/TPI experienced improved progression-free survival and stayed longer on treatment than those receiving placebo. Among FTD/TPI-treated patients, frequencies of any-cause grade ≥ 3 adverse events (AEs) were similar across age subgroups (80% each), although grade ≥ 3 neutropenia was more frequent in older patients [40% (≥ 65 and ≥ 75 years); 29% (< 65 years)]; AE-related discontinuation rates did not increase with age [14% (< 65 years), 12% (≥ 65 years), and 12% (≥ 75 years)].. The results of this subgroup analysis show the efficacy and tolerability of FTD/TPI treatment regardless of age in patients with mGC/GEJC who had received 2 or more prior treatments.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Combinations; Esophageal Neoplasms; Esophagogastric Junction; Frontotemporal Dementia; Humans; Pyrrolidines; Stomach Neoplasms; Thymine; Trifluridine

Trifluridine/tipiracil (FTD/TPI) improved both overall and progression-free survival (OS, PFS) of patients with pre-treated metastatic colorectal cancer (mCRC) in the pivotal phase III RECOURSE trial. However, health-related quality of life (HRQoL) was not assessed directly. To this end and to generate post-authorisation data, the TALLISUR trial was conducted.. In this prospective, multi-centre, Germany-wide, phase IV study, patients with pre-treated mCRC were given the choice to receive either FTD/TPI or best supportive care (BSC). A validated questionnaire, EORTC QLQ-C30, was employed to assess HRQoL. Secondary endpoints included OS, PFS and safety.. Of 194 eligible patients, 185 decided to receive FTD/TPI and 9 to receive BSC. The low number of patients in the BSC-arm did not allow statistically meaningful analyses. On the other hand, treatment with FTD/TPI was associated with maintained HRQoL. Median OS was 6.9 months [95% confidence interval (CI) 6.1-8.2 months] and median PFS was 2.5 months (95% CI 2.1-2.9 months). The most frequent treatment-emergent adverse events were neutropenia (27.6%) and anaemia (22.7%). Febrile neutropenia occurred in 1.1%.. Treatment of patients suffering from pre-treated mCRC with FTD/TPI was associated not only with prolonged survival and delayed progression but also with maintained HRQoL.

Topics: Colorectal Neoplasms; Humans; Prospective Studies; Pyrrolidines; Quality of Life; Thymine; Trifluridine

Initial systemic therapy for patients with metastatic colorectal cancer (mCRC) is usually based on two- or three-drug chemotherapy regimens with fluoropyrimidine (5-fluorouracil (5-FU) or capecitabine), oxaliplatin and/or irinotecan, combined with either anti-VEGF (bevacizumab) or, for RAS wild-type (WT) tumors, anti-EGFR antibodies (panitumumab or cetuximab). Recommendations for patients who are not eligible for intensive combination therapies are limited and include fluoropyrimidine plus bevacizumab or single agent anti-EGFR antibody treatment. The use of a monochemotherapy concept of trifluridine/ tipiracil in combination with monoclonal antibodies is not approved for first-line therapy, yet. Results from the phase II TASCO trial evaluating trifluridine/ tipiracil plus bevacicumab in first-line treatment of mCRC patients and from the phase I/II APOLLON trial investigating trifluridine/ tipiracil plus panitumumab in pre-treated mCRC patients suggest favourable activity and tolerability of these new therapeutic approaches.. To the best of our knowledge, this is the first phase II trial to evaluate the efficacy of trifluridine/tipiracil plus panitumumab in first-line treatment of RAS WT mCRC patients. The administration of anti-EGFR antibodies rather than anti-VEGF antibodies in combination with trifluridine/tipiracil may result in an increased initial efficacy.. EU Clinical Trials Register (EudraCT) 2019-004223-20 . Registered October 22, 2019, ClinicalTrials.gov NCT05007132 . Registered on August 12, 2021.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Body Weight; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Fluorouracil; Humans; Multicenter Studies as Topic; Panitumumab; Prospective Studies; Pyrrolidines; Randomized Controlled Trials as Topic; Thymine; Trifluridine

Trifluridine/tipiracil (FTD/TPI) showed clinical benefit, including improved survival and manageable safety in previously treated patients with metastatic colorectal (mCRC) or gastric/gastroesophageal junction (mGC/GEJC) cancer in the phase III RECOURSE and TAGS trials, respectively. A pooled analysis was conducted to further characterize FTD/TPI safety, including management of haematologic toxicities and use in patients with renal or hepatic impairment.. TAGS and RECOURSE included 335 and 533 FTD/TPI-treated and 168 and 265 placebo-treated patients, respectively. Overall safety of FTD/TPI was similar in TAGS and RECOURSE. Haematologic (neutropenia, anaemia) and gastrointestinal (nausea, diarrhoea) AEs were most commonly observed. Laboratory-assessed grade 3-4 neutropenia occurred in 37% (TAGS)/38% (RECOURSE) of FTD/TPI-treated patients (median onset: 29 days/55 days), and 96% (TAGS)/97% (RECOURSE) of cases resolved regardless of renal/hepatic function. Supportive medications for neutropenia were received by 17% (TAGS) and 9% (RECOURSE); febrile neutropenia was reported in 2% and 4%, respectively. Overall grade ≥3 AEs were more frequent in patients with moderate renal impairment [81% (TAGS); 85% (RECOURSE)] versus normal renal function (74%; 67%); anaemia and neutropenia were more common in patients with renal impairment. FTD/TPI safety (including haematologic AEs) was consistent across patients with normal and mildly impaired hepatic function.. These results support FTD/TPI as a well-tolerated treatment in patients with mGC/GEJC or mCRC, with a consistent safety profile. Safety was largely similar in patients with normal or mildly impaired renal/hepatic function; however, patients with renal impairment should be monitored for haematologic toxicities.

Topics: Adult; Colonic Neoplasms; Colorectal Neoplasms; Esophagogastric Junction; Frontotemporal Dementia; Humans; Neutropenia; Pyrrolidines; Stomach Neoplasms; Thymine; Trifluridine; Uracil

A previous Phase I/II study demonstrated that TAS-102 (trifluridine/tipiracil [FTD/TPI]) plus bevacizumab (Bev) has encouraging efficacy and controllable safety for patients with previously treated metastatic colorectal cancer. Therefore, we designed for assessing the efficacy and safety of FTD/TPI plus Bev in elderly patients with previously untreated metastatic colorectal cancer.. This is a multicenter, single-arm Phase II study included patients ≥70 years old with previously untreated, unresectable metastatic colorectal cancer. Treatment consisted of FTD/TPI plus Bev given every 4 weeks. The primary endpoint was progression-free survival (PFS), assuming a null hypothesis of a PFS of 5 months. The secondary endpoints were the overall survival (OS), overall response rate (ORR), and adverse events (AEs).. Between 5 January 2017 and 13 March 2018, 39 patients were enrolled from 18 institutions. The median patient age was 76.0 years (range, 70-88); the ECOG-PS was 0 in 24 patients and 1 in 15 patients. The median PFS was 9.4 months as a primary endpoint, and the median OS was 22.4 months. The ORR was 40.5% and the disease control rate was 86.5%. Grade 3-4 AEs included neutropenia (71.8%), leukopenia (51.3%), anorexia (15.4%), febrile neutropenia (10.3%), and fatigue (10.3%).. FTD/TPI plus Bev is an effective and well-tolerated regimen for elderly patients with previously untreated metastatic colorectal cancer. Capecitabine/bevacizumab can be selected as a subsequent maintenance therapy without irinotecan and oxaliplatin because FTD/TPI has no cross-resistance with 5-fluorouracil.. UMIN clinical trials registry (UMIN000025241).

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Female; Follow-Up Studies; Humans; Male; Prognosis; Pyrrolidines; Survival Rate; Thymine; Trifluridine

Although the efficacy of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) against metastatic colorectal cancer (mCRC) has been demonstrated, little is known about its effectiveness upon disease stratification by RAS mutations. In this phase II study, we investigated the efficacy and safety profiles of FTD/TPI in mCRC according to RAS mutation status.. Between January and September 2018, 102 patients were enrolled, and 97 patients fulfilled the eligibility criteria (48 in the RAS WT cohort and 49 in the RAS MUT cohort). DCRs in the RAS WT and MUT cohort were 66.7% [90% confidence interval (CI), 53.9%-77.8%, P = 0.0013] and 55.1% (90% CI, 42.4%-67.3%, P = 0.0780), respectively. The median progression-free survival (PFS) and overall survival (OS) were 3.8 and 9.3 months, respectively, in the RAS WT cohort and 3.5 and 8.4 months, respectively, in the RAS MUT cohort. The most common grade 3 or higher adverse event in both cohorts was neutropenia (46% in the RAS WT cohort and 62% in the RAS MUT cohort), without unexpected safety signals.. FTD/TPI plus bevacizumab showed promising activity with an acceptable safety profile for pretreated mCRC, regardless of RAS mutation status, although the efficacy outcomes tended to be better in RAS WT.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Humans; Mutation; Pyrrolidines; Thymine; Trifluridine

We aimed to assess the safety and efficacy of combination treatment with panitumumab plus trifluridine/tipiracil (FTD/TPI) in patients with wild-type RAS metastatic colorectal cancer (mCRC) who were refractory/intolerant to standard therapies other than anti-epidermal growth factor receptor therapy.. APOLLON was an open-label, multicentre, phase 1/2 trial. In the phase 1 part, 3 + 3 de-escalation design was used to investigate the recommended phase 2 dose (RP2D); all patients in the phase 2 part received the RP2D. The primary endpoint was investigator-assessed progression-free survival (PFS) rate at 6 months. Secondary endpoints included PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), time to treatment failure (TTF), and safety.. Panitumumab plus FTD/TPI exhibited favourable anti-tumour activity with a manageable safety profile and may be a therapeutic option for pre-treated mCRC patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Humans; Panitumumab; Pyrrolidines; Thymine; Trifluridine

Adjuvant chemotherapy has reduced the risk of tumor recurrence and improved survival in patients with resected colorectal cancer. Potential utility of circulating tumor DNA (ctDNA) prior to and post surgery has been reported across various solid tumors. We initiated a new type of adaptive platform trials to evaluate the clinical benefits of ctDNA analysis and refine precision adjuvant therapy for resectable colorectal cancer, named CIRCULATE-Japan including three clinical trials. The GALAXY study is a prospectively conducted large-scale registry designed to monitor ctDNA for patients with clinical stage II to IV or recurrent colorectal cancer who can undergo complete surgical resection. The VEGA trial is a randomized phase III study designed to test whether postoperative surgery alone is noninferior to the standard therapy with capecitabine plus oxaliplatin for 3 months in patients with high-risk stage II or low-risk stage III colon cancer if ctDNA status is negative at week 4 after curative surgery in the GALAXY study. The ALTAIR trial is a double-blind, phase III study designed to establish the superiority of trifluridine/tipiracil as compared with placebo in patients with resected colorectal cancer who show circulating tumor-positive status in the GALAXY study. Therefore, CIRCULATE-Japan encompasses both "de-escalation" and "escalation" trials for ctDNA-negative and -positive patients, respectively, and helps to answer whether measuring ctDNA postoperatively has prognostic and/or predictive value. Our ctDNA-guided adaptive platform trials will accelerate clinical development toward further precision oncology in the field of adjuvant therapy. Analysis of ctDNA status could be utilized as a predictor of risk stratification for recurrence and to monitor the effectiveness of adjuvant chemotherapy. ctDNA is a promising, noninvasive tumor biomarker that can aid in tumor monitoring throughout disease management.

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Circulating Tumor DNA; Colonic Neoplasms; Colorectal Neoplasms; Double-Blind Method; Humans; Japan; Neoplasm Recurrence, Local; Oxaliplatin; Prospective Studies; Pyrrolidines; Thymine; Trifluridine

Trifluridine/tipiracil (FTD/TPI) treatment has shown clinical benefit in patients with pretreated metastatic gastric cancer or gastroesophageal junction cancer (mGC/GEJC). Patients who have undergone gastrectomy constitute a significant proportion of patients with mGC/GEJC.. To assess the efficacy and safety of FTD/TPI among patients with previously treated mGC/GEJC who had or had not undergone gastrectomy.. This preplanned subgroup analysis of TAGS (TAS-102 Gastric Study), a phase 3, randomized, placebo-controlled, clinical trial included patients with mGC/GEJC who had received at least 2 previous chemotherapy regimens, and was conducted at 110 academic hospitals in 17 countries in Europe, Asia, and North America, with enrollment between February 24, 2016, and January 5, 2018; the data cutoff was March 31, 2018.. Patients were randomized 2:1 to receive oral FTD/TPI 35 mg/m2 twice daily or placebo twice daily with best supportive care on days 1 through 5 and days 8 through 12 of each 28-day treatment cycle.. The primary end point was overall survival. This subgroup analysis was conducted to examine potential trends and was not powered for statistical significance. Efficacy and safety end points were evaluated in the subgroups.. Of 507 randomized patients (369 [72.8%] male; mean [SD] age, 62.5 [10.5] years), 221 (43.6%) had undergone gastrectomy (147 randomized to FTD/TPI and 74 to placebo) and 286 (56.4%) had not undergone gastrectomy (190 randomized to FTD/TPI and 96 to placebo). In the gastrectomy subgroup, the overall survival hazard ratio (HR) in the FTD/TPI group vs placebo group was 0.57 (95% CI, 0.41-0.79), and the progression-free survival HR was 0.48 (95% CI, 0.35-0.65). In the no gastrectomy subgroup, the overall survival HR in the FTD/TPI group vs placebo group was 0.80 (95% CI, 0.60-1.06), and the progression-free survival HR was 0.65 (95% CI, 0.49-0.85). Among FTD/TPI-treated patients, grade 3 or higher adverse events of any cause occurred in 122 of 145 patients (84.1%) in the gastrectomy subgroup and 145 of 190 (76.3%) in the no gastrectomy subgroup: 64 (44.1%) in the gastrectomy subgroup and 50 (26.3%) in the no gastrectomy subgroup had grade 3 or higher neutropenia, 31 (21.4%) in the gastrectomy subgroup and 33 (17.4%) in the no gastrectomy subgroup had grade 3 or higher anemia, and 21 (14.5%) in the gastrectomy subgroup and 10 (5.3%) in the no gastrectomy subgroup hD grade 3 or higher leukopenia. In the gastrectomy subgroup, 94 (64.8%) had dosing modifications because of adverse events vs 101 (53.2%) in the no gastrectomy subgroup; 15 (10.3%) in the gastrectomy group and 28 (14.7%) in the no gastrectomy group discontinued treatment because of adverse events. Treatment exposure was similar between groups.. The FTD/TPI treatment was tolerable and provided efficacy benefits among patients with pretreated mGC/GEJC regardless of previous gastrectomy.. ClinicalTrials.gov identifier: NCT02500043.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Combinations; Gastrectomy; Humans; Male; Middle Aged; Pyrrolidines; Stomach Neoplasms; Thymine; Trifluridine

The phase II J003 (N = 169) and phase III RECOURSE (N = 800) trials demonstrated a significant improvement in survival with trifluridine (FTD)/tipiracil (TPI) versus placebo in patients with refractory metastatic colorectal cancer. This post hoc analysis investigated pharmacokinetic data of FTD/TPI exposure and pharmacodynamic markers, such as chemotherapy-induced neutropenia (CIN) and clinical outcomes.. A total of 210 patients from RECOURSE were enrolled in this substudy. A limited sampling approach was used, with three pharmacokinetic samples drawn on day 12 of cycle 1. Patients were categorized as being above or below the median area under the plasma concentration-time curve (AUC) for FTD and TPI. We conducted a post hoc analysis using the entire RECOURSE population to determine the correlations between CIN and clinical outcome. We then carried out a similar analysis on the J003 trial to validate the results.. In the RECOURSE subset, patients in the high FTD AUC group had a significantly increased CIN risk. Analyses of the entire population demonstrated that FTD/TPI-treated patients with CIN of any grade in cycles 1 and 2 had significantly longer median overall survival (OS) and progression-free survival (PFS) than patients who did not develop CIN and patients in the placebo group. Patients who required an FTD/TPI treatment delay had increased OS and PFS versus those in the placebo group and those who did not develop CIN. Similar results were obtained in the J003 cohort.. In RECOURSE, patients with higher FTD drug exposure had an increased CIN risk. FTD/TPI-treated patients who developed CIN had improved OS and PFS versus those in the placebo group and those who did not develop CIN. Similar findings were reported in the J003 cohort, thus validating the RECOURSE results. The occurrence of CIN may be a useful predictor of treatment outcomes for FTD/TPI-treated patients. CLINICALTRIALS.. NCT01607957 (RECOURSE).. JapicCTI-090880 (J003).

Topics: Colorectal Neoplasms; Drug Combinations; Humans; Japan; Neutropenia; Pyrrolidines; Thymine; Trifluridine; Uracil

In RECOURSE (, trifluridine/tipiracil significantly improved overall survival and progression-free survival (PFS) versus placebo in patients with pretreated metastatic colorectal cancer (mCRC). PRECONNECT was designed to further characterise safety and clinical use of trifluridine/tipiracil.. In this ongoing, international, multicentre, open-label trial, patients with pretreated mCRC received oral trifluridine/tipiracil 35 mg/m. 793 patients (median age 62 years) from 13 countries received trifluridine/tipiracil for a median of 2.84 months (IQR 2.64). Adverse events (AEs) were experienced by 96.7%; the most common (≥20% of patients) were neutropaenia, asthenia/fatigue, nausea, anaemia and diarrhoea. Grade ≥3 AEs occurred in 73.9% of patients, with the most common being neutropaenia (39.1% of patients), anaemia (9.8%) and asthenia/fatigue (5.0%). Median PFS was 2.8 months (95% CI 2.7 to 2.9). Median time to Eastern Cooperative Oncology Group performance status deterioration (≥2) was 8.9 months (range 0.03-14.72). There was no clinically relevant change from baseline in QoL.. PRECONNECT showed consistent results with the previously demonstrated safety and efficacy profile of trifluridine/tipiracil, with no new safety concerns identified. QoL was maintained during treatment.. NCT03306394.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Humans; Male; Middle Aged; Patient Reported Outcome Measures; Pyrrolidines; Quality of Life; Thymine; Trifluridine; Vascular Endothelial Growth Factor A

We designed an open-label, noncomparative phase II study to assess the safety and efficacy of first-line treatment with trifluridine/tipiracil plus bevacizumab (TT-B) and capecitabine plus bevacizumab (C-B) in untreated patients with unresectable metastatic colorectal cancer (mCRC) who were not candidates for combination with cytotoxic chemotherapies.. From 29 April 2016 to 29 March 2017, 153 patients were randomly assigned (1:1) to either TT-B (N = 77) or C-B (N = 76). The primary end point was progression-free survival (PFS). The primary PFS analysis was performed after 100 events (radiological progression or death) were observed. Secondary end points included overall survival (OS), quality of life (QoL; QLQ-C30 and QLQ-CR29 questionnaires), and safety.. Median (range) duration of treatment was 7.8 (6.0-9.7) months and 6.2 (4.1-9.1) months in the TT-B and C-B groups, respectively. Median (range) PFS was 9.2 (7.6-11.6) and 7.8 (5.5-10.1) months, respectively. Median (range) OS was 18 (15.2 to NA) and 16.2 (12.5 to NA) months, respectively. QoL questionnaires showed no relevant changes over time for either treatment. Therapies were well tolerated. Patients receiving TT-B had more grade ≥3 neutropenia (47% versus 5% with C-B). Patients receiving C-B had more grade ≥3 hand-foot syndrome (12% versus 0% with TT-B) and grade ≥3 diarrhea (8% versus 1% with TT-B), consistent with the known safety profiles of these agents.. TT-B treatment showed promising clinical activity in untreated patients with unresectable mCRC ineligible for intensive therapy, with an acceptable safety profile and no clinically relevant changes in QoL.. NCT02743221 (ClinicalTrials.gov).

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Colorectal Neoplasms; Fluorouracil; Humans; Pyrrolidines; Quality of Life; Thymine; Trifluridine

This study evaluated the cost utility of regorafenib and trifluridine/tipiracil (T/T) compared with that of best supportive care (BSC) in the treatment of patients with metastatic colorectal cancer previously treated with, or not considered candidates for, available therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies; anti-vascular endothelial growth factor agents; and anti-epidermal growth factor receptor agents, in Japan.. Efficacy data, utility values, and costs were extracted from published studies. The cost and effectiveness of regorafenib and of T/T were compared with those of BSC and examined between the 2 agents over a 5-year time horizon using a partitioned survival analysis. The health outcomes were life-years (LYs) and quality-adjusted life-years (QALYs) gained. The costs were year-2018 revisions to the drug prices and medical fees. The uncertainty and robustness of the model were verified by 1-way sensitivity analysis, probability sensitivity analysis, and scenario analysis compared with different clinical studies. A 2% per-annum discount was applied to expenses and QALYs. The willingness-to-pay threshold used was 5 million Japanese yen (JPY).. Regorafenib and T/T had incremental costs of 11,898,982 JPY (107,781 US dollars [USD]) and 5,000,141 JPY (45,291 USD), incremental effects of 0.249 QALYs (0.280 LYs) and 0.344 QALYs (0.421 LYs), and incremental cost-effectiveness ratios of 47,773,791 JPY (432,734 USD) and 14,550,577 JPY (131,799 USD) per QALY, respectively. Results of sensitivity analyses all exceeded the willingness-to-pay threshold of 15 million JPY. In the comparison of the 2 agents, T/T was a dominant alternative over regorafenib.. As a third-line or later treatment of metastatic colorectal cancer in Japan, T/T is cost-effective compared with BSC, whereas regorafenib is not. It is necessary to adjust the price of regorafenib based on the results of this analysis, with the improvement of clinical parameters such as survival time and adverse events.

Topics: Adult; Colorectal Neoplasms; Cost-Benefit Analysis; Drug Combinations; Humans; Japan; Phenylurea Compounds; Pyridines; Pyrrolidines; Quality-Adjusted Life Years; Thymine; Trifluridine

The choice of treatment in patients with metastatic colorectal cancer (mCRC) is generally influenced by tumour and patient characteristics, treatment efficacy and tolerability, and quality of life. Better patient selection might lead to improved outcomes.. This post hoc exploratory analysis examined the effect of prognostic factors on outcomes in the Randomized, Double-blind, Phase 3 Study of trifluridine tipiracil (FTD/TPI) plus Best Supportive Care (BSC) versus Placebo plus BSC in Patients with mCRC Refractory to Standard Chemotherapies (RECOURSE) trial. Patients were redivided by prognosis into two subgroups: those with <3 metastatic sites at randomisation (low tumour burden) and ≥18 months from diagnosis of metastatic disease to randomisation (indolent disease) were included in the good prognostic characteristics (GPC) subgroup; the remaining patients were considered to have poor prognostic characteristics (PPC).. Low tumour burden and indolent disease were factors of good prognosis in late-line mCRC, with patients experiencing longer progression-free survival and greater overall survival.

Topics: Colorectal Neoplasms; Drug Combinations; Female; Humans; Male; Middle Aged; Prognosis; Pyrrolidines; Quality of Life; Thymine; Trifluridine

Trifluridine/tipiracil (TAS-102) has achieved modest efficacy in the late-line treatment of metastatic colorectal cancer. The present study aimed to explore the clinical efficacy and drug toxicities of TAS-102 for patients with metastatic colorectal cancer in real-world clinical setting.. From October 2020 to February 2022, patients with metastatic colorectal cancer who failed from 2 or more lines of prior therapy and treated with TAS-102 monotherapy, in combination with bevacizumab or immune checkpoint inhibitors (ICIs) were analyzed. The evaluation indicators were progression free survival (PFS), objective response rate , disease control rate (DCR), overall survival (OS) and drug toxicities.. A total of 70 patients were enrolled. The objective response rate and DCR were 1.4% and 68.6%. The median PFS and OS were 6.0 (95% CI: 4.1-7.9) and 10.0 (95% CI: 8.3-11.7) months. Compared with TAS-102 monotherapy and TAS-102 plus ICIs, TAS-102 plus bevacizumab obtained superior DCR (75.9% vs. 50% vs. 40%, P = .047), PFS (6.3m vs. 3.0 m vs. 3.0 m, P = .041) and OS (12.0 m vs. 6.5 m vs. 6.0m, P = .013). Patients without prior regorafenib or fruquintinib therapy obtained better median PFS (6.3 vs. 4.3 m, P = .031) and OS (NR vs. 9.0 m, P = .036). Other indicators, including age, tumor site, KRAS status and use of fluoropyrimidine as last regimen before TAS-102, did not affect the clinical efficacy of TAS-102. The most frequent adverse events were leukopenia, neutropenia, anemia, fatigue, nausea, and vomiting.. In real-world clinical setting, TAS-102 showed consistent clinical efficacy and manageable safety with previous prospective clinical studies. Compared with monotherapy and TAS-102 plus ICIs, TAS-102 plus bevacizumab demonstrated better clinical efficacy for metastatic colorectal cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Colorectal Neoplasms; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Humans; Immune Checkpoint Inhibitors; Rectal Neoplasms; Trifluridine; Uracil

Trifluridine/tipiracil hydrochloride (FTD/TPI, Lonsurf®) is an oral antineoplastic agent that has been approved as late-stage chemotherapy for colorectal cancer. Its major mechanism of action is the dysfunction of tumoral DNA including DNA strand breaks and decreased replication. Fruquintinib (ELUNATE®) is a novel kinase inhibitor that selectively inhibits the vascular endothelial growth factor receptor-1, -2, and -3. In this study, we evaluated the antitumor activity of combination therapy with FTD/TPI and fruquintinib in vivo.. The enhancement of the antitumor effects with FTD/TPI and fruquintinib combination, compared to the single drugs given alone was evaluated using two human colorectal cancer xenografts in nude mouse models. FTD/TPI (200 mg/kg) was orally administered for 5 consecutive days followed by 2 days of rest in a 7-day period. Fruquintinib (10 mg/kg) was orally administered consecutively for 2 and 3 weeks in SW48 and HCT 116 tumor-bearing models, respectively. After treatment with these agents, the microvessel density was evaluated by CD31 immunohistochemical analyses.. In both models, FTD/TPI and fruquintinib significantly inhibited tumor growth, and the activity of the combined treatment was significantly superior to that of either monotherapy. Body weight loss of greater than 20% was not observed in any group. A histochemical analysis showed nuclei enlargement, abnormal mitosis, and karyorrhexis in the FTD/TPI treatment group. The microvessel density in the HCT 116 tumors treated with FTD/TPI and fruquintinib was significantly lower than that in the control group.. The combination of FTD/TPI and fruquintinib could be a promising treatment option for colorectal cancer.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Combinations; Frontotemporal Dementia; Humans; Mice; Trifluridine; Vascular Endothelial Growth Factor A

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.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Drug Combinations; Female; Humans; Male; Middle Aged; Phenylurea Compounds; Pyrrolidines; Retrospective Studies; Thymine; Trifluridine; Uracil

Trifluridine/Tipiracil (TAS-102) and regorafenib are FDA-approved in the United States for treatment of refractory metastatic colorectal cancer (mCRC). FDA approvals of these agents were based on modest improvements in overall survival (OS) compared with best supportive care + placebo in the RECOURSE and CORRECT trials, respectively. This study compared real-world clinical outcomes with the use of these agents.. A nationwide deidentified electronic health record-derived database was reviewed for patients diagnosed with mCRC between 2015 and 2020. Patients who received at least 2 lines of standard systemic therapy followed by treatment with either TAS-102 or regorafenib were included for analysis. Kaplan-Meier and propensity score-weighted proportional hazards models were used to compare survival outcomes between groups.. The records of 22,078 patients with mCRC were reviewed. Of these, 1,937 patients received at least 2 lines of standard therapy followed by regorafenib and/or TAS-102. Median OS for the TAS-102 alone or prior regorafenib group (n=1,016) was 6.66 months (95% CI, 6.16-7.18 months) compared with 6.30 months (95% CI, 5.80-6.79 months) for regorafenib alone or prior to TAS-102 (n=921; P=.36). A propensity score-weighted analysis controlling for potential confounders did not demonstrate a significant difference in survival between groups (hazard ratio, 0.99; 95% CI, 0.90-1.09; P=.82). A subgroup analysis did not identify any significant differences in outcomes regarding age, performance status, tumor sidedness, microsatellite instability status, or RAS/RAF status.. This analysis of real-world data found that OS was similar for patients with mCRC who were treated with TAS-102 compared with regorafenib. Median OS with both agents in a real-world setting was similar to that shown in the clinical trials that led to their approvals. A prospective trial comparing TAS-102 and regorafenib would unlikely change current management of patients with refractory mCRC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; Drug Combinations; Humans; Phenylurea Compounds; Prospective Studies; Rectal Neoplasms; Trifluridine; United States; Uracil

Although combination chemotherapy with trifluridine/tipiracil (TAS-102) and bevacizumab (BEV) is highly effective for metastatic unresectable colorectal cancer (mCRC), this combination chemotherapy often induces nausea and vomiting. To identify risk factors for nausea and vomiting, we investigated the occurrence of nausea and vomiting in mCRC patients treated with TAS-102 and BEV.. Study patients with mCRC received TAS-102 and BEV between March 2016 and December 2021. The status of nausea, vomiting, and antiemetic measures in each course were investigated, and factors involved in the occurrence of nausea and vomiting were analysed by logistic regression analysis.. Data from 57 patients were analysed. The incidence rates of nausea and vomiting during the overall period were 57.9% and 17.5%, respectively. Nausea and vomiting were frequent not only in the early courses but also after the sixth course. Multivariate logistic regression analysis showed that the experience of nausea and vomiting in previous treatment with other agents was significantly associated with nausea and vomiting with TAS-102 and BEV.. The experience of nausea and vomiting in previous treatment was associated with increased risk for nausea and vomiting in mCRC patients treated with TAS-102 and BEV.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Colorectal Neoplasms; Drug Combinations; Humans; Nausea; Rectal Neoplasms; Risk Factors; Trifluridine; Uracil; Vomiting

Irinotecan and trifluridine/tipiracil (FTD/TPI) are fourth-line treatment options after third-line nivolumab for advanced gastric cancer (AGC). However, the efficacy and safety of irinotecan and FTD/TPI in the fourth-line setting after third-line nivolumab remains unclear. This study aimed to evaluate the efficacy and safety of irinotecan and FTD/TPI in the fourth-line setting after third-line nivolumab.. We identified 137 AGC patients treated with nivolumab as third-line treatment in our institute between October 2017 and July 2021. Of these, we recruited 19 AGC patients who initiated irinotecan and 23 AGC patients who initiated FTD/TPI in the fourth-line setting until September 2021.. The median overall survival was 5.83 months for irinotecan and 6.31 months for FTD/TPI. Median time-to-treatment failure was 2.07 months for irinotecan and 1.64 months for FTD/TPI. While the frequency of all-grade diarrhea was higher in irinotecan (36% vs. 17%), grade ≥3 neutropenia tended to be higher in FTD/TPI (21% vs. 35%).. Irinotecan and FTD/TPI may be clinically useful as fourth-line treatments after nivolumab.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Combinations; Frontotemporal Dementia; Humans; Irinotecan; Nivolumab; Stomach Neoplasms; Trifluridine; Uracil

The prospective, multicenter, noninterventional TACTIC study assessed effectiveness and safety of trifluridine/tipiracil (FTD/TPI) in patients with metastatic colorectal cancer (mCRC) in a real-world setting in Germany, thus evaluating the external validity of the findings from the pivotal RECOURSE trial. Primary endpoint was overall survival (OS). Secondary objectives included progression-free survival (PFS), safety, and quality of life (QoL). Subgroups comprised patients with good (<3 metastatic sites at inclusion, ≥18 months from diagnosis of first metastasis to inclusion) or poor (remaining patients) prognostic characteristics (GPC/PPC). GPC without liver metastases was considered best prognostic characteristics (BPC). In total, 307 eligible patients (pretreated or not suitable for other available therapies) were treated with FTD/TPI. Overall, median [95%-CI] OS was 7.4 months [6.4-8.6], median PFS was 2.9 months [2.8-3.3]. In BPC (n = 65) and GPC (n = 176) compared to PPC (n = 124) subgroup, median OS (13.3 [9.1-17.6] vs 8.9 [7.6-9.8] vs 5.1 [4.4-7.0] months) and median PFS (4.0 [3.3-5.3] vs 3.4 [3.0-3.7] vs 2.6 [2.4-2.8] months) were longer. Patient-reported QoL, assessed by validated questionnaires (EQ-5D-5L, PRO-CTCAE), was stable throughout FTD/TPI treatment. Predominant FTD/TPI-related adverse events of grades 3 or 4 were neutropenia (13.0%), leukopenia (7.5%), and anemia (5.2%). Altogether, palliative FTD/TPI therapy in patients with pretreated mCRC was associated with prolonged survival, delayed progression, maintained health-related QoL, and manageable toxicity. Low metastatic burden and indolent disease were favorable prognostic factors for survival. TACTIC confirms the effectiveness and safety of FTD/TPI, highlighting its value in routine clinical practice.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; Drug Combinations; Frontotemporal Dementia; Humans; Prospective Studies; Pyrrolidines; Quality of Life; Rectal Neoplasms; Trifluridine; Uracil

Trifluridine-tipiracil (TAS-102), an oral cytotoxic agent used in adult patients with refractory metastatic colorectal cancer (mCRC), has been associated with neutropenia (chemotherapy-induced neutropenia) (CIN)).. We evaluated the efficacy and safety of TAS-102 in a group of 45 mCRC patients (median age 66 years) in Huelva province, Spain, in a retrospective, multicenter observational study.. We showed that the association between TAS-102 and CIN can be used as a predictor of efficacy. 20% (9/45) of patients with an Eastern Cooperative Oncology Group (ECOG) score of 2 had received at least one previous chemotherapy treatment. Overall, 75.5% (34/45) and 28.9% (13/45) had received anti-VEGF and anti-EGFR monoclonal antibodies, respectively. Additionally, 80% (36/45) of patients had received third-line treatment. The mean treatment period, duration of overall survival (OS), and duration of progression-free survival (PFS) were 3.4, 12, and 4 months, respectively. A partial response was seen in 2 patients (4.3%), and disease stabilization was observed in 10 patients (21.3%). Neutropenia was the most frequent grade 3 - 4 toxicity (46.7%; 21/45). Other findings were anemia (77.8%; 35/45), all grades of neutropenia (73.3%; 33/45), and gastrointestinal toxicity (53.3%; 24/45). The dose of TAS-102 needed to be reduced in 68.9% (31/45) of patients, whereas treatment needed to be interrupted in 80% (36/45) of patients. Grade 3 - 4 neutropenia was a positive prognostic factor for OS (p = 0.023).. A retrospective evaluation shows that grade 3 - 4 neutropenia is an independent predictor of treatment response and survival in patients undergoing routine treatment for mCRC, but this finding needs confirmation in a prospective study.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; Drug Combinations; Humans; Middle Aged; Neutropenia; Prospective Studies; Pyrrolidines; Retrospective Studies; Trifluridine

The systemic treatment options for metastatic colorectal cancer (mCRC) are unsatisfactory, and the disease recurs despite the use of numerous medications and their combinations. Trifluridine/Tipiracil is a relatively new drug used in refractory mCRC. Little is known about its real-world effectiveness and prognostic and predictive factors. Therefore, this study aimed to develop a prognostic model for refractory mCRC treated with Trifluridine/Tipiracil.. We retrospectively evaluated the data from 163 patients who had received Trifluridine/Tipiracil as a third or fourth line of treatment for refractory mCRC.. After starting Trifluridine/Tipiracil, 21.5% of patients survived one year, and the median overall survival after Trifluridine/Tipiracil initiation was 251 days (SD: 17.855; 95%CI: 216-286). Median progression-free survival after Trifluridine/Tipiracil initiation was 56 days (SD: 4.826; 95%CI 47-65). Moreover, the median overall survival from diagnosis was 1333 days (SD: 82.84; 95%CI: 1170-1495). In forward stepwise multivariate Cox regression analysis, initial radical treatment (HR = 0.552, 95% CI 0.372-0.819, p < 0.003), the number of cycles of first-line chemotherapy (HR = 0.978, 95% CI 0.961-0.995, p < 0.011), the number of cycles of second-line chemotherapy (HR = 0.955, 95% CI 0.931-0.98, p < 0.011), BRAF mutation (HR = 3.016, 95% CI = 1.207-7.537, p = 0.018), and hypertension (HR = 0.64, 95% CI = 0.44-0.931, p = 0.02) were all associated with survival after Trifluridine/Tipiracil initiation. Our model and model-based nomogram displayed an AUC of 0.623 for one-year survival estimation in the testing cohort. The C-index for the prediction nomogram was 0.632.. We have developed a prognostic model for refractory mCRC treated with Trifluridine/Tipiracil based on five variables. Moreover, we reported a nomogram which could be used by oncologists in clinic visits on a daily basis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; Drug Combinations; Humans; Neoplasm Recurrence, Local; Prognosis; Pyrrolidines; Rectal Neoplasms; Retrospective Studies; Trifluridine; Uracil

Topics: Bevacizumab; Colorectal Neoplasms; Humans; Trifluridine

Topics: Bevacizumab; Colorectal Neoplasms; Humans; Trifluridine

In the pivotal RECOURSE trial, trifluridine/tipiracil improved survival outcomes in refractory metastatic colorectal cancer (mCRC), while demonstrating an acceptable toxicity profile. Routine clinical practice evidence is important to support the ongoing value of recently approved medicines. Our objective was to assess the utilisation patterns and real-world effectiveness of trifluridine/tipiracil in previously treated mCRC patients.. This was a retrospective observational study including consecutive patients who started trifluridine/tipiracil between 1 April 2018 and 30 September 2019 in the medical oncology departments of three major public hospitals in Portugal. The primary outcome measure was overall survival. Associations between overall survival and patient and tumour characteristics were assessed using multivariate Cox regression analyses.. In total, 111 patients were included in the study, with a mean age of 64 years. From these, 45.9% received two prior lines of treatment, 47.8% had three or more previous lines of treatment and 83.6% had Eastern Cooperative Oncology Group (ECOG) performance status 0-1 at baseline. The median duration of trifluridine/tipiracil treatment was 3.7 cycles (95% confidence interval 3.4-4.1). Most patients (80.4%) remained on their planned dose throughout the trifluridine/tipiracil treatment period, fulfilling 100% relative dose intensity. The median overall survival in the total study cohort was 7.9 months (95% confidence interval 6.4-9.8) and the median progression-free survival was 3.4 months (95% confidence interval 3.2-3.9). The median overall survival was significantly higher in patients with a normal serum lactate dehydrogenase (LDH) level (median overall survival 11.2 months for [135, 205] IU/l LDH [95% confidence interval 8.2-NR] and 13.6 months for [205, 251] IU/l LDH [95% confidence interval 8.2-NR]) and in better fitted (ECOG = 0-1) patients (median overall survival 8.0 months; 95% confidence interval 6.7-10.0). The median time to worsening performance status was 6.2 months (95% confidence interval 5.0-8.0). Treatment discontinuation due to adverse events was low (3.1%).. Our study confirms the effectiveness of trifluridine/tipiracil in real-life mCRC patients. Overall survival and progression-free survival outcomes are consistent with the efficacy profile reported in the earlier randomised RECOURSE clinical trial. Like other real-world studies, we found no additional safety concerns in the use of trifluridine/tipiracil.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; Drug Combinations; Humans; Middle Aged; Rectal Neoplasms; Trifluridine; Uracil

Trifluridine/tipiracil (FTD/TPI) and regorafenib (REG) are standard therapies for refractory metastatic colorectal cancer (mCRC). No results of large real-world data directly comparing FTD/TPI + bevacizumab (BEV) with FTD/TPI or REG monotherapy have been reported. We evaluated the efficacy and safety of FTD/TPI + BEV in a real-world setting.. This retrospective study used a Japanese claims database provided by Medical Data Vision Co., Ltd. (Tokyo, Japan). Eligible patients were aged 20 years and over with a diagnosis of mCRC, and received their first dose of FTD/TPI or REG from 2014 to 2021. The primary endpoint was overall survival (OS) in a propensity score matching (PSM) population in which PSM was carried out by matching using a 1 : 1 ratio for the FTD/TPI + BEV group and the control group (FTD/TPI or REG) by propensity score. To enhance robustness, sensitivity analyses of OS were carried out using the inverse probability treatment weighted (IPTW) approach and the analysis in the all eligible population. Secondary endpoints included time to treatment discontinuation (TTD), incidence of adverse events, and post-treatment.. Eligible population was 2369 for the FTD/TPI + BEV group and 9318 for the control group. The PSM population was 1787 for each group. Median OS (mOS) was longer in the FTD/TPI + BEV group compared to the control group [17.0 versus 11.6 months, hazard ratio (HR) = 0.70, P < 0.001] in the PSM population. Similarly, mOS was longer for the FTD/TPI + BEV group compared to that for the control group in IPTW analyses and in the all eligible population (both HRs = 0.68). Median TTD was 3.3 months for the FTD/TPI + BEV group and 1.8 months for the control group in the PSM population (P < 0.001).. Real-world data showed that FTD/TPI + BEV was significantly associated with OS and TTD compared to FTD/TPI or REG. In clinical practice, FTD/TPI + BEV can be a favorable regimen for refractory mCRC.

Topics: Bevacizumab; Colonic Neoplasms; Colorectal Neoplasms; Frontotemporal Dementia; Humans; Japan; Retrospective Studies; Trifluridine; Uracil

Trifluridine/tipiracil plus VEGF inhibition with ramucirumab (RAM) for advanced gastric cancer (AGC) demonstrated clinical activity with an acceptable toxicity profile in previous phase II trial. However, little is known about its efficacy and safety in clinical practice in comparison with trifluridine/tipiracil monotherapy.. We retrospectively investigated efficacy and safety of trifluridine/tipiracil plus RAM and trifluridine/tipiracil monotherapy as third or later line treatment for AGC patients.. Forty-one patients receiving trifluridine/tipiracil plus RAM and 60 patients receiving trifluridine/tipiracil monotherapy were analyzed. The objective response rate (ORR) and the disease control rate (DCR) were 13.5% and 64.9% in the trifluridine/tipiracil plus RAM group, and 3.8% and 42.3% in the trifluridine/tipiracil monotherapy group, respectively (ORR; P = 0.122, DCR; P = 0.052). The median progression-free survival (PFS) and the median overall survival (OS) were 3.0 months and 7.2 months in the trifluridine/tipiracil plus RAM group, and 1.8 months and 3.8 months in the trifluridine/tipiracil monotherapy group, respectively (HR for PFS = 0.66; P = 0.059, HR for OS = 0.50; P = 0.007). Multivariate analysis showed significantly longer PFS (HR = 0.52; P = 0.011) and OS (HR = 0.51; P = 0.031) in the trifluridine/tipiracil plus RAM group compared to the trifluridine/tipiracil monotherapy group. No unexpected adverse events were observed in both groups.. Trifluridine/tipiracil plus RAM might show favorable anti-tumor activity with an acceptable toxicity profile in comparison with trifluridine/tipiracil monotherapy, suggesting one treatment option for AGC patients in salvage line. The combination needs further evaluation in ongoing randomized trials.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Combinations; Humans; Ramucirumab; Retrospective Studies; Stomach Neoplasms; Trifluridine; Uracil

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.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; Drug Combinations; Frontotemporal Dementia; Humans; Neutropenia; Pyrrolidines; Rectal Neoplasms; Retrospective Studies; Risk Factors; Thymine; Trifluridine; Uracil

The aim of this analysis is to assess the pharmacological costs of trifluridine/tipiracil as first-line treatment in metastatic colorectal cancer (mCRC) patients who were not candidates for combination with cytotoxic chemotherapies.. TASCO1 Trial was considered (153 patients). Differences in costs between the 2 arms (trifluridine/tipiracil plus bevacizumab vs. capecitabine plus bevacizumab) was 9113 € (10 264 USD), with a cost savings of 1982 € (2232 USD) per month of overall survival (OS)-gain.. Trifluridine/tipiracil could be consider a cost-effective treatment also in first-line for mCRC patients who were not candidates for combination with cytotoxic chemotherapies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Colorectal Neoplasms; Cost-Benefit Analysis; Drug Combinations; Humans; Pyrrolidines; Rectal Neoplasms; Thymine; Trifluridine; Uracil

The RECOURSE trial supported trifluridine/tipiracil as a treatment option in metastatic colorectal cancer (mCRC). Subsequent analysis demonstrated that low tumour burden and indolent disease are good prognosis factors improving progression-free survival (PFS) and overall survival (OS). This study aimed to evaluate the impact of prognosis group in the OS, PFS and safety of trifluridine/tipiracil in patients with mCRC.. Single-centre, retrospective, and observational study of patients with mCRC who started trifluridine/tipiracil between February 2018 and July 2019. Patients were divided into good prognosis characteristics (GPC) [low tumour burden (less than 3 metastasis site) and indolent disease (≥18 months from first metastasis diagnosis)] and poor prognostic characteristics (PPC) group [high tumour burden (3 or more metastasis sites) and/or aggressive disease (<18 months since the first metastasis diagnosis)].. Median age was 67 years (48-82), 67.3% of the patients were male, and 65.3% had stage IV disease at baseline. Overall, median OS was 7.5 months (95%CI:5.7-9.3). Twenty-two patients (44.9%) presented GPC and 29 (59.1%) had PPC. GPC patients had longer median OS [11.4 (95%CI:6.2-16.7)] versus 3.9 months [(95%CI: 3.3-4.6),p < 0.0001] and PFS [4.9 (95%CI:3.0-6.9) versus 2.6 months (95%CI:2.2-2.8),p < 0.0001]. These differences were more pronounced in GPC patients with no liver metastasis. Grade ≥3 adverse events incidence didn't vary between GPC and PPC subgroups.. Our study validates the improved trifluridine/tipiracil efficacy in patients with GPC in comparison with PPC while maintaining a well-tolerated safety profile. Indolent disease, low tumour burden and the absence of liver metastasis were shown to be good prognosis factors influencing sustained response to trifluridine/tipiracil.

Topics: Aged; Colonic Neoplasms; Colorectal Neoplasms; Female; Humans; Liver Neoplasms; Male; Portugal; Prognosis; Pyrrolidines; Rectal Neoplasms; Retrospective Studies; Thymine; Trifluridine; Uracil

Regorafenib (R) and trifluridine/tipiracil (FTD/TPI) are of proven efficacy in metastatic colorectal cancer (mCRC) patient's refractory to standard therapies. However, it remains unclear which drug should be administered first.. This French observational study was prospectively conducted in 11 centers between June 2017 and September 2019. All consecutive patients with chemorefractory mCRC and receiving FTD/TPI and/or R were eligible. The aim was to evaluate the efficacy and tolerability of FTD/TPI and/or R in real-world setting with adjusted analysis.. A total of 237 mCRC patients (25% R and 75% FTD/TPI) were enrolled. As compared to R, FTD/TPI patients were significantly older and with more metastatic sites. Median OS and PFS were respectively 6.2 and 2.4 months in the FTD/TPI and 6.6 and 2.1 months in the R group. After matching 46 paired patients according to a propensity score, a trend to a longer OS (P = .58), and a significantly longer PFS (P = .048) were observed in the FTD/TPI group. In the 24% of patients receiving the R/T or T/R sequence, median OS from first treatment was similar. Tolerability profiles were similar to published data and dose reductions were more frequent in the R group.. Efficacy and safety results in this real-world prospective study are in line with phase III trials. In a matched population, PFS was significantly longer in the FTD/TPI group. Despite a limited number of patients, clinical outcomes seemed similar in patients treated with the T/R or R/T sequence.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; Drug Combinations; Frontotemporal Dementia; Humans; Phenylurea Compounds; Prospective Studies; Pyridines; Pyrrolidines; Rectal Neoplasms; Thymine; Trifluridine; Uracil

The RECOURSE trial demonstrated a modest benefit in overall survival (OS) for trifluridine/tipiracil (FTD/TPI) versus placebo in pretreated metastatic colorectal cancer (mCRC) patients. Unfortunately, quality of life (QoL) was not assessed. We evaluated QoL and survival of patients treated with FTD/TPI in daily practice.. QUALITAS is a substudy of the Prospective Dutch CRC cohort (PLCRC). From 150 mCRC patients treated with FTD/TPI, QoL (EORTC QLQ-C30 and QLQ-CR29) was assessed monthly from study entry, and linked to clinical data of the Netherlands Cancer Registry. Joint models were constructed combining mixed effects models with Cox PH models. Primary endpoint was difference in QoL over time (which was deemed clinically relevant if ≥10 points). Secondary endpoints were progression-free survival (PFS), time to treatment failure (TTF), and OS. We analyzed the association between QLQ-C30 Summary Score (QoL-SS) at FTD/TPI initiation (baseline) and survival.. There was no clinically relevant change in QoL-SS from baseline to 10 months post-baseline (i.e. the cut-off point after which 90% of patients had discontinued FTD/TPI treatment): -5.3 [95% CI -8.7;-1.5]. Patients who were treated with FTD/TPI for ≥ 3 months (n = 85) reported 6.3 [1.6;11.1] points higher baseline QoL, compared to patients treated < 3 months (n = 65, "poor responders"). In the latter, time to a clinically relevant QoL deterioration was < 2 months. Median PFS, TTF and OS were 2.9 [2.7;3.1], 3.1 [2.9;3.2] and 7.7 [6.6;8.8] months, respectively. Worse baseline QoL-SS was independently associated with shorter OS (HR 0.45 [0.32;0.63]), PFS (0.63 [0.48;0.83]), and TTF (0.64 [0.47;0.86]).. The maintenance of QoL during FTD/TPI treatment in daily practice supports its use. The QoL deterioration in "poor responders" is likely due to disease progression. The strong association between worse baseline QoL and shorter survival suggests that clinicians should take QoL into account when determining prognosis and treatment strategy for individual patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; Drug Combinations; Frontotemporal Dementia; Humans; Prospective Studies; Pyrrolidines; Quality of Life; Rectal Neoplasms; Thymine; Trifluridine

Trifluridine/tipiracil (TFTD), with or without bevacizumab (Bev), and regorafenib are salvage chemotherapy options for metastatic colorectal cancer (mCRC). Here, we examined the influence of precedent drug on the efficacy of subsequent drug.. The subjects were patients with mCRC who received salvage chemotherapy with TFTD (with/without Bev) followed by regorafenib (TFTD→Rego group/TFTD+Bev→Rego group), or reverse sequence (Rego→TFTD group) at the National Cancer Center Hospital between November 2013 and December 2020. The overall survival (OS), progression-free survival (PFS), disease control rate (DCR), tumor growth rate (TGR), and tumor growth kinetics (TGK) in the first evaluation were assessed in the three groups.. A total of 69 patients, including 27 in the TFTD→Rego group, 13 in the TFTD+Bev→Rego group, and 29 in the Rego→TFTD group, were identified. There were no significant differences in the OS among the three groups, and in the PFS and DCR between the precedent and subsequent therapies in any of the groups. The median TGR (%/month) and TGK (mm/month) in the precedent→subsequent therapy were 50.9→32.7 (p = 0.044) and 8.76→7.79 in the TFTD→Rego group, 25.4→36.1 and 7.49→9.92 in the TFTD+Bev→Rego group, and 40.8→24.4 (p = 0.027) and 8.02→7.20 in the Rego→TFTD group, respectively.. In crossover use of TFTD with/without Bev and regorafenib, both agents showed similar efficacy in terms of the conventional parameters, but the differences observed in the TGR and TGK might suggest some influence of prior regorafenib treatment on the efficacy of subsequent TFTD therapy, and vice versa.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Humans; Neoplasm Recurrence, Local; Phenylurea Compounds; Pyridines; Pyrrolidines; Thymine; Trifluridine; Uracil

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Combinations; Humans; Pyrrolidines; Survivors; Thymine; Trifluridine

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Colorectal Neoplasms; Drug Combinations; Humans; Middle Aged; Prognosis; Pyrrolidines; Rectal Neoplasms; Retrospective Studies; Thymine; Trifluridine; Uracil

The combination of trifluridine-tipiracil and bevacizumab was compared with trifluridine-tipiracil monotherapy in a randomized, open-label, phase II trial, resulting in a statistically significant and clinically relevant improvement in progression-free survival (PFS), with tolerable toxicity in patients with refractory metastatic colorectal cancer (mCRC); however, evidence supporting the role of this combination in a real-world setting is limited.. The aim of our work was to provide further evidence on the activity and safety of this combination in a real-world series of Western mCRC patients refractory or intolerant to previous therapies.. We conducted a retrospective, observational study of patients with mCRC refractory or intolerant to standard therapies. Patients were treated with trifluridine-tipiracil and bevacizumab. Previous therapy with fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab, aflibercept, regorafenib, and cetuximab or panitumumab (only RAS wild-type) was allowed, as was previous participation in clinical trials. Clinicopathological characteristics, overall response rate (ORR), disease control rate (DCR), overall survival (OS), PFS, and safety data were retrospectively collected and analyzed.. We recorded 31 patients treated between 1 December 2017 and 30 June 2022. Median age was 69 years (range 38-82 years), 39% were male, 100% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1, tumor location was left-sided in 77% of cases, 54% had synchronous presentation, 35% were RAS mutant, 3% were BRAF mutant, and 71% underwent primary tumor resection; 64% of patients had liver metastases, 55% had lung metastases, and 23% had peritoneal carcinomatosis. The median number of previous treatment lines was 2 (range 0-5), and 84% of patients received at least one previous anti-angiogenic agent. The ORR and DCR were 3% and 71%, respectively. With a median follow-up of 8 months (range 2-39), median PFS was 6 months (95% confidence interval [CI] 3.1-8.9 months) and median OS was 14 months (95% CI 10.1-17.8 months). Adverse events of any grade were reported in 58% of patients. The most common grade 3-4 toxicities were neutropenia (19%) and anemia (6%); 35% of patients required either dose delays or dose reductions due to toxicity. Granulocyte colony-stimulating factor (G-CSF) prophylaxis was administered either on first or subsequent cycles of treatment in 35% of patients. No treatment-related deaths occurred. Sixty percent of the patients who discontinued treatment eventually received one or more lines of subsequent therapy.. Our series provides further evidence on the activity and safety of the combination of trifluridine-tipiracil and bevacizumab in a real-world series of Western refractory mCRC patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Colorectal Neoplasms; Female; Humans; Male; Middle Aged; Retrospective Studies; Trifluridine; Uracil

Gastric cancer mortality remains among the highest of all cancers. Trifluridine/tipiracil (FTD/TPI) represents Canada's first standard-of-care, third-line, systemic therapy for metastatic gastric/gastroesophageal cancer. We characterized real-world treatment patterns in patients enrolled to receive FTD/TPI through Taiho Pharma Canada's Patient Support Program.. Demographic and clinical information were collected from November 2019 to November 2021 for adult patients with refractory metastatic gastric/gastroesophageal cancer throughout Canada. We examined all variables using descriptive statistics and performed survival and association analyses.. 162 patients enrolled to receive FTD/TPI with a median age of 65 years, 12 of whom had HER2 positive disease. Among 123 patients who started FTD/TPI, median follow-up was 3.1 months and median progression-free survival (PFS) was 3.5 months (95% CI 3.2-4.0). Among 121 patients who discontinued FTD/TPI, median treatment duration was 2.39 cycles (IQR 1.14-3.86). A total of 52% discontinued treatment due to disease progression, and 27% had a dose reduction or delay. On multivariable logistic regression, prior FOLFIRI was a statistically significant predictor of treatment modification.. Through the Patient Support Program, FTD/TPI is an actively utilized treatment option in heavily pretreated metastatic gastric/gastroesophageal cancer, despite its recent introduction. With longer-than-expected treatment duration and PFS, FTD/TPI likely addresses an important unmet need for effective and tolerable therapies in this setting.

Topics: Adult; Aged; Canada; Colorectal Neoplasms; Esophageal Neoplasms; Esophagogastric Junction; Frontotemporal Dementia; Humans; Stomach Neoplasms; Trifluridine; Uracil

To evaluate the cost-effectiveness of trifluridine/tipiracil (FTD/TPI) compared with best supportive care (BSC) for the treatment of patients with metastatic gastric cancer(mGC), including gastroesophageal junction adenocarcinoma(GEJ), who have received at least two prior therapies for metastatic disease and are eligible for third-line treatment, in Greece.. A partitioned survival model was locally adapted from a public payer perspective over a 10-year time horizon. Clinical, safety and utility data were extracted from literature. Resource consumption data obtained from a panel of local experts using a questionnaire developed for the study was combined with unit costs obtained from official sources. All costs reflect the year 2020 (€). Outcomes of the model were patients' life years (LYs) and quality-adjusted life years (QALYs), total costs and incremental cost-effectiveness ratio (ICER) per QALY and LY gained.. The total cost per patient was estimated to be €6,965 for FTD/TPI and €1,906 for BSC, while FTD/TPI was associated with 0.180 and 0.107 increments in LYs and QALYs, respectively, compared with BSC, resulting in an ICER of €47,144 per QALY gained and €28,112 per LY gained.. FTD/TPI was estimated to be a cost-effective treatment option for eligible third line mGC patients, including GEJ in Greece.

Topics: Adenocarcinoma; Colorectal Neoplasms; Cost-Benefit Analysis; Greece; Humans; Pyrrolidines; Quality-Adjusted Life Years; Stomach Neoplasms; Thymine; Trifluridine

In the RECOURSE trial which lead to its accreditation, Lonsurf (trifluridine/tipiracil) was shown to extend progression free survival (PFS) by 1.8 months in metastatic colorectal cancer. This Trust audit aims to assess the average quantity of cycles of Lonsurf received by participants and the length of time it extends PFS. Similarly, to identify how many participants required a dose-reduction or experienced toxicities which necessitated supportive therapies. Quantitative data was collected retrospectively from all participants who had received ≥1 cycle of Lonsurf from The Clatterbridge Cancer Centre (CCC) from 2016 until June 2020. Participant electronic patient records were accessed to identify toxicity grading, length of treatment received, the date progression was identified, if dose reductions were applied and if supportive therapies were administered. Lonsurf extends PFS in patients with metastatic colorectal cancer at CCC by 3.0 months (95% CI: 2.73-3.27) and average treatment length was 2.4 months. However, 78 participants (41.5%) received a dose reduction due to toxicities. A total of 955 toxicities were recorded by participants; the most commonly reported toxicities irrespective of grade were fatigue (33.8%), diarrhoea (13.8%) and nausea (12.3%). The most common grade ≥3 toxicities were constipation and infection. The most frequently utilised supportive therapies were loperamide (49.6%) and domperidone (49.1%). Granulocyte colony stimulating factor (GCSF) was required by patients on 5 occasions (0.3%) in total. Lonsurf extends median PFS in patients with metastatic colorectal cancer by 3.0 months. The most common grade ≥3 toxicities which necessitated supportive therapies or a dose reduction were gastrointestinal and infection.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; Drug Combinations; Humans; Progression-Free Survival; Rectal Neoplasms; Retrospective Studies; Trifluridine; Uracil

The orally administered combination trifluridine/tipiracil has been approved as third line treatment in mCRC, demonstrating survival benefit and acceptable toxicity profile in the phase III RECOURSE study.. We performed a multicenter retrospective real-world analysis of patients with mCRC receiving trifluridine/tipiracil between 2016 and 2019 in eight cancer centers across the United Kingdom.. A total of 236 patients were included with median age of 69 years. All patients had received at least 2 lines of fluoropyrimidine-based chemotherapy doublet with oxaliplatin or irinotecan. About 10% of patients had ECOG ≥ 2. Median duration of trifluridine/tipiracil treatment was 3 months with an ORR of 2.1% and disease control rate of 21.6%. Median OS was 7.6 and median PFS 3.3 months. A dose reduction was required in 27% of patients, while 7.6% discontinued treatment due to toxicity. The most common grade 3 toxicities were neutropenia (34%), fatigue (10%), anemia (9%) and febrile neutropenia (5%). Baseline NLR <5 and CEA <200 had favorable prognostic (HR: 0.52 and 0.39, P≤ .001) and predictive value (OR: 4.1 and 6.7, P< .05). Development of grade 3 neutropenia predicted treatment response (OR: 0.32, P< .001). Following treatment with trifluridine/tipiracil 41% were referred for phase I trial or rechallenged with chemotherapy.. Trifluridine/tipiracil is well tolerated in refractory mCRC patients with comparable efficacy and toxicity profile to that of the phase III RECOURSE. Pretreatment NLR and CEA could serve as potential markers for patient selection, while treatment-induced grade 3 neutropenia predicted response. Prospective validation is needed.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Humans; Prognosis; Pyrrolidines; Retrospective Studies; Thymine; Trifluridine; Uracil

Recently, trifluridine/tipiracil (FTD/TPI) treatment was established as a later-line treatment for metastatic colorectal cancer (mCRC). However, FTD/TPI treatment is frequently associated with hematological toxicity. The aim of this study was to evaluate the efficacy and safety of FTD/TPI in elderly patients with mCRC in a real-world setting.. We retrospectively reviewed the medical records of 74 patients with mCRC who were treated with FTD/TPI.. The treatment effect of the elderly patient group was not inferior to that of the younger patient group. Although the incidence of hematological toxicity in the elderly patient group was higher than that in the younger patient group, there were no significant differences in the rate of treatment discontinuation due to adverse events between the two groups.. In elderly patients with mCRC, FTD/TPI treatment was effective for prolonging survival. However, it should be noted that elderly patients showed a higher rate of hematological toxicity than younger patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Humans; Male; Progression-Free Survival; Pyrrolidines; Retrospective Studies; Thymine; Trifluridine

Although the effectiveness of trifluridine/tipiracil(TFTD)with bevacizumab for unresectable colorectal cancer that was refractory to previous standard chemotherapy was reported, its effectiveness as a first-line treatment, especially for elderly frail patients, is unclear. An 85-year-old woman complaining of anorexia was diagnosed with unresectable sigmoid colon cancer with multiple metastases. Her general status was very poor, and her performance status(PS)was 4. We first performed laparoscopic transverse colostomy. As her general status gradually improved, we administered TFTD with bevacizumab as a first-line treatment based on the patient's strong request for chemotherapy. The patient underwent this regimen in the outpatient clinic for 9 months(9 courses). Although the size of the liver metastases increased, lung metastases and abdominal disseminations were under control and her PS became 0. She has been taking mFOLFOX6 with bevacizumab (80%)as a second-line treatment. TFTD with bevacizumab treatment was safe and efficacious as a first-line treatment for a frail elderly patient with unresectable colorectal cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Female; Frail Elderly; Humans; Liver Neoplasms; Pyrrolidines; Thymine; Trifluridine

Regorafenib (REG) and trifluridine/tipiracil (FTD/TPI) have have been shown to improve overall survival in patients with refractory metastatic colorectal cancer. The aim of our study was to evaluate the efficacy and safety profiles of these agents administered in sequence in real world practice.. Clinical data of patients treated beyond the 2°line with REG or FTD/TPI between January 2016 and August 2020, were retrospectively collected from eight institutes in the Lazio Region.. We included 49 patients treated with both drug sequences. A total of 28 G3/G4 toxicity events (53.8%) were recorded in the FTD/TPI-to-REG sequence vs. 24 (46.1%) in the reverse sequence. Median overall survival for the patients included in the FTP/TPI-to-REG group was 20 months (95%CI=16.7-23.3) vs. 27 months in the reverse group (95%CI=17.8-36.2). The disease control rate was 45.0% for patients treated with the REG-to-FTD/TPI sequence vs. 24.1% in those treated with the FTD/TPI-to-REG sequence (p=0.18).. The sequence REG-to-FTD/TPI and vice versa can extend survival, whereas only REG-to-FTD/TPI stabilizes cancer growth.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Phenylurea Compounds; Progression-Free Survival; Pyridines; Pyrrolidines; Thymine; Trifluridine

Nivolumab and trifluridine/tipiracil have significantly improved the overall survival of patients with heavily pretreated metastatic gastric cancer in different placebo-controlled phase III trials. Accordingly, nivolumab and trifluridine/tipiracil have been approved and recommended for patients with heavily pretreated metastatic gastric cancer in Japan. The aim of this study was to assess the cost-effectiveness of trifluridine/tipiracil against nivolumab.. A partitioned survival model, which consisted of three health states, namely, 'pre-progression,' 'post-progression,' and 'death,' was constructed. Efficacy and safety data were derived from the TAGS and ATTRACTION-2 trials. Costs were estimated based on the standard clinical pathway and national insurance fee schedules. One-way and probabilistic sensitivity analyses were performed. The threshold value was set to JPY 7 500 000 (USD 68 182) for each quality-adjusted life-year.. The expected median overall survival and progression-free survival were 5.59 and 1.99 months for trifluridine/tipiracil and 5.26 and 1.55 months for nivolumab, respectively. The quality-adjusted life-year and expected costs per patient were 0.4379 and JPY 2 054 625 (USD 18 678) for trifluridine/tipiracil and 0.5295 and JPY 5 018 148 (USD 45 620) for nivolumab, respectively. The expected median progression-free survival and overall survival were equivalent with trifluridine/tipiracil and nivolumab, whereas the expected quality-adjusted life-year with trifluridine/tipiracil was slightly lower than that with nivolumab. However, trifluridine/tipiracil reduced the total treatment cost by JPY 2 963 523 (USD 26 996) compared with that of nivolumab. The incremental cost-effectiveness ratio of nivolumab versus trifluridine/tipiracil was JPY 32 352 489 (USD 294 113) per quality-adjusted life-year gained.. Trifluridine/tipiracil was more cost-effective than nivolumab for patients with heavily pretreated metastatic gastric cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Cost-Benefit Analysis; Drug Combinations; Humans; Japan; Nivolumab; Pyrrolidines; Stomach Neoplasms; Thymine; Trifluridine; Uracil

Metastatic gastric cancer and cancer of the esophagogastric junction (GC/EGJ) is an aggressive disease with poor prognosis. In the TAGS study, trifluridine/tipiracil (FTD/TPI) improved overall survival (OS) compared with placebo in heavily pre-treated patients. This unplanned, exploratory subgroup analysis of the TAGS study aimed to clarify outcomes when FTD/TPI was used as third-line (3L) treatment and fourth- or later-line (4L+) treatment.. Patients were divided into a 3L group (126 and 64 in FTD/TPI and placebo arms, respectively) and 4L+ group (211 and 106 in FTD/TPI and placebo arms, respectively). Endpoints included OS, progression-free survival (PFS), time to Eastern Cooperative Oncology Group performance status (ECOG PS) deterioration to ≥2, and safety.. Baseline characteristics were generally well balanced between FTD/TPI and placebo for 3L and 4L+ treatment. Median OS (mOS) for FTD/TPI versus placebo was: 6.8 versus 3.2 months {hazard ratio (HR) [95% confidence interval (CI)] = 0.68 (0.47-0.97), P = 0.0318} in the 3L group; and 5.2 versus 3.7 months [0.73 (0.55-0.95), P = 0.0192] in the 4L+ group. Median PFS for FTD/TPI versus placebo was 3.1 versus 1.9 months [0.54 (0.38-0.77), P = 0.0004] in the 3L group; and 1.9 versus 1.8 months [0.57 (0.44-0.74), P < 0.0001] in the 4L+ group. Time to deterioration of ECOG PS to ≥2 for FTD/TPI versus placebo was 4.8 versus 2.0 months [HR (95% CI) = 0.60 (0.42-0.86), P = 0.0049] in the 3L group; and 4.0 versus 2.5 months [0.75 (0.57-0.98), P = 0.0329] in the 4L+ group. The safety of FTD/TPI was consistent in all subgroups.. This analysis confirms the efficacy and safety of FTD/TPI in patients with GC/EGJ in third and later lines with a survival benefit that seems slightly superior in 3L treatment. When FTD/TPI is taken in 3L as recommended in the international guidelines, physicians can expect to provide patients with an mOS of 6.8 months.

Topics: Colorectal Neoplasms; Humans; Pyrrolidines; Stomach Neoplasms; Thymine; Trifluridine; Uracil

In the UK, Trifluridine-tipiracil (Lonsurf) is used to treat metastatic colorectal cancer in the third-line setting, after prior exposure to fluoropyrimidine-based regimes. Current data on the real-world use of Lonsurf lack long-term follow-up data. A retrospective evaluation of patients receiving Lonsurf at our Cancer Centre in 2016-2017 was performed, all with a minimum of two-year follow-up. Fifty-six patients were included in the review. The median number of cycles of Lonsurf administered was 3. Median follow-up was 6.0 months, with all patients deceased at the time of analysis. Median progression-free survival (PFS) was 3.2 months, and overall survival (OS) was 5.8 months. The median interval from Lonsurf discontinuation to death was two months, but seven patients received further systemic treatment and median OS gained was 12 months. Lonsurf offered a slightly better PFS but inferior OS to that of the RECOURSE trial, with PFS similar to real-world data previously presented. Interestingly, 12.5% had a PFS > 9 months, and this cohort had primarily left-sided and RAS wild-type disease. A subset received further systemic treatment on Lonsurf discontinuation with good additional OS benefit. Lonsurf may alter the course of disease for a subset of patients, and further treatment on progression can be considered in carefully selected patients.

Topics: Colorectal Neoplasms; Drug Combinations; Humans; Pyrrolidines; Retrospective Studies; Thymine; Trifluridine; United Kingdom

Trifluridine/tipiracil (FTD/TPI) and regorafenib prolong survival for patients with refractory metastatic colorectal cancer (mCRC); limited comparative effectiveness data exist.. A retrospective, longitudinal cohort study of patients with mCRC who initiated FTD/TPI or regorafenib (index therapy) between 2012 and 2017 at a U.S. tertiary oncology center, Dana-Farber Cancer Institute, was conducted. Using best tumor response assessments, real-world overall response rates (rwORR) and disease control rates (rwDCR) were described and analyzed using logistic regression. Survival rate was examined for each month after index therapy using Kaplan-Meier. Overall survival (OS) was assessed using Cox proportional hazards models. Subgroup analyses among patients with index therapy as second- or third-line were performed.. One hundred twenty-six and 95 patients were treated with FTD/TPI or regorafenib as index therapy, respectively. Patients treated with FTD/TPI versus regorafenib had a better response (rwORR 52.5% vs. 34.2%; adjusted odds ratio [OR] = 2.6; all p value <.05; rwDCR 64.2% vs. 46.1%; adjusted OR = 2.5; all p value <.05). Similar findings were observed for FTD/TPI versus regorafenib as second- or third-line therapy (rwORR 54.8% vs. 25.9%; adjusted OR = 4.1; all p value <.05; rwDCR 69.0% vs. 37.0%; adjusted OR = 4.9; all p value <.05). A greater proportion of patients treated with FTD/TPI versus regorafenib survived at 3 months (86.2% vs. 73.4%; p value = .016) and 4 months (79.6% vs. 65.8%; p value = .017). Adjusted OS hazard ratio for FTD/TPI versus regorafenib was 0.80, p value = .157.. Patients treated with FTD/TPI had better tumor response and disease control than patients treated with regorafenib. Subgroup analysis in second- or third-line suggests that early use of FTD/TPI may have clinical benefits.. In this retrospective cohort study, patients with refractory metastatic colorectal cancer treated with trifluridine/tipiracil (FTD/TPI) were significantly less likely than those treated with regorafenib to have dose modifications and more likely to have higher real-world objective response rate (rwORR) and real-world disease control rate (rwDCR) while treated. Patients treated with FTD/TPI versus regorafenib had significantly higher odds of having rwORR or rwDCR in adjusted analyses. Monthly survival rates were higher overall in patients treated with FTD/TPI versus regorafenib in the first 6 months of follow-up, particularly at months 3 and 4. This study offers insight into patients' treatment experience in real-world clinical settings.

Topics: Colorectal Neoplasms; Humans; Longitudinal Studies; Phenylurea Compounds; Pyridines; Pyrrolidines; Retrospective Studies; Thymine; Trifluridine

Trifluridine and tipiracil (FTD + TPI) and regorafenib (REG) are approved treatments for the treatment of refractory metastatic colorectal cancer (mCRC). This study assesses adherence and duration of therapy with FTD + TPI versus REG and explores the effect of sequencing on adherence.. Adults diagnosed with mCRC were identified in the IQVIA Real-World Data Adjudicated Claims: U.S. database (October 2014-July 2017). The observation period spanned from the index date (first dispensing of FTD + TPI or REG) to the earliest of a switch to another mCRC agent, the end of continuous enrollment, or the end of data availability. Medication possession ratio (MPR), proportion of days covered (PDC), and persistence and time to discontinuation (gap ≥45 days) were compared between FTD + TPI and REG users and among switchers (FTD + TPI-to-REG vs. REG-to-FTD + TPI).. A total of 469 FTD + TPI and 311 REG users were identified. FTD + TPI users had higher compliance with an MPR ≥80% (odds ratio [OR], 2.47; p < .001) and PDC ≥80% (OR, 2.77; p < .001). FTD + TPI users had better persistence (82.8% vs. 68.0%; p < .001) and lower risk of discontinuation (hazard ratio [HR], 0.76; p = .006). Among switchers (96 FTD + TPI-to-REG; 83 REG-to-FTD + TPI), those switching from FTD + TPI to REG were more likely to have an MPR ≥80% (OR, 2.91; p < .001) and PDC ≥80% (OR, 4.60; p < .001) compared with REG-to-FTD + TPI switchers while treated with these drugs. Additionally, FTD + TPI-to-REG switchers had a lower risk of first treatment discontinuation (HR, 0.66; p = .009).. FTD + TPI users had significantly higher adherence and persistence, and patients who were treated with FTD + TPI before switching to REG also had higher adherence and persistence outcomes.. Trifluridine plus tipiracil (FTD + TPI) and regorafenib (REG) prolong survival in refractory metastatic colorectal cancer (mCRC) but have different tolerability profiles. This study assessed real-world adherence to treatment with FTD + TPI versus REG and compared outcomes among patients who switched from FTD + TPI to REG and vice versa. FTD + TPI was associated with significantly higher medication adherence and longer time to discontinuation than REG. Patients treated with FTD + TPI prior to switching to REG also showed higher adherence outcomes. Findings could help inform decision making regarding the choice and sequencing of treatment with FTD + TPI versus REG in patients with mCRC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Colorectal Neoplasms; Drug Combinations; Female; Humans; Longitudinal Studies; Male; Medication Adherence; Middle Aged; Neoplasm Metastasis; Phenylurea Compounds; Pyridines; Pyrrolidines; Retrospective Studies; Thymine; Trifluridine

Topics: Colorectal Neoplasms; Drug Combinations; Humans; Neutropenia; Pyrrolidines; Thymine; Trifluridine; Uracil

Topics: Colorectal Neoplasms; Humans; Neutropenia; Pyrrolidines; Thymine; Trifluridine

Topics: Colorectal Neoplasms; Humans; Neutropenia; Pyrrolidines; Thymine; Trifluridine

Topics: Colorectal Neoplasms; Cost-Benefit Analysis; Drug Combinations; England; Humans; Pyrrolidines; Thymine; Trifluridine; Uracil; Wales

Topics: Bevacizumab; Colorectal Neoplasms; Drug Combinations; Humans; Pyrrolidines; Thymine; Trifluridine

Quality of life (qol) is important for oncology patients, especially for those with late-stage disease. The present study was initiated to address the lack of published prospective data about the qol benefits of trifluridine/tipiracil (ftd/tpi) compared with best supportive care (bsc) in patients with refractory metastatic colorectal cancer (mcrc).. This prospective, cross-sectional, non-interventional study used multidimensional validated scales to evaluate patient-reported qol in two study cohorts of patients and also to measure differences in mcrc-related symptoms and pain in a real-world clinical setting.. Our findings demonstrate that patients with refractory mcrc report better overall qol when treated with ftd/tpi than with bsc alone. In that population, statistically significant differences in mean qol measures favoured ftd/tpi over bsc for physical symptom distress, psychological distress, activity impairment, overall valuation of life, and symptomatology. The overall better qol for patients receiving ftd/tpi implies that treatment was well tolerated and was associated with a lower symptom burden. No significant differences for pain were observed between the groups.. This study suggests that ftd/tpi is a well-tolerated option for the treatment of patients with refractory mcrc, showcasing the value of capturing real-world qol data in routine clinical practice.

Topics: Antineoplastic Agents; Colorectal Neoplasms; Cross-Sectional Studies; Female; Humans; Male; Prospective Studies; Pyrrolidines; Quality of Life; Thymine; Trifluridine

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Combinations; Humans; Phenylurea Compounds; Pyridines; Pyrrolidines; Thymine; Trifluridine

TAGS trial revealed the efficacy and safety of trifluridine/tipiracil(Lonsurf®)treatment in patients with metastatic gastric cancer following gastrectomy. Here, we successfully treated 38 months survival case after recurrences following radical gastrectomy for advanced adenocarcinoma of esophago-gastric junction using historical recommended chemotherapy regimens and trifluridine/tipiracil as a fifth-line chemotherapy. Trifluridine/tipiracil therapy contributed to effective and safety treatment even in late-line chemotherapy for recurrent gastric cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Combinations; Humans; Neoplasm Recurrence, Local; Pyrrolidines; Stomach Neoplasms; Survivors; Thymine; Trifluridine; Uracil

To evaluate the cost-effectiveness of trifluridine and tipiracil hydrochloride (FTD/TPI) compared with best supportive care (BSC) or regorafenib for the treatment of patients with metastatic colorectal cancer who have been previously treated with or are not considered candidates for available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents and anti-EGFR agents in Greece.. A partitioned survival model was locally adapted from a third-party payer perspective over a 10 year time horizon. Efficacy data and utility values were extracted from published studies. Resource consumption data were obtained from local experts using a questionnaire developed for the purpose of the study and was combined with unit costs obtained from official sources. All costs reflect the year 2017 in euros. Primary outcomes were patients' life years (LYs), quality-adjusted life years (QALYs), total costs and incremental cost-effectiveness ratios (ICERs) per QALY and LYs gained.. Total life time cost per patient for FTD/TPI, BSC and regorafenib was estimated to be €10,087, €1,879 and €10,850, respectively. In terms of health outcomes, FTD/TPI was associated with 0.25 and 0.11 increment in LYs compared with BSC and regorafenib, respectively. Furthermore, FTD/TPI was associated with 0.17, and 0.07 increment in QALYs compared with BSC and regorafenib, resulting in ICERs of €32,759 per LY gained and €49,326 per QALY gained versus BSC. Moreover, FTD/TPI was a dominant alternative over regorafenib.. The results indicate that FTD/TPI may represent a cost-effective treatment option compared with other alternative therapies as a third-line treatment of metastatic colorectal cancer in Greece.

Topics: Adult; Antimetabolites; Colorectal Neoplasms; Cost-Benefit Analysis; Greece; Humans; Pyrrolidines; Survival Analysis; Thymine; Trifluridine

Despite major progress in treating advanced colorectal cancer (CRC), prognosis in this population after progression on standard treatment remains dismal and the development of new drugs represents an unmet need. Historically, fluoropyrimidines have played a major role in the treatment of metastatic CRC. TAS-102, a novel combination of trifluridine and tipiracil hydrochloride, has demonstrated improvement in overall survival in the refractory CRC setting, with a safe toxicity profile. Areas covered: A literature review of published clinical studies was performed. Herein, the authors review the pharmacological and clinical data of TAS-102 when used in metastatic CRC, both as a single agent as well as in novel combinations under investigation. Expert opinion: The addition of TAS-102 to the therapeutic armamentarium of metastatic CRC is an encouraging breakthrough considering the demonstrated survival benefit and favorable tolerability profile. Combinations with other agents are under clinical investigation in different settings in an attempt to widen its use. To optimize treatment in today's era of molecular oncology, efforts should be focused on understanding primary and secondary resistance mechanisms, along with the identification of potential biomarkers of response.

Topics: Colorectal Neoplasms; Drug Combinations; Humans; Prognosis; Pyrrolidines; Thymine; Trifluridine; Uracil

Topics: Colorectal Neoplasms; Humans; Phenylurea Compounds; Pyridines; Pyrrolidines; Retrospective Studies; Thymine; Trifluridine

Topics: Colorectal Neoplasms; Double-Blind Method; Drug Combinations; Humans; Progression-Free Survival; Pyrrolidines; Respect; Thymine; Trifluridine; Uracil

Salvage chemotherapy for refractory metastatic colorectal cancer using trifluridine/tipiracil (FTD/TPI) and regorafenib has shown survival benefits. We evaluated the antitumor effects of FTD or FTD/TPI combined with regorafenib in vitro and in vivo. SW620, HCT 116, and HT-29 human colorectal cancer cell lines were treated with FTD and regorafenib simultaneously and sequentially. Cell death, incorporation of FTD into DNA, and molecules related to FTD and regorafenib-associated cell death were investigated. The antitumor effects of FTD combined with regorafenib in SW620 and COLO205 xenografts were also evaluated. Cell death was greater after sequential treatment with FTD followed by regorafenib in SW620 cells, but not in HCT 116 and HT-29 cells, than after treatment with FTD alone, which was attributable to thymidylate synthase reduction with the induction of apoptosis. In contrast, simultaneous and sequential exposure to regorafenib followed by FTD, but not FTD alone, attenuated the cell death effect. Furthermore, combined FTD/TPI treatment followed by regorafenib had greater antitumor activity than either monotherapy in SW620 and COLO205 xenograft models. Treatment results following regorafenib administration subsequent to FTD or FTD/TPI suggest that sequential therapy with FTD/TPI prior to regorafenib may be effective in a clinical setting.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Colorectal Neoplasms; Humans; Male; Mice, Nude; Phenylurea Compounds; Pyridines; Pyrrolidines; Thymine; Trifluridine

Trifluridine/tipiracil (TAS-102, Lonsurf®), a novel oral anti-tumor agent combining an anti-neoplastic thymidine-based nucleoside analogue (trifluridine, FTD) with a thymidine phosphorylase inhibitor (tipiracil hydrochloride, TPI) presents a new treatment option for metastatic colorectal cancer (mCRC) patients refractory or intolerant to standard therapies. FTD/TPI was approved in the European Union (EU) in April 2016 and launched on the German market in August 15, 2016.. We investigated the characteristics of patients (pts) with mCRC treated with FTD/TPI at 118 centers in Germany from January 12 to August 14, 2016 and analyzed the safety in a clinical real-world setting.. In Germany, a total of 226 mCRC patients were included into a compassionate-use-program (CUP) and received FTD/TPI. For 45.5% of patients (n = 101), 253 adverse events (AE) were documented, most of them drug-related (n = 135). From January 12 (2016) to March 2 (2017), 124 serious adverse events (SAE) were reported (74 drug related). The most common serious adverse drug reactions (SADR) were leukopenia (12 events), neutropenia (8 events), anemia (7 events), diarrhea and nausea (5 events each) (observation period January 12 2016 to October 7 2016). In total, 122 patients (54%) discontinued FTD/TPI treatment, mostly due to progression (n = 75) followed by AEs (n = 21), deaths (n = 16), and non-specified reasons (n = 16). Interestingly, 12 patients with ECOG PS ≥2 achieved up to 3 cycles of FTD/TPI and in this patient population only 3 treatment discontinuations due to AEs were documented and the safety profile was comparable to the entire population.. The patient characteristics as well as the safety profile of FTD/TPI documented in the German CUP were consistent with those reported in the pivotal trial RECOURSE without unexpected safety signals.

Topics: Aged; Antineoplastic Agents; Colorectal Neoplasms; Compassionate Use Trials; Drug-Related Side Effects and Adverse Reactions; Female; Germany; Humans; Male; Middle Aged; Prospective Studies; Pyrrolidines; Thymine; Trifluridine

Professor Alfredo Falcone and Dr Lisa Salvatore speak to Roshaine Gunawardana, Managing Commissioning Editor: Professor Alfredo Falcone is the Director of the Department of Oncology and the Specialization School at the University Hospital of Pisa, Italy. He trained in Pisa and Genoa, Italy, and has held major positions in Italian oncology since 2000. He currently has more than 300 publications, including papers in peer-reviewed international and national journals, book chapters, and more than 600 abstracts of presentations to international and national conferences. The majority of his papers regard clinical and translational research, with a particular focus on metastatic colorectal cancer. Dr Lisa Salvatore is a medical oncologist in the Department of Translational Research and New Technologies in Medicine and Surgery at the University of Pisa. She has been an author on about 40 publications in major peer-reviewed publications and has made numerous presentations in national and international conferences. Her main interest is focused on clinical and translational research in metastatic colorectal cancer.

Topics: Achievement; Antineoplastic Combined Chemotherapy Protocols; Career Choice; Clinical Trials as Topic; Colorectal Neoplasms; Disease Management; Drug Discovery; Humans; Neoplasm Metastasis; Neoplasm Staging; Pyrrolidines; Research; Thymine; Treatment Outcome; Trifluridine

A novel oral agent that consists of trifluridine and tipiracil hydrochloride (TFTD) has been established as salvage-line treatment for metastatic colorectal cancer (mCRC). Adherence to TFTD is crucial to maintaining appropriate curative effects. This study sought to clarify adherence to TFTD and identify candidate factors deteriorating adherence at our institution.. A total of 50 consecutive mCRC patients who received TFTD monotherapy between June 1, 2014 and July 31, 2015 were analyzed in this study. Adherence to TFTD was checked by pharmacists using a self-reported treatment diary and interviewing nonadherents at a pharmaceutical outpatient clinic. The adherence rate was defined as the number of patient intakes per 20 scheduled intakes in one cycle. We retrospectively surveyed the factors from the electronic patient record associated with reduced adherence. We measured relative dose intensity, defined as the dose intensity divided by the initial dose (each in milligrams per square meter per week).. Patient characteristics were as follows: males/females, 20/30; median age, 61 years (range, 34-83 years); performance status 0/1, 37/13. Median relative dose intensity of TFTD was 91.0%. Adherence rates were 95.0% for the first cycle of TFTD, 97.3% for the second cycle, 98.0% for the third cycle, and 98.2% for the fourth cycle. Factors associated with deteriorated adherence to TFTD were nausea/vomiting/decreased appetite (27.1%, 23 instances), pain (25.9%, 22 instances), neutropenia (11.8%, 10 instances), and missed dose (4.7%, 4 instances). Increased nonadherence to TFTD was associated with Eastern Cooperative Oncology Group performance status 1, while increased TFTD adherence in the first cycle was associated with prior regimens ≥4.. The high frequency of treatment-related gastrointestinal disorder is the main factor affecting adherence to TFTD. Intensive supportive care in the management of these symptoms could assist adequate adherence to TFTD in mCRC patients.

Topics: Abdominal Pain; Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Appetite; Colorectal Neoplasms; Female; Humans; Male; Medication Adherence; Middle Aged; Nausea; Neutropenia; Pyrrolidines; Retrospective Studies; Self Report; Thymine; Trifluridine; Vomiting

Trifluridine/tipiracil (TFTD) is a combination drug that is used for the treatment of metastatic colorectal cancer and was formerly known as TAS-102. It is a combination of two active pharmaceutical compounds, trifluridine, an antineoplastic thymidine-based nucleoside analog, and tipiracil, which enhances the bioavailability of trifluridine in vivo. TFTD is used for the treatment of patients with unresectable advanced or recurrent colorectal cancer that is resistant to standard therapies. In the present study, the anticancer effects of trifluridine in combination with nintedanib, an oral triple angiokinase inhibitor, on human colorectal cancer cell lines were investigated. The cytotoxicity against DLD-1, HT-29, and HCT116 cell lines was determined by the crystal violet staining method. The combination of trifluridine and nintedanib exerted an additive effect on the growth inhibition of DLD-1 and HT-29 cells and a sub-additive effect on HCT116 cells, as determined by isobologram analyses. Subsequently, the human colorectal cancer cell lines were implanted subcutaneously into nude mice to allow the evaluation of the in vivo tumor growth inhibitory effects of TFTD and nintedanib combination therapy. TFTD (150 mg/kg/day) and/or nintedanib (40 mg/kg/day) were orally administered to the mice twice daily from day 1 to day 14. The tumor growth inhibition with combination therapy was 61.5, 72.8, 67.6 and 67.5% for the DLD-1, DLD-1/5-FU, HT-29, and HCT116 xenografts, respectively. This was significantly (P<0.05) higher than the effects of monotherapy with either TFTD or nintedanib. These results demonstrated the effectiveness of the combination of TFTD and nintedanib in the treatment of colorectal cancer xenografts. The concentration of trifluridine incorporated into DNA in the HT-29 and HCT116 tumors was determined by liquid chromatography-tandem mass spectrometry. The incorporation levels following treatment with TFTD and nintedanib for 14 consecutive days were higher than those associated with TFTD treatment alone. The preclinical findings indicate that the combination therapy with TFTD and nintedanib is a promising treatment option for colorectal cancer.

Topics: Administration, Oral; Animals; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; HCT116 Cells; HT29 Cells; Humans; Indoles; Inhibitory Concentration 50; Male; Mice, Inbred BALB C; Mice, Nude; Pyrrolidines; Thymine; Trifluridine; Tumor Burden; Xenograft Model Antitumor Assays