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Trifluridine/tipiracil and regorafenib: new weapons in the war against metastatic colorectal cancer.Clinical Advances in Hematology &... Aug 2016Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States. Approximately 20% of patients have metastatic disease at diagnosis, and... (Review)
Review
Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States. Approximately 20% of patients have metastatic disease at diagnosis, and a vast number of these patients die within 5 years. The advent of modern chemotherapeutics has improved median overall survival for these patients; nonetheless, we must keep striving for better outcomes. Trifluridine/tipiracil (TAS-102) and regorafenib are agents newly approved by the US Food and Drug Administration that show promise in the treatment of metastatic colorectal cancer. These drugs have the benefit of being formulated for oral administration and have different side effect profiles. These differences are important in the selection of the best therapy for each patient, especially if the patient is prone to a side effect that is unique to just one of the treatments. In this review, we discuss the mechanism of action, side effect profile, and clinical efficacy of trifluridine/tipiracil, and compare them with those of regorafenib. Future trials will evaluate the use of these drugs in earlier lines of therapy, alone and in combination with other agents. We now have 2 more agents in the arsenal against metastatic colorectal cancer and the future is looking brighter for patients, although we still have a long way to go.
Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colorectal Neoplasms; Humans; Neoplasm Metastasis; Phenylurea Compounds; Pyridines; Treatment Outcome; Trifluridine
PubMed: 27487107
DOI: No ID Found -
Expert Opinion on Drug Safety Jun 2018TAS102 is an oral thymidine-based nucleoside analog that has been approved for the treatment of patients with metastatic colorectal cancer (mCRC) previously treated... (Review)
Review
TAS102 is an oral thymidine-based nucleoside analog that has been approved for the treatment of patients with metastatic colorectal cancer (mCRC) previously treated with, or not candidates for, available therapies including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies, anti-vascular endothelial growth factor (VEGF) agents and, if RAS wild-type, anti-epidermal growth factor receptor (EGFR) therapy. The pivotal RECOURSE phase III trial demonstrated a significant improvement in disease control rate, progression-free survival (PFS), and overall survival (OS) as compared with placebo in patients with refractory mCRC. Areas covered: This manuscript aims to review the clinical development of TAS102 in CRC, with a particular focus on safety, and to provide some perspective regarding its role in clinical practice. A literature search was conducted of MEDLINE and EMBASE databases for published studies (January 2004-December 2016) using the search terms TAS102, trifluridine-tipiracil, metastatic or advanced CRC, clinical trial, toxicity, safety, pharmacology, pharmacokinetics, and therapy. Expert opinion: TAS102 significantly improves survival of patients with refractory mCRC and has manageable toxicity. An expanding role in the treatment of CRC is expected for TAS102 in the near future, as its favorable safety profile makes TAS102 a suitable drug to be combined with other cytotoxic and targeted agents.
Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Drug Combinations; Humans; Molecular Targeted Therapy; Neoplasm Metastasis; Pyrrolidines; Survival Rate; Thymine; Treatment Outcome; Trifluridine; Uracil
PubMed: 29745737
DOI: 10.1080/14740338.2018.1475557 -
Current Oncology (Toronto, Ont.) May 2023Colorectal cancer is the most prevalent gastrointestinal neoplasm. When metastatic, the disease has limited systemic treatment options. Novel targeted therapies have... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSION
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: Humans; Bevacizumab; Uracil; Colorectal Neoplasms; Trifluridine; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Rectal Neoplasms
PubMed: 37366880
DOI: 10.3390/curroncol30060397 -
International Journal of Cancer Oct 2023The randomized phase II VELO trial showed that the addition of panitumumab to trifluridine/tipiracil significantly improves progression-free survival (PFS) as compared... (Randomized Controlled Trial)
Randomized Controlled Trial
Panitumumab plus trifluridine/tipiracil as anti-EGFR rechallenge therapy in patients with refractory RAS wild-type metastatic colorectal cancer: Overall survival and subgroup analysis of the randomized phase II VELO trial.
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: Humans; Panitumumab; Colorectal Neoplasms; Trifluridine; Colonic Neoplasms; Rectal Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37391938
DOI: 10.1002/ijc.34632 -
Drugs May 1982Trifluridine (trifluorothymidine) is an antiviral agent for topical use in the eye, and is structurally related to idoxuridine. In vitro studies have shown that it... (Review)
Review
Trifluridine (trifluorothymidine) is an antiviral agent for topical use in the eye, and is structurally related to idoxuridine. In vitro studies have shown that it effectively inhibits the replication of herpes simplex virus type 1, which causes primary keratoconjunctivitis and recurrent epithelial keratitis in man. In masked comparative studies, predominantly in patients with dendritic ulcers, trifluridine 1% solution was effective in over 90% of patients; in such studies it was comparable with vidarabine in treating dendritic ulcers, and was at least as effective as, and in some studies more effective than, idoxuridine. The drug was also effective in treating a small number of patients with geographic ulcers (sometimes associated with the usage of topical corticosteroids), and this could be an important advantage if confirmed in further well-designed studies. However, experience at present is too limited to reliably determine the usual response rate in this difficult therapeutic area. In open studies the drug proved to be particularly useful in treating ulcers previously unresponsive to idoxuridine or vidarabine, and in treating patients intolerant of idoxuridine, with a high success rate and minimal side effects being reported. The role of trifluridine in treating deep stromal disease, uveitis, or adenovirus kerato-conjunctivitis has not been established. The drug is well tolerated and cross-hypersensitivity and cross-toxicity between trifluridine, idoxuridine and vidarabine are rare. Thus, trifluridine is an effective alternative to the drugs available for treating herpetic keratitis, and seems especially useful in 'difficult' cases.
Topics: Adenoviridae Infections; Animals; Antiviral Agents; Eye; Eye Diseases; Humans; Keratitis; Keratitis, Dendritic; Kinetics; Thymidine; Trifluridine; Virus Diseases
PubMed: 6284470
DOI: 10.2165/00003495-198223050-00001 -
Cancer Science Dec 2023Despite advanced therapeutics, esophageal squamous cell carcinoma (ESCC) remains one of the deadliest cancers. Here, we propose a novel therapeutic strategy based on...
Despite advanced therapeutics, esophageal squamous cell carcinoma (ESCC) remains one of the deadliest cancers. Here, we propose a novel therapeutic strategy based on synthetic lethality combining trifluridine/tipiracil and MK1775 (WEE1 inhibitor) as a treatment for ESCC. This study demonstrates that trifluridine induces single-strand DNA damage in ESCC cells, as evidenced by phosphorylated replication protein 32. The DNA damage response includes cyclin-dependent kinase 1 (CDK1) (Tyr15) phosphorylation as CDK1 inhibition and a decrease of the proportion of phospho-histone H3 (p-hH3)-positive cells, indicating cell cycle arrest at the G2 phase before mitosis entry. The WEE1 inhibitor remarkedly suppressed CDK1 phosphorylation (Try15) and reactivated CDK1, and also increased the proportion of p-hH3-positive cells, which indicates an increase of the number of cells into mitosis. Trifluridine combined with a WEE1 inhibitor increased trifluridine-mediated DNA damage, namely DNA double-strand breaks, as shown by increased γ-H2AX expression. Moreover, the combination treatment with trifluridine/tipiracil and a WEE1 inhibitor significantly suppressed tumor growth of ESCC-derived xenograft models. Hence, our novel combination treatment with trifluridine/tipiracil and a WEE1 inhibitor is considered a candidate treatment strategy for ESCC.
Topics: Humans; Esophageal Squamous Cell Carcinoma; Trifluridine; Esophageal Neoplasms; Phosphorylation; Histones; Cell Cycle Proteins; Cell Line, Tumor; Protein-Tyrosine Kinases
PubMed: 37724648
DOI: 10.1111/cas.15966 -
Current Oncology (Toronto, Ont.) Dec 2022Gastric cancer mortality remains among the highest of all cancers. Trifluridine/tipiracil (FTD/TPI) represents Canada's first standard-of-care, third-line, systemic...
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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; Humans; Colorectal Neoplasms; Esophageal Neoplasms; Esophagogastric Junction; Frontotemporal Dementia; Stomach Neoplasms; Trifluridine; Uracil; Canada
PubMed: 36661660
DOI: 10.3390/curroncol30010011 -
Gan To Kagaku Ryoho. Cancer &... Jan 2016Treatment options for patients with metastatic colorectal cancer (mCRC), who are refractory to standard chemotherapy, are limited. In a global multicenter randomized... (Review)
Review
Treatment options for patients with metastatic colorectal cancer (mCRC), who are refractory to standard chemotherapy, are limited. In a global multicenter randomized double-blind phase III study (RECOURSE study), TAS-102 (TFTD) administration significantly improved overall survival rate with favorable safety profile in mCRC patients refractory to standard chemotherapy (HR=0.68, p<0.001). TFTD was approved initially in Japan in March 2014 and is currently under review by health authorities in the United States and Europe. TFTD is expected to play an important role in salvage-line treatment for patients with mCRC. In this review, we present the history of its clinical development and the experimental data that elucidate the underlying molecular mechanism of action of TFTD and its key component, trifluridine.
Topics: Animals; Cell Cycle; Colorectal Neoplasms; DNA; Drug Combinations; Drug Design; Drug Resistance, Neoplasm; Humans; Pyrrolidines; Thymine; Trifluridine; Uracil
PubMed: 26809521
DOI: No ID Found -
Gastric Cancer : Official Journal of... Nov 2023Trifluridine/tipiracil plus VEGF inhibition with ramucirumab (RAM) for advanced gastric cancer (AGC) demonstrated clinical activity with an acceptable toxicity profile...
Efficacy and safety of trifluridine/tipiracil plus ramucirumab in comparison with trifluridine/tipiracil monotherapy for patients with advanced gastric cancer-single institutional experience.
BACKGROUND
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.
METHODS
We retrospectively investigated efficacy and safety of trifluridine/tipiracil plus RAM and trifluridine/tipiracil monotherapy as third or later line treatment for AGC patients.
RESULTS
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.
CONCLUSIONS
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: Humans; Uracil; Stomach Neoplasms; Trifluridine; Retrospective Studies; Colorectal Neoplasms; Drug Combinations; Antineoplastic Combined Chemotherapy Protocols; Ramucirumab
PubMed: 37665515
DOI: 10.1007/s10120-023-01427-9 -
Scientific Reports Jul 2022Understanding the immunological effects of chemotherapy is of great importance, especially now that we have entered an era where ever-increasing pre-clinical and...
Understanding the immunological effects of chemotherapy is of great importance, especially now that we have entered an era where ever-increasing pre-clinical and clinical efforts are put into combining chemotherapy and immunotherapy to combat cancer. Single-cell RNA sequencing (scRNA-seq) has proved to be a powerful technique with a broad range of applications, studies evaluating drug effects in co-cultures of tumor and immune cells are however scarce. We treated a co-culture comprised of human colorectal cancer (CRC) cells and peripheral blood mononuclear cells (PBMCs) with the nucleoside analogue trifluridine (FTD) and used scRNA-seq to analyze posttreatment gene expression profiles in thousands of individual cancer and immune cells concurrently. ScRNA-seq recapitulated major mechanisms of action previously described for FTD and provided new insight into possible treatment-induced effects on T-cell mediated antitumor responses.
Topics: Colorectal Neoplasms; Frontotemporal Dementia; Humans; Leukocytes, Mononuclear; Pyrrolidines; Single-Cell Analysis; Thymine; Trifluridine
PubMed: 35831404
DOI: 10.1038/s41598-022-16077-7