Initial Attack on Latent Metastasis Using TAS-102 for ct DNA Identified Colorectal Cancer Patients After Curative Resection
Ontology highlight
ABSTRACT:
DISEASE(S): Trifluridine And Tipiracil,Colorectal Neoplasms,Circulating Tumor Dna,Neoplasms
PROVIDER: 2344525 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
Similar Datasets
Project description:Integrative analysis of colorectal cancer (CRC) whole genomes and matched transcriptomes revealed that somatic promoter mutations are associated with increased Chromodomain helicase DNA-binding protein 2 (CHD2) levels. In both primary and metastatic CRC patients, elevated CHD2 levels are associated with worse prognosis and overall survival. We find that CHD2 increases promoter-transcription start site-chromatin accessibility and transcriptional upregulation of multiple oncogenes. In vitro, elevated CHD2 promoted CRC cell proliferation, migration and growth. In orthotopic xenografts, CHD2 promoted higher tumor burden and abdominal metastases, most prominently to the liver. FTD/TPI is an FDA approved chemotherapy for advanced chemo-refractory CRC. In orthotopic CRC models, FTD/TPI was highly effective in reducing metastases and prolonging survival for CHD2 high expressing CRCs. Thus, high CHD2 expression may be a potential CRC chemopredictive biomarker for FTD/TPI. Overall, these results provide new insights into the role of non-coding mutations and CHD2 levels to promote CRC growth and metastasis.
2021-02-12 | GSE146398 | GEO
Project description:Intervention name : Lonsurf combination tablet T15/T20
INN of the intervention : trifluridine + tipiracil hydrochloride
Dosage And administration of the intervention : In 1 course consisting of 28 days, FTD/TPI or placebo will be orally administered twice daily after breakfast and after dinner for 5 consecutive days (Days 1 to 5 and Days 8 to 12), followed by withdrawal for 2 days. After repeating this cycle twice, the subject is withdrawn from study treatment for 14 days.
Control intervention name : Placebo
INN of the control intervention : -
Dosage And administration of the control intervention : In 1 course consisting of 28 days, FTD/TPI or placebo will be orally administered twice daily after breakfast and after dinner for 5 consecutive days (Days 1 to 5 and Days 8 to 12), followed by withdrawal for 2 days. After repeating this cycle twice, the subject is withdrawn from study treatment for 14 days.
Primary outcome(s): efficacy
Disease-Free Survival 1 (DFS1)
The time from the date of enrollment to any of the following events, whichever occurs first: a relapse, the first development of a secondary large intestine carcinoma lesion other than a relapse (an intramucosal cancer lesion will not be treated as an event) that is confirmed after the date of enrollment, and death from any cause. In principle, events will be assessed by the investigator.
Study Design: This trial is a randomized, double-blind, multinational Phase III study to evaluate the efficacy and safety of preemptive treatment with FTD/TPI compared with administration of placebo as follow-up, which is the standard of care, in patients who underwent curative resection of colorectal cancer and then tested positive for ctDNA.
| 2658591 | ecrin-mdr-crc
Project description:The purpose of this study is to evaluate the combination of panitumumab and Triflridine/Tipiracil (FTD/TPI; TAS-102) in patients with RAS wild-type metastatic colorectal cancer (CRC) refractory to standard chemotherapy (oxaliplatin, fluoropyrimidines, irinotecan and angiogenesis inhibitors).
| 2202964 | ecrin-mdr-crc
Project description:BackgroundsAs a new oral chemotherapy drug, TAS-102 is currently recommended as the third-line treatment for metastatic colorectal cancer (mCRC). Recently, studies have reported the efficacy of TAS-102 combined with bevacizumab in colon cancer patients after standard treatment fails. Here, we evaluated the efficacy and safety of TAS-102 combined with bevacizumab versus TAS-102 as a single agent by a systematic review and a meta-analysis.MethodsPubMed, Web of Science and Cochrane libraries were searched. Studies involving bevacizumab combined with TAS-102 in mCRC were included. Study characteristics (author, year of publication, country et al.), efficacy (disease control rate(DCR), progression-free survival(PFS), overall survival(OS)) and adverse effects were extract from studies. Forest plots were created based on Cox model analysis.ResultsAfter screening 550 studies, a total of 3 studies were included, which compared the safety and effectiveness of TAS-102 with or without bevacizumab. Analysis based on Cox regression showed that the combined treatment group had advantages in 6-month (OR= 2.93, 95% CI: 1.72 to 5.00, P<0.0001), 12-month(OR= 2.18, 95% CI: 1.24 to 3.81, P=0.006), and 18-month (OR=3.08, 95% CI: 1.34 to 7.12, P=0.008) OS. The combined treatment group demonstrated superiority in 6-month PFS rates (OR= 2.50, 95% CI: 1.18 to 5.31, P=0.02). The incidence of thrombocytopenia in the dual-drug treatment group was higher (OR= 1.96, 95% CI: 1.14 to 3.36 P=0.01). The proportion of serious adverse events were similar in tow groups (OR= 1.01, 95% CI: 0.76 to 1.34 P=0.93).ConclusionBevacizumab combined with TAS-102 could improve the prognosis of patients with mCRC who have failed standard treatment. In terms of side effects, the addition of bevacizumab did not increase serious adverse reactions, but the occurrence of thrombocytopenia was worth noting.
| S-EPMC8637322 | biostudies-literature
Project description:Interventions: investigational material(s)
Generic name etc : Lonsurf combination tablet T15/T20
INN of investigational material : trifluridine + tipiracil hydrochloride
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : In 1 course consisting of 28 days, FTD/TPI or placebo will be orally administered twice daily after breakfast and after dinner for 5 consecutive days (Days 1 to 5 and Days 8 to 12), followed by withdrawal for 2 days. After repeating this cycle twice, the subject is withdrawn from study treatment for 14 days.
control material(s)
Generic name etc : Placebo
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : In 1 course consisting of 28 days, FTD/TPI or placebo will be orally administered twice daily after breakfast and after dinner for 5 consecutive days (Days 1 to 5 and Days 8 to 12), followed by withdrawal for 2 days. After repeating this cycle twice, the subject is withdrawn from study treatment for 14 days.
Primary outcome(s): efficacy
Disease-Free Survival 1 (DFS1)
The time from the date of enrollment to any of the following events, whichever occurs first: a relapse, the first development of a secondary large intestine carcinoma lesion other than a relapse (an intramucosal cancer lesion will not be treated as an event) that is confirmed after the date of enrollment, and death from any cause. In principle, events will be assessed by the investigator.
Study Design: This trial is a randomized, double-blind, multinational Phase III study to evaluate the efficacy and safety of preemptive treatment with FTD/TPI compared with administration of placebo as follow-up, which is the standard of care, in patients who underwent curative resection of colorectal cancer and then tested positive for ctDNA.
| 102757 | ecrin-mdr-crc
Project description:Interventions: A: FTD/TPI monotherapy
FTD/TPI (35 mg/m2 given orally twice daily on days 1-5 and 8-12 in a 28-day cycle)
B: Bi-weekly FTD/TPI+BEV combination
Bi-weekly FTD/TPI (35 mg/m2 given orally twice daily on days 1-5 in a 14-day cycle) with BEV (5 mg/kg on day1, every 2 weeks)
Primary outcome(s): Overall survival
Study Design: randomized controlled trial, open(masking not used), active control, parallel assignment, treatment purpose
| 2614546 | ecrin-mdr-crc
Project description:Interventions: Patients will receive biweekly FTD/TPI (35mg twice daily on days 1-5, every 2 weeks) with BEV (5mg/kg on day 1, every 2weeks).Between second cycles and fourth cycles, the dose of FTD/TPI will be escalated if patients meet criteria of FTD/TPI dose escalation.
Primary outcome(s): Disease control rate
Study Design: single arm study, open(masking not used), uncontrolled control, single assignment, treatment purpose
| 78988 | ecrin-mdr-crc
Project description:Trifluridine/tipiracil (TAS-102) is an oral chemotherapy approved for the treatment of metastatic colorectal cancer. The efficacy and tolerability of TAS-102 were shown in phase II-III clinical trials and in several real-life studies. The elderly and other special subgroups are underrepresented in published literature. We conducted a retrospective multicenter study to assess the effectiveness and safety of TAS-102 in consecutive patients with pretreated mCRC. In particular, we estimated the effectiveness and safety of TAS-102 in elderly patients (aged ≥70, ≥75 and ≥80 years) and in special subgroups, e.g., patients with concomitant heart disease. One hundred and sixty patients were enrolled. In particular, 71 patients (44%) were 70 years of age or older, 50 (31%) were 75 years of age or older, and 23 (14%) were 80 years of age or older. 19 patients (12%) had a concomitant chronic heart disease, three (2%) patients were HIV positive, and one (<1%) patient had a DPYD gene polymorphism. In 115 (72%) cases TAS-102 was administered as a third-line treatment. The median overall survival (OS) in the overall population was 8 months (95% confidence interval [CI], 6-9), while the median progression-free survival (PFS) was 3 months (95% CI, 3-4). No significant age-related reduction in effectiveness was observed in the subpopulations of elderly patients included. The toxicity profile was acceptable in both the whole and subgroups' population. Our study confirms the effectiveness and safety of TAS-102 in patients with pretreated mCRC, suggesting a similar risk-benefit profile in the elderly.
| S-EPMC10340604 | biostudies-literature
Project description:Inhibition of nucleoside metabolism is an important principle in cancer therapy as evidenced by the role of fluoropyrimidines, such as 5-fluorouracil (5-FU), and antifolates in the treatment of many cancers. TAS-102 is an oral combination therapy consisting of trifluridine (FTD), a thymidine-based nucleoside analog, plus tipiracil hydrochloride (TPI), a novel thymidine phosphorylase inhibitor that improves the bioavailability of FTD. TAS-102 has demonstrated efficacy in 5-FU-refractory patients based on a different mechanism of action and has been approved for the treatment of metastatic colorectal cancer in Japan. This review describes the mechanism of action of TAS-102, highlighting key differences between TAS-102 and 5-FU-based therapies. While both FTD and 5-FU inhibit thymidylate synthase (TS), a central enzyme in DNA synthesis, sufficient TS inhibition by FTD requires continuous infusion; therefore, it is not considered a clinically relevant mechanism with oral dosing. Instead, the primary cytotoxic mechanism with twice-daily oral dosing, the schedule used in TAS-102 clinical development, is DNA incorporation. FTD incorporation into DNA induces DNA dysfunction, including DNA strand breaks. Uracil-based analogs such as 5-FU may also be incorporated into DNA; however, they are immediately cleaved off by uracil-DNA glycosylases, reducing their ability to damage DNA. Moreover, the TPI component may enhance the durability of response to FTD. With its distinct mechanism of action and metabolism, TAS-102 is a promising treatment option for patients resistant to or intolerant of 5-FU-based fluoropyrimidines.
| S-EPMC4624296 | biostudies-literature
Project description:Current National Comprehensive Cancer Network (NCCN) and European Society of Medical Oncology (ESMO) guidelines recommend regorafenib or trifluridine/tipiracil (TAS-102) for the third-line therapy of metastatic colorectal cancer (mCRC). In this analysis, we evaluated hospitalizations during regorafenib or TAS-102 treatment and the impact of hospitalizations on overall survival (OS). This retrospective analysis was based on unselected, consecutive mCRC patients treated with regorafenib and/or TAS-102 at the tertiary cancer centers in Salzburg and Wels-Grieskirchen, Austria. Between January 2013 and May 2019, 93 patients started third- or fourth-line therapy with regorafenib or TAS-102. Tumor therapy (regorafenib versus TAS-102, HR: 1.95 [95% CI: 1.07-3.54], p = 0.03) and the Eastern Cooperative Oncology Group (ECOG) performance status (2-3 versus 0-1, HR: 4.04 [95% CI: 2.11-7.71], p < 0.001) showed a statistically significant association with hospitalization risk in multivariate analysis. The corresponding hospitalization probability from initiation of third- or fourth-line was 30% with regorafenib versus 18% with TAS-102 at five weeks and 41% versus 28% at ten weeks, respectively. Hospitalizations irrespective of cause during regorafenib or TAS-102 therapy did neither impact median survival in patients undergoing only third-line therapy (never-hospitalized: 5.7 months [95% CI: 3.9-10.5] versus hospitalized: 5.4 months [95% CI: 2.8-9.6], p = 0.45), nor in patients receiving third- and fourth-line therapy (12.2 months [95% CI: 10.6-28.8] versus 18.6 months [95% CI: 6.3-not reached], p = 0.90). In conclusion, apart from poor ECOG performance status, regorafenib therapy was associated with an increased hospitalization probability during palliative systemic third- and fourth-line therapy in mCRC. However, hospitalizations during regorafenib or TAS-102 therapy did not impact OS beyond second-line therapy.
| S-EPMC7599669 | biostudies-literature