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PURPOSE: This phase I trial is to determine the recommended dose of the TAS-102, irinotecan plus bevacizumab regimen and assess its safety and efficacy in patients with metastatic colorectal cancer refractory to fluoropyrimidine and oxaliplatin treatment. METHODS: A 3 + 3 designed dose escalation was performed. Patients were administered TAS-102 (30-35 mg/m2 twice daily on days 1-5) and irinotecan (150-165 mg/m2 on day 1) combined with a fixed dose of bevacizumab (5 mg/kg on day 1) every two weeks. The primary endpoint was the determination of the recommended phase II dose. RESULTS: Eighteen patients were enrolled: 6 at the Level 1 (TAS-102 30 mg/m2 twice daily, irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg), six at the Level 2 (TAS-102 35 mg/m2 twice daily, irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg), and six at the Level 3 (TAS-102 30 mg/m2 twice daily, irinotecan 165 mg/m2 plus bevacizumab 5 mg/kg). Five dose-limiting toxicities occurred: one observed at Level 1 (thrombocytopenia), two at Level 2 (neutropenia and diarrhea), and two at Level 3 (fatigue and neutropenia). The RP2D was established as TAS-102 30 mg/m2 twice daily and irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg. The most frequent grade 3/4 treatment-related adverse events were neutropenia (33.3%), diarrhea (16.7%), and thrombocytopenia (11.1%). No treatment-related death occurred. Two patients (11.1%) experienced partial responses and 14 (77.8%) had stable disease. CONCLUSION: The regimen of TAS-102, irinotecan, and bevacizumab is tolerable with antitumor activity for metastatic colorectal cancer patients refractory to first-line fluoropyrimidines and oxaliplatin treatment.
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Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Neoplasias Colorrectales , Combinación de Medicamentos , Irinotecán , Pirrolidinas , Timina , Trifluridina , Uracilo , Humanos , Timina/administración & dosificación , Trifluridina/administración & dosificación , Trifluridina/uso terapéutico , Trifluridina/efectos adversos , Bevacizumab/administración & dosificación , Bevacizumab/efectos adversos , Bevacizumab/uso terapéutico , Masculino , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Femenino , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Persona de Mediana Edad , Pirrolidinas/administración & dosificación , Pirrolidinas/efectos adversos , Pirrolidinas/uso terapéutico , Anciano , Irinotecán/administración & dosificación , Irinotecán/efectos adversos , Irinotecán/uso terapéutico , Uracilo/análogos & derivados , Uracilo/administración & dosificación , Uracilo/uso terapéutico , Uracilo/efectos adversos , Adulto , Metástasis de la NeoplasiaRESUMEN
Single-agent TAS102 (trifluridine/tipiracil) and regorafenib are FDA-approved treatments for metastatic colorectal cancer (mCRC). We previously reported that regorafenib combined with a fluoropyrimidine can delay disease progression in clinical case reports of multidrug-resistant mCRC patients. We hypothesized that the combination of TAS102 and regorafenib may be active in CRC and other gastrointestinal (GI) cancers and may in the future provide a treatment option for patients with advanced GI cancer. We investigated the therapeutic effect of TAS102 in combination with regorafenib in preclinical studies employing cell culture, colonosphere assays that enrich for cancer stem cells, and in vivo. TAS102 in combination with regorafenib has synergistic activity against multiple GI cancers in vitro including colorectal and gastric cancer, but not liver cancer cells. TAS102 inhibits colonosphere formation and this effect is potentiated by regorafenib. In vivo anti-tumor effects of TAS102 plus regorafenib appear to be due to anti-proliferative effects, necrosis and angiogenesis inhibition. Growth inhibition by TAS102 plus regorafenib occurs in xenografted tumors regardless of p53, KRAS or BRAF mutations, although more potent tumor suppression was observed with wild-type p53. Regorafenib significantly inhibits TAS102-induced angiogenesis and microvessel density in xenografted tumors, as well inhibits TAS102-induced ERK1/2 activation regardless of RAS or BRAF status in vivo. TAS102 plus regorafenib is a synergistic drug combination in preclinical models of GI cancer, with regorafenib suppressing TAS102-induced increase in microvessel density and p-ERK as contributing mechanisms. The TAS102 plus regorafenib drug combination may be further tested in gastric and other GI cancers.
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Combinación de Medicamentos , Sinergismo Farmacológico , Neoplasias Gastrointestinales , Mutación , Células Madre Neoplásicas , Neovascularización Patológica , Compuestos de Fenilurea , Proteínas Proto-Oncogénicas B-raf , Proteínas Proto-Oncogénicas p21(ras) , Piridinas , Pirrolidinas , Factor de Transcripción STAT3 , Timina , Trifluridina , Uracilo , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Trifluridina/farmacología , Compuestos de Fenilurea/farmacología , Animales , Piridinas/farmacología , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/genética , Neoplasias Gastrointestinales/patología , Neoplasias Gastrointestinales/metabolismo , Uracilo/farmacología , Uracilo/análogos & derivados , Ratones , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Timina/farmacología , Línea Celular Tumoral , Pirrolidinas/farmacología , Pirrolidinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , AngiogénesisRESUMEN
Colorectal cancer remains the third most common cancer worldwide and the second cause of cancer-related death. Treatment advances and precision oncological medicine for these tumours have been stalled in comparison to those for other common tumours such as lung and breast cancer. However, the recent publication of the SUNLIGHT trial results with the trifluridine/tipiracil (TAS-102)-bevacizumab combination and the irruption of new molecular targets with guided treatments have opened new possibilities in third-line metastatic colorectal cancer management. Anti-EGFR rechallenge, anti-HER2 targeted therapies or the promising results of Pressurised Intraperitoneal Aerosol Chemotherapy (PIPAC), are some of the available options that may modify what is presumably third-line colorectal treatment. Hereby, we present the evidence of the different treatment options in third-line colorectal cancer and beyond, as well as the possibilities of sequencing them.
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Background: Several studies demonstrated trifluridine/tipiracil (TAS-102) plus bevacizumab (BEV) had better efficacy than the monotherapy of TAS-102 in refractory metastatic colorectal cancer (mCRC). However, it remains unclear whether Chinese population can benefit from this combination or not. Hence, we conducted this retrospective cohort study to compare the efficacy and safety between TAS-102 plus BEV with TAS-102 monotherapy in refractory mCRC. Methods: This retrospective cohort study enrolled patients (any age) with refractory mCRC from Hunan Cancer Hospital. The main inclusion criteria were histopathologically and/or radiographically confirmed refractory mCRC, World Health Organization (WHO) performance status of 0 to 2, adequate organ function, and initial treatment of TAS-102 with or without BEV between November 2020 and October 2022. Previous therapy with fruquintinib or regorafenib was allowed but not mandatory. Baseline demographic and clinical characteristics were collected appropriately. Every 2 or 3 treatment cycles, the patients were assessed by computed tomography (CT) scans and clinical assessments until disease progression or loss to follow-up. The National Cancer Institute Common Terminology Criteria for Adverse Events 5.0 (NCI-CTCAE 5.0) were presented as n (%). The primary endpoint was investigator-evaluated overall survival (OS). As this is a retrospective cohort study, sample size calculation was not performed. Eligible patients would be enrolled as many as possible. Results: A total of 90 patients were enrolled, including 58 patients who received TAS-102 plus BEV and another 32 patients who received TAS-102 monotherapy. The known baseline characteristics were comparable (P<0.05). With a median follow-up of 4.60 months (range, 0.20-22.80), the median OS (mOS) time in the TAS-102 plus BEV group was longer than that in the TAS-102 monotherapy group (10.83 vs. 7.43 months), but the difference was not significant (P=0.79). The median progression-free survival (mPFS) time was comparable between the two groups (4.67 vs. 4.30 months, P=0.96). Multivariate Cox regression analysis demonstrated that undergoing therapy after TAS-102 either with or without BEV was an independent risk factor for OS [hazard ratio (HR) =0.25; 95% confidence interval (CI): 0.09-0.71, P<0.01], and previous treatment with cetuximab was an independent protective factor for PFS (HR =0.17; 95% CI: 0.03-0.91, P=0.04). Of the 70 patients who were evaluated, those receiving TAS-102 plus BEV showed trend of a higher objective response rate (ORR) and disease control rate (DCR) than those who received TAS-102 monotherapy (P=0.16 and P=0.29, respectively). Adverse events (AEs) were similar between the two groups, except that the incidence of platelet count decrease (grade ≥3) was significantly higher in the TAS-102 plus BEV group. Conclusions: There was a trend in favor of the combination of BEV plus TAS-102 regarding OS and DCR, without reaching statistical significance, and it means that there was no clear advantage of one over the other in terms of efficacy. Further prospective studies are still necessary to draw a definite conclusion.
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BACKGROUND: TAS-102 (Lonsurf®) is an oral fluoropyrimidine consisting of a combination of trifluridine (a thymidine analog) and tipiracil (a thymidine phosphorylation inhibitor). The drug is effective in metastatic colorectal cancer (mCRC) patients refractory to fluorouracil, irinotecan and oxaliplatin. This study is a real-world analysis, investigating the interplay of genotype/phenotype in relation to TAS-102 sensitivity. METHODS: Forty-seven consecutive mCRC patients were treated with TAS-102 at the National Cancer Institute of Naples from March 2019 to March 2021, at a dosage of 35 mg/m2, twice a day, in cycles of 28 days (from day 1 to 5 and from day 8 to 12). Clinical-pathological parameters were described. Activity was evaluated with RECIST criteria (v1.1) and toxicity with NCI-CTC (v5.0). Survival was depicted through the Kaplan-Meyer curves. Genetic features of patients were evaluated with Next Generation Sequencing (NGS) through the Illumina NovaSeq 6000 platform and TruSigt™Oncology 500 kit. RESULTS: Median age of patients was 65 years (range: 46-77). Forty-one patients had 2 or more metastatic sites and 38 patients underwent to more than 2 previous lines of therapies. ECOG (Eastern Cooperative Oncology Group) Performance Status (PS) was 2 in 19 patients. The median number of TAS-102 cycles was 4 (range: 2-12). The most frequent toxic event was neutropenia (G3/G4 in 16 patients). There were no severe (> 3) non-haematological toxicities or treatment-related deaths. Twenty-six patients experienced progressive disease (PD), 21 stable disease (SD). Three patients with long-lasting disease control (DC: complete, partial responses or stable disease) shared an FGFR4 (p.Gly388Arg) mutation. Patients experiencing DC had more frequently a low tumour growth rate (P = 0.0306) and an FGFR4 p.G388R variant (P < 0.0001). The FGFR4 Arg388 genotype was associated with better survival (median: 6.4 months) compared to the Gly388 genotype (median: 4 months); the HR was 0.25 (95% CI 0.12- 0.51; P = 0.0001 at Log-Rank test). CONCLUSIONS: This phenotype/genotype investigation suggests that the FGFR4 p.G388R variant may serve as a new marker for identifying patients who are responsive to TAS-102. A mechanistic hypothesis is proposed to interpret these findings.
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Neoplasias Colorrectales , Combinación de Medicamentos , Metástasis de la Neoplasia , Pirrolidinas , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos , Timina , Trifluridina , Uracilo , Humanos , Trifluridina/uso terapéutico , Trifluridina/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Pirrolidinas/uso terapéutico , Masculino , Femenino , Uracilo/análogos & derivados , Uracilo/uso terapéutico , Uracilo/efectos adversos , Persona de Mediana Edad , Anciano , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/genética , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Objectives The purpose of this meta-analysis is to evaluate the efficacy and safety of TAS-102 in treating metastatic colorectal cancer (mCRC) using the most recent data available. Methods The literature on the efficacy and safety of TAS-102 versus placebo and/or best supportive care (BSC) in mCRC was obtained through a systematic search of PubMed, Embase, and Web of Science databases through January 2023. Identify the included literature and extract pertinent data, such as the overall survival (OS), progression-free survival (PFS), time to treatment failure (TTF), disease control rate (DCR), incidence of adverse events (AEs) and serious adverse events (SAEs). Results There were eight eligible articles that included 2903 patients (1964 TAS-102 versus 939 Placebo and/or BSC). In this meta-analysis, TAS-102 treatment resulted in longer OS, PFS, TTF, and higher DCR in patients with mCRC versus placebo and/or BSC. TAS-102 improved OS and PFS in subgroup analyses of mCRC patients with KRAS wild-type and KRAS mutant-type. In addition, TAS-102 did not increase the incidence of serious adverse events. Conclusion TAS-102 can enhance the prognosis of mCRC patients whose standard therapy has failed, regardless of KRAS mutation status, and its safety is acceptable (AU)
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Humanos , Protocolos de Quimioterapia Combinada Antineoplásica , Proteína Oncogénica p21(ras) , Pirrolidinas , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Timina/administración & dosificación , Trifluridina/administración & dosificación , Uracilo/administración & dosificaciónRESUMEN
We report a case of a 62-year-old male who was diagnosed with advanced rectal cancer. The attending gastro-enterologist initiated chemotherapy using capecitabine plus oxaliplatin and bevacizumab; however, this treatment regimen was discontinued, as the patient developed a skin rash. Once the skin rash improved, chemotherapy was re-initiated using a combination of trifluridine and tipiracil hydrochloride (TAS-102). The patient developed high fever and dyspnea 2 months after initiation of TAS-102. Chest high-resolution computed tomography showed bilateral diffuse ground glass opacities in all lung lobes with traction bronchiectasis. At this time, the gastro-enterologist consulted our department. The patient was put on non-invasive positive pressure ventilation due to worsening respiratory symptoms. The patient was suspected to develop TAS-102-induced interstitial pneumonia based on positive TAS-102 drug-induced lymphocyte stimulation test. The patient's respiratory symptoms and radiological findings improved after corticosteroid treatment. The corticosteroid dose was gradually decreased by 5 mg. Thereafter, chemotherapy was re-initiated using different anti-cancer agents.
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The tumor-suppressor p53 is commonly inactivated in colorectal cancer and pancreatic ductal adenocarcinoma, but existing treatment options for p53-mutant (p53Mut) cancer are largely ineffective. Here, we report a therapeutic strategy for p53Mut tumors based on abnormalities in the DNA repair response. Investigation of DNA repair upon challenge with thymidine analogs reveals a dysregulation in DNA repair response in p53Mut cells that leads to accumulation of DNA breaks. Thymidine analogs do not interrupt DNA synthesis but induce DNA repair that involves a p53-dependent checkpoint. Inhibitors of poly(ADP-ribose) polymerase (PARPis) markedly enhance DNA double-strand breaks and cell death induced by thymidine analogs in p53Mut cells, whereas p53 wild-type cells respond with p53-dependent inhibition of the cell cycle. Combinations of trifluorothymidine and PARPi agents demonstrate superior anti-neoplastic activity in p53Mut cancer models. These findings support a two-drug combination strategy to improve outcomes for patients with p53Mut cancer.
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Neoplasias Colorrectales , Neoplasias Pancreáticas , Humanos , Proteína p53 Supresora de Tumor/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Reparación del ADN , Poli(ADP-Ribosa) Polimerasas/genética , Poli(ADP-Ribosa) Polimerasas/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , ADN/uso terapéutico , Timidina/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genéticaRESUMEN
OBJECTIVES: The purpose of this meta-analysis is to evaluate the efficacy and safety of TAS-102 in treating metastatic colorectal cancer (mCRC) using the most recent data available. METHODS: The literature on the efficacy and safety of TAS-102 versus placebo and/or best supportive care (BSC) in mCRC was obtained through a systematic search of PubMed, Embase, and Web of Science databases through January 2023. Identify the included literature and extract pertinent data, such as the overall survival (OS), progression-free survival (PFS), time to treatment failure (TTF), disease control rate (DCR), incidence of adverse events (AEs) and serious adverse events (SAEs). RESULTS: There were eight eligible articles that included 2903 patients (1964 TAS-102 versus 939 Placebo and/or BSC). In this meta-analysis, TAS-102 treatment resulted in longer OS, PFS, TTF, and higher DCR in patients with mCRC versus placebo and/or BSC. TAS-102 improved OS and PFS in subgroup analyses of mCRC patients with KRAS wild-type and KRAS mutant-type. In addition, TAS-102 did not increase the incidence of serious adverse events. CONCLUSION: TAS-102 can enhance the prognosis of mCRC patients whose standard therapy has failed, regardless of KRAS mutation status, and its safety is acceptable.
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Neoplasias del Colon , Neoplasias Colorrectales , Pirrolidinas , Neoplasias del Recto , Timina , Humanos , Trifluridina/efectos adversos , Uracilo/efectos adversos , Neoplasias Colorrectales/patología , Proteínas Proto-Oncogénicas p21(ras) , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Recto/tratamiento farmacológico , Combinación de Medicamentos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Background: For metastatic colorectal cancer (mCRC), the efficacy of third-line or above treatments is not ideal. Combining targeted vascular endothelial growth factor (VEGF) or vascular endothelial growth factor receptor (VEGFR) biological agents with chemotherapy or anti-programmed death receptor 1 (PD-1) treatment can bring longer survival benefits to patients with mCRC compared with the application of a single drug. In this study, fruquintinib was used as the research drug, and the main purpose was to compare the efficacy and safety of fruquintinib in combination with sintilimab (FS) or trifluridine and tipiracil (TAS-102) (FT) in the third-line or above treatment in mCRC patients. Methods: Based on real-world clinical practice, mCRC patients who progressed after second-line or higher-line chemotherapy regimens and received FS or FT as third-line or above treatment from December 2020 to November 2022 were analyzed. Progression-free survival (PFS) was the primary endpoint. Safety, disease control rate (DCR) and objective response rate (ORR) were secondary end points. Results: In the FS group, 47 patients received FS, and in the FT group, 45 patients received FT. The DCR values in the FS and FT groups were 80.9% (38/47) and 55.6% (25/45), respectively (P<0.05). The median PFS (mPFS) in the FS group was 6.0 months, and the mPFS in the FT group was 3.5 months (P<0.05). Most adverse events (AEs) were grade 1-2 in severity. Conclusions: As a third-line or above regimen in mCRC patients, compared to FT, treatment with FS provides a higher DCR and longer mPFS and is better tolerated. The combination of fruquintinib and sintilimab may become a new treatment option for mCRC patients.
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Patients with KRAS-mutated and microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) often have limited options in salvage-line treatment. Reasonable combination strategy may be a valuable exploration. Here, we report a patient with KRAS-mutated and MSS metastatic rectal adenocarcinoma at stage IVB. After failure of previous standard treatment, a durable stable disease was achieved under the fifth-line treatment of TAS-102 plus bevacizumab and transcatheter arterial chemoembolization (TACE). To date, the patient had a PFS of more than 11.6 months with significantly declined tumor markers, alleviated clinical symptoms and improved quality of life. This case suggests that TAS-102 combined with re-challenged bevacizumab and well-timed TACE intervention is an effective strategy for KRAS-mutated and MSS mCRC, with good tolerance and manageable safety, even following disease progression on prior fruquintinib and regorafenib therapies.
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BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
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Neoplasias del Colon , Neoplasias Colorrectales , Demencia Frontotemporal , Humanos , Uracilo/farmacología , Uracilo/uso terapéutico , Bevacizumab/farmacología , Bevacizumab/uso terapéutico , Estudios Retrospectivos , Neoplasias Colorrectales/patología , Japón/epidemiología , Trifluridina/efectos adversos , Demencia Frontotemporal/inducido químicamente , Neoplasias del Colon/tratamiento farmacológicoRESUMEN
BACKGROUND: Trifluridine/tipiracil (TAS-102) is an anticancer drug for metastatic colorectal cancer (CRC). This study aimed to analyze the effects and risk factors about effects of TAS-102 in real-world patients with metastatic CRC (the EROTAS-R study). METHODS: This study retrospectively analyzed 271 patients aged ≥ 20 years who underwent TAS-102 for metastatic CRC at nine related institutions from 2014 to 2021. Therapeutic results of TAS-102 + bevacizumab (Bev) and TAS-102, effect predictors, adverse events (AE), and AE predictors were examined. RESULTS: The backgrounds of all cases were as follows: average age, 66.7 ± 10.9 years; male ratio, 59.5%; performance status (PS) 0/1/2, 43.5%/50.6%/5.9%; and tumor site right/left, 25.5%/74.5%. The therapeutic results of 109 cases receiving TAS-102 + Bev and 162 cases receiving TAS-102 were as follows: disease control rate, 53.2% vs. 28.0% (p < 0.01); progressive free survival (PFS), 6.2 vs. 4.2 months (p < 0.01); and overall survival (S), 11.8 vs. 9.3 months (p = 0.03). Multivariate analysis for effect-related factors (odds ratio (OR), 95%confidence interval (CI)) showed the following: PS1 + 2 (0.257, 0.134-0.494, p < 0.01) and a combination of Bev (3.052, 1.598-5.827, p < 0.01). The rates of grade 3 AE for TAS-102 + Bev and TAS-102 were 53.2% and 48.8%, respectively (p = 0.47). Various AE predictors were as follows: male sex (p = 0.69), age ≥ 75 years (p = 0.59), PS1 + 2 (p = 0.20), body surface area < 1.53 m2 (p = 0.26), eGFR < 50 ml/min (p = 0.02), and AST ≥ 50 IU/L (p = 0.64). CONCLUSION: A better OS and PFS comparing TAS-102 + Bev to TAS-102 for CRC was achieved in a large number of real-world patients.
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Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Humanos , Masculino , Persona de Mediana Edad , Anciano , Trifluridina/efectos adversos , Uracilo/efectos adversos , Neoplasias Colorrectales/patología , Estudios Retrospectivos , Combinación de Medicamentos , Bevacizumab/efectos adversos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Recto/tratamiento farmacológico , Factores de Riesgo , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
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.
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Based on results of prior trials (TAGS, REGARD, RAINBOW), the combination of ramucirumab beyond progression with TAS-102 (trifluridine/tipiracil) seems to be promising in advanced esophagogastric adenocarcinoma (EGA). In this multicenter, non-randomized, open-label, investigator-initiated pilot trial, ramucirumab-pretreated patients with metastatic EGA received a maximum of 4 cycles of ramucirumab (8 mg/kg i.v. on day 1 and 15, Q2W) plus TAS-102 (35 mg/m2 p.o. bid on day 1-5 and day 8-12; Q2W). Primary endpoint was tolerability and toxicity, defining a positive trial if the SAE rate according to CTCAE 5.0 will increase <30% (up to 55%) compared to historical results from TAGS trial (SAE rate 43%). Secondary endpoints were further evaluation of safety and assessment of efficacy according to tumor response and overall and progression-free survival (OS/PFS). Twenty patients, 20% gastric and 80% GEJ cancers and 55% with ECOG 0 were enrolled. In total, nine SAEs were reported in 25% [95% CI: 8.7-49.1] of the patients, all without relationship to the systemic therapy. The median OS and PFS were 9.1 months [5.4-10.1] and 2.9 months [1.7-4.8], respectively. In addition, a disease control rate of 45% was obtained. The trial showed a favorable safety profile with a numerically lower incidence of SAEs for the combination of ramucirumab with TAS-102 compared to historical TAGS trial. Furthermore, the combination demonstrated efficacy in the beyond progression setting and therefore warrants further evaluation in a randomized trial compared to TAS-102 alone.
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Adenocarcinoma , Neoplasias Gástricas , Humanos , Trifluridina/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Insuficiencia del Tratamiento , Adenocarcinoma/patología , Neoplasias Gástricas/patología , Unión Esofagogástrica/patología , RamucirumabRESUMEN
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.
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Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Humanos , Bevacizumab/uso terapéutico , Uracilo , Neoplasias Colorrectales/patología , Trifluridina/farmacología , Trifluridina/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Recto/tratamiento farmacológicoRESUMEN
The posterior line treatment of unresectable advanced or metastatic gastrointestinal (GI) tumors has always been a challenging point. In particular, for patients with microsatellite stable (MSS)/mismatch repair proficient (pMMR) 0GI tumors, the difficulty of treatment is exacerbated due to their insensitivity to immune drugs. Accordingly, finding a new comprehensive therapy to improve the treatment effect is urgent. In this study, we report the treatment histories of three patients with MSS/pMMR GI tumors who achieved satisfactory effects by using a comprehensive treatment regimen of apatinib combined with camrelizumab and TAS-102 after the failure of first- or second-line regimens. The specific contents of the treatment plan were as follows: apatinib (500 mg/d) was administered orally for 10 days, followed by camrelizumab (200 mg, ivgtt, day 1, 14 days/cycle) and TAS-102 (20 mg, oral, days 1-21, 28 days/cycle). Apatinib (500 mg/d) was maintained during treatment. Subsequently, we discuss the possible mechanism of this combination and review the relevant literature, and introduce clinical trials on anti-angiogenesis therapy combined with immunotherapy.
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A clinical case of a 61-year-old female diagnosed with stage IV right colon adenocarcinoma (unresectable liver and multiple lymph node metastases at the time of diagnosis), Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma rat sarcoma viral oncogene homolog (NRAS) and v-raf murine sarcoma viral oncogene homolog B (BRAF) wild-type, proficient mismatch repair (pMMR), in whom a complete response to the third-line of systemic treatment with trifluridine/tipiracil (TAS-102) was obtained. The complete response has been maintained for more than 2 years after its suspension.
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BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Humanos , Estados Unidos , Trifluridina/uso terapéutico , Uracilo/uso terapéutico , Estudios Prospectivos , Neoplasias Colorrectales/patología , Compuestos de Fenilurea/uso terapéutico , Combinación de Medicamentos , Neoplasias del Colon/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Introduction: Regorafenib and TAS-102 are two orally-administered drugs used to treat refractory metastatic colorectal cancer (mCRC). This study was performed to explore any differences between different therapy sequences: TAS-102 first or regorafenib first. Patients and methods: This is a retrospective and real-practice study in mCRC patients treated according to the ESMO guidelines. They received TAS-102 first (regorafenib second, TR) or regorafenib first (TAS-102 second, RT) at standard doses. Responses to therapy and toxicities were evaluated by RECIST and CTCAE v4.0, respectively. Associations between clinical and pathologic variables and different therapy sequences were evaluated by χ2-test. p <0.05 was considered statistically significant. A description of any differences in overall survival (OS) between TR and RT was the primary outcome. OS curves were depicted through the Kaplan−Meier product limit. All statistical analyses were performed by the Excel software and MedCalc® version 20.112. Results: Sixty-five patients were analyzed. Twenty-eight received regorafenib before TAS-102, 37 vice versa. Responsiveness to first-line chemotherapy as well as disease control were not different between RT and TR patients. G4 toxicities were very rare. The three most common G1/G2 toxicities with regorafenib were fatigue, anemia, and cutaneous rash; anemia, fatigue, and neutropenia with TAS-102. Compliance to treatment was lower in TAS-102 patients compared to regorafenib. Interestingly, analysis of OS showed a significant difference at Log Rank test (p = 0.0366) in favor of TR (median OS: 4.5 months) compared to RT (median OS: 3.0 months; HR: 0.55; 95% CI: 0.31−0.96). Conclusions: we found a significant difference in terms of survival in favor of the TR sequence of treatment. Larger studies are needed to confirm these data and explore specific biomarkers predicting the correct sequence of oral drugs in the treatment of refractory mCRC patients.