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1.
Mutat Res ; 849: 503128, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32087849

RESUMO

A physiological decrease in extracellular pH (pHe) alters the efficiency of DNA repair and increases formation of DNA double-strand breaks (DSBs). Whether this could translate into genetic instability and variations, was investigated using the TK6 cell model, in which positive selection of the TK1 gene loss-of-function mutations can be achieved from resistance to trifluorothymidine. Cell exposure to suboptimal pH (down to 6.9) for 3 weeks resulted in the 100 % frequency of a stronger frameshift mutation that has spread to both TK1 alleles, whereas weaker frameshift mutations within the 3'exon were eliminated during the selection. Suboptimal pHe values were also found to alter the proportion of the TK1 splicing variant expressed as percent spliced in index values and promote selection of truncated exons as well as intron retention. Although recovery at pH 7.4 did not reverse the selected frameshift mutation, reversal of splice variants and exon truncation towards control values were observed. Hence, suboptimal pHe can induce a combination of mutational events and splicing alterations within the same gene in the resistant clones. This model of positive selection for loss-of-function clearly demonstrates that suboptimal pHe may confer a similar growth advantage when such instability occurs within tumor suppressor genes.


Assuntos
Processamento Alternativo , Mutação da Fase de Leitura , Linfócitos/metabolismo , Modelos Genéticos , Mutagênese , Timidina Quinase/genética , Antimetabólitos/farmacologia , Linhagem Celular Tumoral , DNA/genética , DNA/metabolismo , Quebras de DNA de Cadeia Dupla , Reparo do DNA/efeitos dos fármacos , Éxons , Espaço Extracelular/química , Espaço Extracelular/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Íntrons , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Timidina Quinase/metabolismo , Trifluridina/farmacologia
4.
Expert Rev Gastroenterol Hepatol ; 14(2): 65-70, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31920125

RESUMO

Introduction: Trifluridine/tipiracil is a novel oral cytotoxic chemotherapy consisting of a thymidine-based nucleoside analog, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil. Trifluridine/tipiracil was approved for the treatment of metastatic colorectal cancer refractory to standard therapies. A phase II trial in Japan demonstrated that this therapy has antitumor activity and is tolerated by patients with advanced gastric cancer (AGC); as a result, the phase III TAGS trial (Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer) was initiated.Area covered: Trifluridine/tipiracil has proved effective for heavily pretreated AGC and has thus been approved for use in the United States in February 2019, Japan in August 2019 and the European Union in September 2019. Detail of the phase III TAGS trial is discussed in this review.Expert opinion: Trifluridine/tipiracil after at least two previous courses of systemic chemotherapy improved rates of survival of gastric cancer; thus it has become one of the treatment options in affected patients. Currently, several clinical trials of trifluridine/tipiracil in combination with other anticancer agents such as ramucirumab (an anti-vascular endothelial growth factor receptor 2 monoclonal antibody) for patients with AGC are ongoing.


Assuntos
Antineoplásicos/administração & dosagem , Pirrolidinas/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Trifluridina/administração & dosagem , Uracila/análogos & derivados , Administração Oral , Antineoplásicos/farmacologia , Ensaios Clínicos como Assunto , Combinação de Medicamentos , Humanos , Pirrolidinas/farmacologia , Neoplasias Gástricas/secundário , Trifluridina/farmacologia , Uracila/administração & dosagem , Uracila/farmacologia
5.
Med Sci Monit ; 25: 9179-9191, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31790382

RESUMO

BACKGROUND This study aimed to conduct a systematic review of the literature to identify key randomized controlled clinical trials (RCTs), followed by network meta-analysis, to compare the efficacy and safety profiles of regorafenib, fruquintinib, and TAS-102 in previously treated patients with metastatic colorectal carcinoma (mCRC). MATERIAL AND METHODS Systematic literature review was performed using the Medline, Embase, and Cochrane library online databases to identify published randomized controlled trials (RCTs). Hazard ratios (HRs) for progression-free survival (PFS), overall survival (OS), and the odds ratios (ORs) for the objective response rate (ORR), disease control rate (DCR), adverse events (AEs), serious adverse events (SAEs), and fatal adverse events (FAEs) were compared indirectly using network meta-analysis based on a random-effects model. RESULTS Five RCTs that included 2,604 patients fulfilled the eligibility criteria and were analyzed. Indirect comparisons showed that fruquintinib was associated with significant superiority for PFS (HR, 0.57; 95% CI, 0.34-0.95) and DCR (OR, 1.80; 95% CI, 1.08-3.01) when compared with TAS-102 in patients with mCRC. However, there was no significant difference between OS or ORR between regorafenib, fruquintinib, and TAS-102. Fruquintinib was associated with a significantly higher risk of SAEs when compared with TAS-102 or regorafenib. There was no significant difference in the risk of AEs or FAEs following indirect comparison between fruquintinib, regorafenib, and TAS-102. CONCLUSIONS The findings from network meta-analysis showed that fruquintinib was associated with significant superiority for PFS and DCR compared with TAS-102, but fruquintinib was associated with significantly increased risk for SAEs compared with regorafenib and TAS-102.


Assuntos
Benzofuranos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Pirrolidinas/uso terapêutico , Quinazolinas/uso terapêutico , Trifluridina/uso terapêutico , Uracila/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzofuranos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Combinação de Medicamentos , Humanos , Metanálise em Rede , Compostos de Fenilureia/farmacologia , Piridinas/farmacologia , Pirrolidinas/farmacologia , Quinazolinas/farmacologia , Neoplasias Retais/tratamento farmacológico , Trifluridina/farmacologia , Uracila/farmacologia , Uracila/uso terapêutico
6.
J BUON ; 24(5): 2198-2204, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31786894

RESUMO

PURPOSE: To assess whether regorafenib and TAS-102 treatments are associated with a change in Skeletal Muscle Area (SMA) as well as to compare Skeletal Muscle Mass (SMM) loss levels between regorafenib and TAS-102 treatments and prognostic significance in the patients with metastatic colorectal cancer (mCRC). METHODS: A total of 36 mCRC patients, who received regorafenib or TAS-102 in the third-line and subsequent settings were assessed in the analysis. SMM changes were assessed with CT scans findings, and they were categorized into two groups as SMM-loss (SMM decrease ≥2%) and SMM-stable (SMM change <2%). RESULTS: The SMM change after regorafenib therapy was significantly worse compared with TAS-102 therapy (p=0.001). The median overall survival (OS) was longer in SMM-stable group than in SMM-loss group (12.8 months; 95%CI:9.8-15.7) vs. 6.4 months; 95%CI:5.2-7.7, respectively;p=0.04). Cox regression analysis showed that SMM loss was independent prognostic indicator for OS (HR, 2.87; 95%CI: 1.07-7.42, p=0.03). CONCLUSION: Although patients who received regorafenib had more SMM loss than those who received TAS-102, there was no difference in OS between drugs.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Músculo Esquelético/fisiopatologia , Prognóstico , Sarcopenia/fisiopatologia , Idoso , Neoplasias Colorretais/fisiopatologia , Intervalo Livre de Doença , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/efeitos dos fármacos , Metástase Neoplásica , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Pirrolidinas/administração & dosagem , Pirrolidinas/efeitos adversos , Sarcopenia/induzido quimicamente , Sarcopenia/epidemiologia , Trifluridina/administração & dosagem , Trifluridina/efeitos adversos , Uracila/administração & dosagem , Uracila/efeitos adversos , Uracila/análogos & derivados
7.
BMC Cancer ; 19(1): 1253, 2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31881856

RESUMO

BACKGROUND: A previous phase I/II C-TASK FORCE study of trifluridine/tipiracil plus bevacizumab for patients with heavily pretreated metastatic colorectal cancer (mCRC) showed promising activity with an acceptable toxicity profile. This retrospective study aimed to investigate the safety and efficacy of trifluridine/tipiracil plus bevacizumab compared with trifluridine/tipiracil monotherapy in patients with heavily pretreated mCRC in clinical settings. METHODS: Records of patients with mCRC refractory to standard therapies who initiated trifluridine/tipiracil plus bevacizumab from January 2016 to March 2018 or trifluridine/tipiracil monotherapy from June 2014 to December 2015 were retrospectively reviewed at our institution. RESULTS: Totally, 60 patients received trifluridine/tipiracil plus bevacizumab and 66 received trifluridine/tipiracil monotherapy. All patients had previously received standard chemotherapy. Median progression-free survival (PFS) was 3.7 months [95% confidence interval (CI), 2.3-5.1] in the trifluridine/tipiracil plus bevacizumab group and 2.2 months (95% CI, 1.8-2.6) in the trifluridine/tipiracil monotherapy group [hazards ratio (HR) 0.69; 95% CI 0.48-0.99]. PFS rate at 16 weeks was 46.6% for the trifluridine/tipiracil plus bevacizumab group and 33.9% for the trifluridine/tipiracil monotherapy group. Although a relatively higher incidence of grade ≥ 3 neutropenia was observed in the trifluridine/tipiracil plus bevacizumab group than that in the other group (50.0% vs. 40.9%, p = 0.371), the incidence of febrile neutropenia was not high (3.3% vs. 7.8%, p = 0.444). CONCLUSIONS: In real-world settings, trifluridine/tipiracil plus bevacizumab prolonged PFS and helped achieve higher 16-week PFS rate compared with trifluridine/tipiracil monotherapy in patients with heavily pretreated mCRC with manageable toxicities. TRIAL REGISTRATION: Retrospectively registered.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Pirrolidinas/uso terapêutico , Trifluridina/uso terapêutico , Uracila/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Retrospectivos , Uracila/uso terapêutico , Adulto Jovem
8.
Clin Adv Hematol Oncol ; 17 Suppl 7(3): 1-19, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31730588

RESUMO

The standard treatment for patients with metastatic colorectal cancer (mCRC) in the first- and second-line setting is generally chemotherapy, which can be augmented with vascular endothelial growth factor-targeted therapies and, for patients with KRAS wild-type status, epidermal growth factor receptor-targeted therapies. However, nearly all patients ultimately develop disease progression and require later lines of therapy. Traditionally, physicians recycled chemotherapy in the later lines, with many patients showing diminished or no response. However, the past several years have seen the introduction of 2 agents for patients with refractory mCRC entering the third-line setting. The multitargeted tyrosine kinase inhibitor regorafenib and the cytotoxic combination of trifluridine/tipiracil have demonstrated significant improvements in overall survival in patients with refractory mCRC. Although these agents do not seem to induce complete responses, they can lead to durable stable disease. Regorafenib and trifluridine/tipiracil differ in their safety profiles. Physicians and patients must be properly educated on how to recognize and mitigate adverse events. For regorafenib, a dose-escalating strategy improves tolerability without impacting efficacy. When sequencing these agents, physicians should consider patient characteristics, including comorbidities, prior adverse reactions to treatments, and overall performance status. Ongoing studies are further defining the role of regorafenib and trifluridine/tipiracil in the treatment of mCRC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Terapia de Salvação , Neoplasias Colorretais/patologia , Combinação de Medicamentos , Humanos , Metástase Neoplásica , Compostos de Fenilureia/administração & dosagem , Prognóstico , Piridinas/administração & dosagem , Pirrolidinas/administração & dosagem , Taxa de Sobrevida , Trifluridina/administração & dosagem , Uracila/administração & dosagem , Uracila/análogos & derivados
9.
Recenti Prog Med ; 110(7): 325-329, 2019.
Artigo em Italiano | MEDLINE | ID: mdl-31379366

RESUMO

TAS-102 represents an important therapeutic resource for patients with metastatic refractory colorectal cancer. Albeit generally well tolerated, clinically relevant neutropenia may interfere with the regular delivery of full-dose cycles with a possible detrimental effect on the dose-intensity. Judicious and personalized use of colony-stimulating growth factors as well as alterative schedules of drug delivery could mitigate neutropenia, so contributing to an even better therapeutic index of the drug.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neutropenia/induzido quimicamente , Pirrolidinas/efeitos adversos , Trifluridina/efeitos adversos , Uracila/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Combinação de Medicamentos , Humanos , Neutropenia/prevenção & controle , Pirrolidinas/administração & dosagem , Trifluridina/administração & dosagem , Uracila/administração & dosagem , Uracila/efeitos adversos
10.
Anticancer Res ; 39(8): 4343-4350, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366528

RESUMO

BACKGROUND/AIM: TAS-102 is recommended as salvage-line therapy for metastatic colorectal cancer (mCRC), but practical predictors for its efficacy are lacking. PATIENTS AND METHODS: In a single-institutional retrospective study of 33 patients treated with TAS-102, we investigated the predictive value of the pretreatment neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR), and lymphocyte-monocyte (LMR) ratios for progression-free (PFS) and overall (OS) survival. Predictive ability using cut-offs of the median value (3.14) and 5 for NLR were compared. RESULTS: In univariate analysis, Eastern Cooperative Oncology Group performance score, NLR, and PLR were negatively significantly associated with PFS and OS. The number of treatment lines was negatively associated with PFS. The NLR cut-off of 5 was superior to the median value. Multivariate analyses showed a significant prognostic impact for NLR at cut-off 5 (hazard ratio(HR)=6.26, p=0.02 for PFS; HR=6.97, p=0.07 for OS). CONCLUSION: The pretreatment NLR is a prognostic biomarker for patients with mCRC who receive TAS-102 treatment.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Colorretais/tratamento farmacológico , Prognóstico , Trifluridina/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/sangue , Neoplasias Colorretais/patologia , Combinação de Medicamentos , Feminino , Humanos , Contagem de Leucócitos , Contagem de Linfócitos , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neutrófilos/patologia , Contagem de Plaquetas , Intervalo Livre de Progressão , Pirrolidinas , Estudos Retrospectivos , Uracila/análogos & derivados
11.
Anticancer Res ; 39(7): 3565-3570, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262880

RESUMO

BACKGROUND/AIM: Trifluridine (FTD) is a key component of the novel oral antitumor drug trifluridine/tipiracil that has been approved for the treatment of metastatic colorectal cancer. In this study, a comprehensive analysis of DNA replication profile in FTD-treated colon cancer cells was performed. MATERIALS AND METHODS: HCT-116 cells were exposed to BrdU or FTD and subjected to DNA immunoprecipitation. Immunoprecipitated DNA was sequenced; the density of aligned reads along the genome was calculated. Peak finding, gene ontology, and motif analysis were performed using MACS, GREAT, and MEME, respectively. RESULTS: We identified 6,043 and 5,080 high-confidence FTD and BrdU peaks in HCT-116 cells, respectively. Of 6,043 FTD peaks, 2,911 peaks were uncommon to BrdU. We observed that FTD was preferentially incorporated into genomic regions containing simple repeats, CpG islands, and gene bodies. Conserved motifs in FTD peaks contained dinucleotide repeats such as (GT)n. CONCLUSION: Global FTD incorporation patterns delineated FTD, preferentially incorporating loci in cancer cells.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Bromodesoxiuridina/farmacologia , Neoplasias Colorretais/genética , Replicação do DNA/efeitos dos fármacos , Trifluridina/farmacologia , Células HCT116 , Humanos , Análise de Sequência de DNA
12.
Anticancer Res ; 39(7): 3967-3969, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262929

RESUMO

BACKGROUND/AIM: The aim of this report was to evaluate the onset of grade≥3 neutropenia during the first-cycle in patients with metastatic colorectal cancer (mCRC) treated with trifluridine/tipiracil and its relationship with clinical parameters of interest, such as overall survival (OS). PATIENTS AND METHODS: We performed a retrospective analysis of all consecutive patients with mCRC, treated with trifluridine/tipiracil in third or later treatment lines in mCRC, at our Medical Oncology Unit between July 2017 and December 2018. We evaluated 15 patients. RESULTS: Median age was 63 years (range: 46-80 years). Trifluridine/tipiracil was used in third-line treatment in 10 patients (66.7%). The only serious adverse events were grade 3 (26.7%) and grade 4 (13.3%) neutropenia. Median follow-up time (FUT) was 53 months (range=17-91 months). At the last FUT, 5 patients (33.3%) were deceased. Median OS was 5 months (range=1-15 months). At the univariate analysis, the onset of grade ≥3 neutropenia at the first cycle showed a statistically positive impact on OS (p=0.046). CONCLUSION: The onset of grade ≥3 neutropenia at the first-cycle is associated with longer median OS compared to no onset of neutropenia also in real-life.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Neutropenia/induzido quimicamente , Trifluridina/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/patologia , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirrolidinas , Análise de Sobrevida , Uracila/análogos & derivados
13.
Am J Health Syst Pharm ; 76(6): 339-348, 2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-31361848

RESUMO

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, safety, dosing, and place in therapy of trifluridine-tipiracil are reviewed. SUMMARY: Trifluridine-tipiracil is an oral antineoplastic agent consisting of trifluridine (a trifluorothymidine, a thymidine-based nucleoside analog) and tipiracil (a thymidine phosphorylase inhibitor), at a molar ratio of 1:0.5. Tipiracil blocks the degradation of trifluridine by thymidine phosphorylase, which improves the bioavailability of trifluridine and allows for oral administration. A Phase III study comparing trifluridine-tipiracil versus placebo in metastatic colorectal cancer (mCRC) patients refractory to or intolerant of standard therapy (n = 800) showed a benefit in overall survival (the primary endpoint) and progression-free survival compared with placebo. The most common grade ≥ 3 adverse events in trifluridine-tipiracil groups in Phase II and III trials were neutropenia, anemia, and leukopenia. The recommended dose of trifluridine-tipiracil is 35 mg/m2 twice a day after meals in a 28-day cycle comprising 2 weeks of 5 days of treatment and 2 days of rest (days 1-5 and 8-12 [every] 28 days), followed by 2 weeks of rest. Trifluridine-tipiracil is approved for the treatment of patients with mCRC previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an antivascular endothelial growth factor biological therapy and, if RAS wild-type, an antiepidermal growth factor receptor therapy. CONCLUSION: Trifluridine-tipiracil is a new treatment option for patients with mCRC who have received at least 2 prior lines of standard chemotherapy (including fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and an antiepidermal growth factor receptor antibody in patients with KRAS wild-type tumors). Ongoing trials are investigating trifluridine/tipiracil in combination with other anticancer agents for mCRC and its use in other malignancies, such as metastatic gastric cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Pirrolidinas/farmacologia , Trifluridina/farmacologia , Uracila/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Combinação de Medicamentos , Humanos , Intervalo Livre de Progressão , Pirrolidinas/uso terapêutico , Timidina Fosforilase/antagonistas & inibidores , Timidina Fosforilase/metabolismo , Trifluridina/uso terapêutico , Uracila/farmacologia , Uracila/uso terapêutico
14.
Clin Transl Oncol ; 21(12): 1781-1785, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31209792

RESUMO

INTRODUCTION: Our aim was to assess efficacy and safety and prognostic factors associated with TAS-102 in clinical practice. METHOD: Retrospective, multicenter, and observational study including patients with advanced refractory colorectal cancer who started TAS-102 between March 2016 and August 2018. The primary end point was overall survival (OS). Secondary end points included progression-free survival, toxicity and analyze prognostic factors present at the beginning of TAS-102. RESULT: 84 patients were evaluable. The median OS was 8.30 (95% CI 6.23-9.87) months and PFS was 2.62 (95% CI 2.36-3.05) months. In multivariate analysis, ECOG 0 and reduced dose combined with more cycles were associated with better prognosis. Patients with an ECOG > 0 had worse prognosis (HR 3.34, 95% CI 1.09-10.27, p = 0.035). 95.2% experienced some type of adverse effect and 45.2% had grade ≥ 3 toxicities. CONCLUSION: Results suggest reconsidering TAS-102 in patients with ECOG > 0, something that should be investigated in prospective randomized clinical trials.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Pirrolidinas/uso terapêutico , Neoplasias Retais/tratamento farmacológico , Trifluridina/uso terapêutico , Uracila/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Esquema de Medicação , Combinação de Medicamentos , Estudos de Viabilidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Pirrolidinas/efeitos adversos , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento , Trifluridina/efeitos adversos , Uracila/efeitos adversos , Uracila/uso terapêutico
15.
Clin Colorectal Cancer ; 18(2): 159-166.e3, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31060856

RESUMO

BACKGROUND: Current guidelines of the National Comprehensive Cancer Network and the European Society of Medical Oncology recommend regorafenib or trifluridine/tipiracil (TAS-102) for third-line therapy of metastatic colorectal cancer (mCRC). We evaluated the impact of regorafenib and TAS-102 treatment on skeletal muscle dynamics and sarcopenia. PATIENTS AND METHODS: This retrospective analysis was based on unselected, consecutive mCRC patients treated with regorafenib and/or TAS-102 during third or later line of therapy at our tertiary-care cancer center in Salzburg, Austria. The skeletal muscle index (SMI, cm2/m2) and sarcopenia were evaluated from cross-sectional computed tomographic images at the level of the third lumbar vertebra. RESULTS: Between January 2013 and April 2018, a total of 45 patients had received regorafenib and/or TAS-102. At initial mCRC diagnosis and at initiation of third-line therapy, 24% and 54% of patients presented with sarcopenia. A statistically significant skeletal muscle loss was observed during regorafenib treatment (median SMI change: -2.75 cm2/m2 [-6.3%]; P < .0001), which was not the case during TAS-102 therapy (-1.5 cm2/m2 [-3.5%]; P = .575). Furthermore, subclassification of patients into 3 groups-normal muscle mass, stable sarcopenia, and new-onset sarcopenia-at initiation of third-line therapy permitted discrimination of overall survival, with 1-year overall survival rates of 61%, 29%, and 16%, respectively (P = .04). CONCLUSION: The frequency of sarcopenia increases during the course of mCRC and negatively affects survival. In contrast to TAS-102, regorafenib is associated with increased skeletal muscle loss during mCRC treatment and should therefore be used with caution in mCRC patients with preexisting sarcopenia or a history of recent weight loss.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Compostos de Fenilureia/efeitos adversos , Piridinas/efeitos adversos , Pirrolidinas/efeitos adversos , Terapia de Salvação/efeitos adversos , Sarcopenia/epidemiologia , Trifluridina/efeitos adversos , Uracila/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Áustria , Neoplasias Colorretais/complicações , Neoplasias Colorretais/mortalidade , Combinação de Medicamentos , Feminino , Seguimentos , Humanos , Vértebras Lombares , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/efeitos dos fármacos , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , Pirrolidinas/administração & dosagem , Estudos Retrospectivos , Terapia de Salvação/métodos , Sarcopenia/diagnóstico , Sarcopenia/etiologia , Índice de Gravidade de Doença , Taxa de Sobrevida , Tomografia Computadorizada por Raios X , Trifluridina/administração & dosagem , Uracila/administração & dosagem , Uracila/efeitos adversos
16.
Acta Oncol ; 58(8): 1149-1157, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31002008

RESUMO

Background: The treatment options for patients with therapy refractory metastatic colorectal cancer (mCRC) are sparse. TAS-102 (FTD/TPI) is a new oral anti-tumour agent composed of a nucleoside analogue, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil, indicated for patients with mCRC who are refractory to standard therapies. This study summarizes published and unpublished experience with FTD/TPI in clinical practice settings. Patients and methods: The Medline/PubMed, Embase and Cochrane Library databases were searched to identify observational studies on FTD/TPI monotherapy for mCRC. Papers describing use of FTD/TPI monotherapy outside clinical trials in series of patients evaluable for effectiveness were eligible. The outcomes of interest were median progression free survival (mPFS), median overall survival (mOS) as well as mean PFS time restricted to six months (PFS6m) and mean OS time restricted to one year (OS1y). Results of the pooled analyses of observational studies were compared to the results of the Japanese phase II trial and the two phase III trials, RECOURSE and TERRA. Results: Seven published and two unpublished studies with 1008 patients from 64 centres were included for analysis. The pooled mPFS was 2.2 months (95% CI 2.1 to 2.3 months), and the pooled mOS was 6.6 months (95% CI 6.1 to 7.1 months). PFS6m was 2.9 months (95% CI 2.6 to 3.1 months) and OS1y was 6.8 (95% CI 6.0 to 7.5) months. While these results all reflect RECOURSE, the pooled mOS is lower than in the phase II trial and the OS1y is inferior to both the phase II trial and TERRA. Conclusion: This systematic review and a meta-analysis indicates that in real life settings, the survival benefit of FTD/TPI monotherapy in patients with therapy refractory mCRC reflects the outcomes in RECOURSE but is inferior to outcomes in the two Asian efficacy trials. What is already known TAS 102 (Lonsurf) is an oral fixed dose combination of trifluridine (FTD) and tipiracil (TPI) indicated as salvage-line treatment in patients with therapy refractory metastatic colorectal cancer (mCRC). A Japanese phase II trial and two phase III trials, RECOURSE and TERRA, demonstrated that FTD/TPI prolonged overall survival. What this study adds This systematic review and meta-analysis of real life data from 64 sites indicates that the effectiveness in daily clinical practice settings of FTD/TPI monotherapy in late stage mCRC reflects the outcomes in RECOURCE but is inferior to the outcomes in the Japanese phase II trial and TERRA.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Pirrolidinas/uso terapêutico , Trifluridina/uso terapêutico , Uracila/análogos & derivados , Administração Oral , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Combinação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Estudos Observacionais como Assunto , Intervalo Livre de Progressão , Uracila/uso terapêutico
17.
Anticancer Res ; 39(2): 1029-1034, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30711991

RESUMO

AIM: This study aimed to clarify the tolerability of a trifluridine/tipiracil combination tablet (TAS-102) in patients with advanced or recurrent colorectal cancer over 75 years of age. PATIENTS AND METHODS: Patients were divided into groups under the age of 75 years (n=62), and 75 years and over (n=17). The treatment period with TAS-102 tablet, reasons for discontinuation, adverse events (AEs), and overall survival (OS) were compared between the groups. RESULTS: The incidence of AEs (including neutropenia, anemia, nausea, malaise, and anorexia) was similar for both groups and the treatment enforcement periods for different regimens were not statistically significant between the groups (p=0.207). No major differences were observed in the reasons for discontinuation, such as AEs or progressive disease, between the two groups. CONCLUSION: TAS-102 therapy for advanced/recurrent colorectal cancer is considered to be highly tolerable in patients 75 years and older. These findings are important for AE monitoring and guidance for patients taking TAS-102.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Trifluridina/efeitos adversos , Trifluridina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/induzido quimicamente , Anorexia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Metástase Neoplásica , Recidiva Local de Neoplasia , Neutropenia/induzido quimicamente , Pirrolidinas , Estudos Retrospectivos , Comprimidos , Resultado do Tratamento , Uracila/análogos & derivados
18.
Anticancer Res ; 39(2): 1051-1057, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30711994

RESUMO

BACKGROUND/AIM: New drugs for metastatic colorectal cancer (mCRC) have been recently developed for use in later-line chemotherapy and have contributed to further prolongation of the survival of patients. However, in later-line chemotherapy, treatment failure may lead to discontinuation of chemotherapy and the transition to best supportive care. Therefore, a biomarker able to predict the effects of later-line chemotherapy is required. The C-reactive protein-to-albumin ratio (CAR), which is an inflammatory marker, has been reported to correlate with therapeutic outcome in patients with mCRC who underwent first-line chemotherapy. However, the significance of the CAR as a marker for predicting the chemotherapeutic outcome in patients with mCRC treated with later-line chemotherapy is unknown. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 40 patients with mCRC who were treated with trifluridine/thymidine phosphorylase inhibitor (FTD/TPI) as a later-line chemotherapy. The CAR was calculated from the blood samples obtained within 1 week before the initiation of FTD/TPI by dividing the serum C-reactive protein level by the serum albumin level. RESULTS: According to the receiver operating characteristic curve analysis, we set 0.122 as the CAR cut-off, and patients were classified into groups with high or low CAR. The low-CAR group had a significantly higher disease control rate than the high-CAR group. The progression-free and overall survival rates were significantly better in the low-CAR group than in the high-CAR group. A high-CAR was associated with a greater number of prior regimens, higher serum lactate dehydrogenase level and more organs with metastases, considered to be correlated with the rate of disease progression. However, no significant differences were observed in the incidence of grade 3 or more adverse events, the relative dose intensity, or the rate of discontinuing chemotherapy between the two groups. CONCLUSION: The CAR may be a useful indicator for predicting the chemotherapeutic outcome in patients with mCRC treated with FTD/TPI as a late-line chemotherapy. The correlation between a high-CAR and poor prognosis was presumed to be due to the rate of cancer growth and increased resistance to chemotherapy rather than an insufficient dose of the drug.


Assuntos
Albuminas/análise , Antineoplásicos/uso terapêutico , Proteína C-Reativa/análise , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Trifluridina/uso terapêutico , Idoso , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Inflamação , Estimativa de Kaplan-Meier , L-Lactato Desidrogenase/metabolismo , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Curva ROC , Estudos Retrospectivos , Sensibilidade e Especificidade , Timidina Fosforilase/antagonistas & inibidores , Resultado do Tratamento
19.
Br J Clin Pharmacol ; 85(6): 1239-1246, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30628113

RESUMO

AIMS: Trifluridine/tipiracil (FTD/TPI) prolongs survival in refractory metastatic colorectal cancer, but limited data exist on its use in patients with hepatic impairment. This Phase I, open-label, nonrandomized study investigated the safety, tolerability and pharmacokinetics of FTD/TPI in patients with advanced solid tumours (except breast cancer) and varying degrees of hepatic impairment, to provide dosing recommendations. METHODS: Patients aged ≥18 years with advanced solid tumours and normal hepatic function, or mild, moderate or severe hepatic impairment according to National Cancer Institute criteria, were planned to be enrolled. Patients received FTD/TPI 35 mg/m2 orally twice daily on days 1-5 and 8-12 of each 28-day cycle. RESULTS: Twenty-four patients were enrolled to the normal hepatic function (n = 8) and mild (n = 10) and moderate (n = 6) hepatic impairment cohorts. Overall, 12 patients (50.0%) had at least 1 adverse event leading to study discontinuation. In the moderate hepatic impairment cohort, 5 of 6 patients experienced grade ≥ 3 elevation in bilirubin. No patients with severe hepatic impairment were enrolled. FTD area under the curve at steady state decreased by 18% and 22% in the mild and moderate cohorts, respectively; however, no clear change was observed in TPI area under the curve. CONCLUSIONS: FTD/TPI can be safely administered in patients with normal hepatic function and mild hepatic impairment, with no initial dose adjustment. FTD/TPI is not recommended for use in patients with moderate hepatic impairment because of findings of grade 3 or 4 increased blood bilirubin. Therefore, FTD/TPI is not recommended for patients with moderate or severe hepatic impairment.


Assuntos
Antineoplásicos/farmacocinética , Hepatopatias/complicações , Fígado/metabolismo , Neoplasias/tratamento farmacológico , Pirrolidinas/farmacocinética , Trifluridina/farmacocinética , Uracila/análogos & derivados , Administração Oral , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Bilirrubina/sangue , Esquema de Medicação , Combinação de Medicamentos , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Hepatopatias/diagnóstico , Hepatopatias/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Neoplasias/complicações , Neoplasias/diagnóstico , Pirrolidinas/administração & dosagem , Pirrolidinas/efeitos adversos , Índice de Gravidade de Doença , Resultado do Tratamento , Trifluridina/administração & dosagem , Trifluridina/efeitos adversos , Estados Unidos , Uracila/administração & dosagem , Uracila/efeitos adversos , Uracila/farmacocinética
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