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1.
Chin Clin Oncol ; 12(1): 5, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36922354

RESUMO

BACKGROUND AND OBJECTIVE: Intrahepatic cholangiocarcinoma (iCCA) is a rare hepatic malignancy with poor prognosis, which has seen an increased incidence over the last decade. Most patients present with advanced disease that is not amenable to surgical resection, and those who are able to undergo resection, frequently develop recurrent disease. With the rise of precision medicine, several targetable mutations have been described for iCCA and are currently under investigations. The development of improved targeted therapies is critical to prolonged overall survival (OS), and the use of targeted agents for iCCA is currently the focus of several ongoing randomized controlled trials. The objective of this review is to summarize current guidelines for diagnosis, surgical resection, and systemic treatment, which includes ongoing clinical trials investigated targeted therapies. METHODS: A comprehensive review was performed using MEDLINE/PubMed with the end search date of October 1, 2022. In PubMed the terms "intrahepatic cholangiocarcinoma," "bile duct cancer", "targeted therapies", and "clinical trials" were searched. KEY CONTENT AND FINDINGS: The mainstay of treatment for iCCA is R0 resection with lymphadenectomy. Following surgical resection, new guidelines recommend 6 months of adjuvant capecitabine. Among patients with advanced or metastatic disease, systemic chemotherapy plays a significant role in prolonging survival for these patients. CONCLUSIONS: Surgical resection represents the mainstay of treatment followed by 6 months of adjuvant capecitabine. While additional data is needed through randomized controlled trials, targeted therapies including fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase (IDH), and erythroblastic oncogene B2 (ErbB2) inhibitors offer promising results as adjuncts to current standard of care in iCCA, particularly among individuals with unresectable disease. Future recommendations regarding the use of targeted therapy will emerge as clinical trial data become available.


Assuntos
Antineoplásicos , Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Capecitabina/uso terapêutico , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ductos Biliares Intra-Hepáticos , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/diagnóstico
3.
Medicine (Baltimore) ; 102(11): e33214, 2023 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-36930122

RESUMO

RATIONALE: Colorectal cancer is the second leading cause of cancer-related deaths in the world. About 50% of patients will have metastases during the course of the disease. The common sites of metastasis are the liver, lung, peritoneum, lymph, etc. Metastatic carcinoma to the testes is uncommon. We found a case of ascending colon cancer metastasized to the testis in the clinic. PATIENT CONCERNS: We reported a 50-year-old male patient who was found to have testicular metastases >4 years after intestinal cancer surgery, and multiple metastases in the peritoneum and pelvis were found 1 week later. DIAGNOSES: After enhanced computed tomography and pathological biopsy, the patient was diagnosed with testicular metastasis of colon cancer. INTERVENTIONS: Capecitabine combined with bevacizumab is currently undergoing palliative treatment. OUTCOMES: The patients died of tumor progression on June 28, 2021. LESSONS: The testicular metastasis of colorectal cancer is a sign of peritoneum and multiple metastases. When the testicular metastasis occurs in colorectal cancer patients, it usually indicates that the patient has a poor prognosis.


Assuntos
Adenocarcinoma , Neoplasias do Colo , Neoplasias Testiculares , Masculino , Humanos , Pessoa de Meia-Idade , Adenocarcinoma/patologia , Neoplasias Testiculares/patologia , Bevacizumab , Capecitabina/uso terapêutico
6.
BMC Med ; 21(1): 94, 2023 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-36927541

RESUMO

BACKGROUND: Previous studies have shown that monotherapy with apatinib, an oral tyrosine kinase inhibitor, has promising efficacy for treating recurrent or metastatic (RM) nasopharyngeal carcinoma (NPC) patients. In this study, we aimed to assess the efficacy and safety of apatinib combined with capecitabine as a second-line therapy or beyond for treating RM-NPC patients who failed the first-line platinum-based chemotherapy. METHODS: In this single-arm, phase II study, we enrolled RM-NPC patients who had at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). The sample size was determined using Simon's two-stage design. All patients were administered with apatinib 500 mg once daily and capecitabine 1000 mg/m2 twice per day on days 1-14 of each 21-day cycle. The primary endpoint was the objective response rate (ORR), and the secondary endpoints comprised disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: We enrolled 64 patients from September 2018 to August 2020. The ORR and DCR were 39.1% (95% CI, 27.1-52.1) and 85.9% (95% CI, 75.0-93.4), respectively. The median DoR was 14.4 months (95% CI, 7.8-21.0). As of April 20, 2021, the median follow-up duration was 12.0 months. The median PFS was 7.5 months (95% CI, 5.0-10.0) and the median OS was 15.7 months (95% CI, 11.3-20.1). The most common toxicities of any grade were anemia (75.0%), hand-foot syndrome (65.6%), and proteinuria (64.0%). Grade 3-4 toxicities were observed in 36 (56.3%) patients, with hypertension (14.1%), mucositis (12.4%), and fatigue (10.9%) most commonly observed. CONCLUSIONS: Apatinib plus capecitabine shows promising efficacy as a second-line treatment option in pretreated platinum-refractory RM-NPC patients. Dose selection of this combination needs further investigation considering the toxicity. TRIAL REGISTRATION: Chi-CTR1800017229.


Assuntos
Neoplasias Nasofaríngeas , Humanos , Capecitabina/efeitos adversos , Estudos Prospectivos , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico
7.
BMJ Open ; 13(3): e066976, 2023 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-36927585

RESUMO

INTRODUCTION: Short-course radiotherapy (SCRT) with systemic therapy has the potential to further improve the long-term efficacy in patients with locally advanced rectal cancer (LARC). To maximise the benefits of neoadjuvant therapy for improved prognosis, it is important to determine the optimal mix of chemotherapy, immunotherapy and SCRT. METHODS AND ANALYSIS: Fifty treatment-naïve patients with operable LARC (T3-4 and/or N+) will be recruited. Patients will be synchronously treated with capecitabine plus oxaliplatin (CAPOX) chemotherapy, tislelizumab and preoperative split-course hypofraction radiotherapy (SCHR) (5×7 Gy) before surgery. Chemotherapy for CAPOX starts on day 1 of every 21-day cycle: on day 1, oxaliplatin 130 mg/m2 will be injected intravenously. On days 1-14, capecitabine 1000 mg/m2 was ingested two times a day. Simultaneously, tocilizumab 200 mg will be given intravenously on the first day of every 21-day cycle. A single 7 Gy SCHR treatment (day 7 of each 21-day cycle) will be delivered five times during the seventh day of treatment. The primary endpoint will be pathological complete response. The secondary outcomes will be the 3-year disease-free survival, local recurrence rate, overall survival, sphincter-sparing surgery rate, R0 resection rate, predictive biomarkers and quality of life. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of Xiehe Affiliated Hospital of Fujian Medical University (XAHFMU) (No. 2021YF025-01). Results from our study will be disseminated in international peer-reviewed journals. All study procedures were developed in order to assure data protection and confidentiality. TRIAL REGISTRATION NUMBER: NCT05176964.


Assuntos
Fluoruracila , Neoplasias Retais , Humanos , Capecitabina/uso terapêutico , Fluoruracila/uso terapêutico , Oxaliplatina/uso terapêutico , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/patologia , Canal Anal/patologia , Estudos Prospectivos , Qualidade de Vida , Tratamentos com Preservação do Órgão , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Neoadjuvante/métodos , Quimiorradioterapia , Estadiamento de Neoplasias , Ensaios Clínicos Fase II como Assunto
8.
Isr Med Assoc J ; 25(2): 126-130, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36841982

RESUMO

BACKGROUND: Anal squamous cell carcinoma (ASqCC) is a rare malignancy, traditionally treated with combined chemoradiation, with a continuous infusion of 5-fluorouracil (5-FU) and mitomycin C (MMC). Replacing intravenous (IV) 5-FU with oral capecitabine (oral fluoropyrimidine) has been reported as a non-inferior treatment option. However, these data are scarce, with variable results. OBJECTIVES: To examine the outcome of patients with ASqCC treated with either IV 5-FU or capecitabine concomitantly with radiation therapy. To compare treatment side effects, local recurrence, and general outcome. METHODS: We reviewed charts of patients who were diagnosed with stage I-III ASqCC. All participating patients received chemoradiation at the Assuta Medical Center between 2011 and 2019. RESULTS: In this study, 43 patients with ASqCC were eligible; 14 received 5-FU and 29 were treated with capecitabine. Basic characteristics were similar between the two groups, with longer follow-up for the 5-FU group. Six months following treatment, 100% (13/13 with adequate follow-up) of the 5-FU group had complete clinical response, compared to 84% in the capecitabine group (21/24), P = 0.143. The local recurrence incidence was higher in the 5-FU group at 23% (7, 10, 26 months following therapy, and none in the capecitabine group (P = 0.088). Although local and hematological toxicities were similar between groups, one patient receiving capecitabine died during chemoradiotherapy. CONCLUSIONS: Oral capecitabine demonstrated non-inferior disease control in ASqCC treated with chemoradiotherapy. We recommend oral capecitabine over continuous IV 5-FU in locally and locally advanced ASqCC. Close monitoring of side effects is required to reduce major toxicity.


Assuntos
Neoplasias do Ânus , Carcinoma de Células Escamosas , Humanos , Capecitabina/efeitos adversos , Fluoruracila/efeitos adversos , Neoplasias do Ânus/tratamento farmacológico , Neoplasias do Ânus/patologia , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/patologia , Mitomicina , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
9.
Gan To Kagaku Ryoho ; 50(2): 233-235, 2023 Feb.
Artigo em Japonês | MEDLINE | ID: mdl-36807182

RESUMO

The patient was a 50-year-old male. At the age of 48 years, he had undergone total gastrectomy and right hemicolectomy simultaneously for gastric and ascending colon cancers. Since adjuvant chemotherapy has become common practice for patients with ascending colon cancer, capecitabine was administered for 6 months. One year and 6 months after the surgery, he was diagnosed with recurrence of the ascending colon cancer at the anastomotic site and underwent local colectomy. Considering he was pathologically diagnosed as pT4a, mFOLFOX6 therapy was prescribed as postoperative adjuvant chemotherapy. On the day the 11th course of treatment was initiated, the patient complained of weakness; however, his blood test results showed no abnormalities; therefore, he was followed-up as an outpatient. Three days later, he presented to the hospital with exacerbated symptoms and was diagnosed with rhabdomyolysis due to a marked increase in CK(2,031 U/L). Rhabdomyolysis was determined to be the adverse effect of oxaliplatin because out of all the drugs prescribed to the patient, this condition is listed as a side effect only in oxaliplatin's package insert. Fortunately, outpatient treatment was enough to alleviate rhabdomyolysis. Subsequently, adjuvant chemotherapy was completed without oxaliplatin. The patient has been followed-up without recurrence for 9 months after the surgery.


Assuntos
Neoplasias do Colo , Rabdomiólise , Masculino , Humanos , Pessoa de Meia-Idade , Oxaliplatina/uso terapêutico , Fluoruracila , Intervalo Livre de Doença , Capecitabina , Neoplasias do Colo/tratamento farmacológico , Quimioterapia Adjuvante , Rabdomiólise/induzido quimicamente , Rabdomiólise/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
10.
Life Sci ; 319: 121523, 2023 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-36842762

RESUMO

AIM: We investigated the ability of baicalein (BAI) to enhance the anticancer potential of capecitabine (CAP) in the MCF-7 cell line and its protective effect on CAP-induced cardiotoxicity in female Wistar rats. METHODS AND KEY FINDINGS: In vitro study involved evaluating the effect of BAI and/or CAP on cell viability, cell cycle progression, and BAX and Bcl2 gene expression in MCF-7 cells. Co-treatment of BAI with CAP significantly reduced the viability of MCF-7 cells, improved their cytotoxic effect, markedly elevated the percentage of the sub-G1 population, drastically reduced the G2/M population, and significantly altered the mRNA expression of BAX and Bcl2 genes compared with each treatment alone. In vivo study revealed that the oral administration of CAP (140 mg/kg BW) to adult female rats significantly elevated the levels of serum creatine kinase-myocardial band (CK-MB), lactate dehydrogenase (LDH), tumor necrosis factor (TNF)-α, and interleukin (IL)-1ß and cardiac TNF-α, IL-1ß malondialdehyde (MDA) concentration, whereas it reduced the serum and cardiac total antioxidant capacity (TAC), level of cardiac glutathione (GSH) and activity of glutathione peroxidase (GPx) with a vast array of circulatory, inflammatory, degenerative, and necrotic alterations in the cardiac tissue. Furthermore, CAP administration significantly upregulated the mRNA expression of NF-κB, TLR4, MyD88, ATF6, CHOP, and JNK genes. Concurrent administration of BAI (200 mg/kg BW) and CAP significantly improved the biochemical alterations and cardiac oxidant/antioxidant status and architecture. In addition, it modulated the TLR4/MyD88/NF-κB pathway and endoplasmic reticulum stress. SIGNIFICANCE: Altogether, BAI can augment the anticancer potential of CAP and alleviate its cardiotoxic effects during cancer treatment.


Assuntos
Antioxidantes , Traumatismos Cardíacos , Feminino , Humanos , Ratos , Animais , Ratos Wistar , Antioxidantes/farmacologia , Antioxidantes/metabolismo , NF-kappa B/metabolismo , Capecitabina/toxicidade , Capecitabina/metabolismo , Células MCF-7 , Proteína X Associada a bcl-2/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Receptor 4 Toll-Like/metabolismo , Estresse Oxidativo , Apoptose , Cardiotoxicidade/metabolismo , Glutationa/metabolismo , RNA Mensageiro/metabolismo
11.
Int J Pharm ; 635: 122735, 2023 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-36803928

RESUMO

The present research aims to synthesize the capecitabine-loaded core-shell nanoparticles of acrylamide-grafted melanin and itaconic acid-grafted psyllium (Cap@AAM-g-ML/IA-g-Psy-NPs) to deliver the drug to the targeted colonic area, enhancing their anti-cancer activity. The drug release behavior of Cap@AAM-g-ML/IA-g-Psy-NPs was studied at several biological pH in which maximum drug release (95 %) was observed at pH 7.2. The drug release kinetic data was in accordance with the first-order (R2 = 0.9706) kinetic model. The cytotoxicity of Cap@AAM-g-ML/IA-g-Psy-NPs was investigated on HCT-15 cell line and Cap@AAM-g-ML/IA-g-Psy-NPs demonstrated outstanding toxicity towards HCT-15 cell line. In-vivo study on DMH-induced colon cancer rat model also exhibited that Cap@AAM-g-ML/IA-g-Psy-NPs enhanced anticancer activity against cancer cells as compared to capecitabine. Histology studies of heart, liver and kidney cells indicate that inflation due to cancer induction by DMH is significantly reduced when treated with Cap@AAM-g-ML/IA-g-Psy-NPs. Thus, the present study procures a worthwhile and nominal approach toward the synthesis of Cap@AAM-g-ML/IA-g-Psy-NPs for anticancer applications.


Assuntos
Nanopartículas , Psyllium , Ratos , Animais , Capecitabina , Portadores de Fármacos , Melaninas , Acrilamida , Nanopartículas/uso terapêutico , Liberação Controlada de Fármacos
12.
Expert Rev Anticancer Ther ; 23(3): 243-256, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36803258

RESUMO

INTRODUCTION: There have been significant advances in the treatment of hepatobiliary cancers, especially for advanced-stage disease. However, data is limited for optimal therapy selection in the first line and sequencing of available options. AREAS COVERED: This review covers the systemic treatment of hepatobiliary cancers with an emphasis on the advanced stage. The previously published and ongoing trials will be discussed to create an algorithm for the current practice and to give future perspectives on how the field could go forward. EXPERT OPINION: While there is no standard-of-care option in the adjuvant treatment of hepatocellular cancer, capecitabine is the standard of care for biliary tract cancer. The efficacy of adjuvant gemcitabine and cisplatin and the added benefit of radiotherapy to chemotherapy are yet to be defined. For the advanced stage, immunotherapy-based combinations became the standard of care for both hepatocellular and biliary tract cancers. The molecularly targeted therapy has profoundly changed the second-line and later treatment for biliary tract cancers, while the optimal second-line treatment for advanced hepatocellular cancer is yet to be defined due to rapid advances in the first-line setting.


Assuntos
Neoplasias do Sistema Biliar , Neoplasias Hepáticas , Humanos , Neoplasias do Sistema Biliar/tratamento farmacológico , Gencitabina , Capecitabina , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico
13.
Cells ; 12(3)2023 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-36766741

RESUMO

This study aimed to evaluate the benefit of additional administration of oxaliplatin during fluorouracil-based neoadjuvant radiochemotherapy (nRCT) in terms of pathologic complete remission (pCR), disease-free survival (DFS), and overall survival (OS) in patients with advanced rectal cancer. Between 2006 and 2021, 669 patients (pts) were diagnosed with locally advanced rectal cancer, of whom a total of 414 pts with nRCT were identified and included in the study. A total of 283 pts were treated by nRCT using concurrent chemotherapy with fluorouracil or capecitabine; 131 pts were treated using a combination of fluorouracil or capecitabine and oxaliplatin. Propensity score matching analyses (PSM) with 114 pts in each group were used to balance the patients' characteristics. OS, DFS, pCR-rate, and potential prognostic factors were compared between the two groups. The median follow-up time was 59.5 weeks in the fluorouracil-group and 43 weeks in the fluorouracil/oxaliplatin group (p = 0.003). After PSM, the pCR-rate (including sustained clinical complete remission) was 27% (31/114 pts) in the fluorouracil/oxaliplatin group and 16% (18/114 pts) in the fluorouracil-group (p = 0.033). There was no difference between these two groups for both 10-year OS and DFS neither before nor after PSM, respectively (OS: 72.6% vs. 55.4%, p = 0.066, and 67.8% vs. 55.1%, p = 0.703, and DFS: 44.8% vs. 46.8%, p = 0.134, and 44.7% vs. 42.3%, p = 0.184). Multivariate analysis identified regression grading according to Dworak grade 4 (HR: 0.659; CI: 0.471-0.921; p = 0.015) and age over 60 years (HR: 2.231; CI: 1.245-4.001; p = 0.007) as independent predictors for OS. In conclusion, the addition of oxaliplatin to fluorouracil during nRCT significantly improved pCR-rate without having an impact on survival.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Retais , Humanos , Pessoa de Meia-Idade , Oxaliplatina/uso terapêutico , Capecitabina/uso terapêutico , Taxa de Sobrevida , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/patologia , Fluoruracila/uso terapêutico , Quimiorradioterapia
14.
Technol Cancer Res Treat ; 22: 15330338231152350, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36727222

RESUMO

Background: Chemotherapy combined with antivascular endothelial growth factor (VEGF) or anti-epidermal growth factor receptor monoclonal antibodies is the most promising approach to prolong survival and improve the quality of life of patients with unresectable metastatic colorectal cancer (mCRC). Anlotinib is an oral antiangiogenic tyrosine kinase inhibitor that targets VEGF receptors 1/2/3, fibroblast growth factor receptors 1-4, and platelet-derived growth factor receptors a/ß. Since anlotinib combined with oxaliplatin and capecitabine (CAPEOX) as a first-line treatment was previously shown to be effective and safe for patients with RAS/BRAF wild-type (WT) mCRC, we designed this randomized, open-label, parallel-group, non-inferiority, phase III study to evaluate the efficacy and safety of anlotinib plus CAPEOX versus bevacizumab plus CAPEOX in patients with RAS/BRAF WT mCRC. Methods/design: The primary inclusion criteria are Eastern Cooperative Oncology Group performance status 0/1, confirmed RAS/BRAF WT colorectal adenocarcinoma, and unresectable metastases assessed by a multidisciplinary team. The main exclusion criteria are as follows: high microsatellite instability or deficient mismatch repair status, resectable or potentially resectable metastases, and previous systemic therapy for mCRC. A total of 698 patients will be randomized into the anlotinib and bevacizumab groups in a 1:1 ratio. Patients will receive 4 to 8 cycles of induction therapy (CAPEOX plus anlotinib or bevacizumab), followed by maintenance treatment (capecitabine plus anlotinib or bevacizumab) until disease progression or unacceptable toxicity. Progression-free survival (PFS) assessed by an independent review committee is the primary endpoint, whereas investigator-assessed PFS, overall survival, objective response rate, disease control rate, duration of response, resection rate of liver metastases, quality of life, and safety are the secondary endpoints. Enrollment commenced in May 2021. Discussion: A prospective, randomized, phase III trial will provide a meaningful comparison of the efficacy and safety of anlotinib plus CAPEOX with standard treatment for patients with unresectable RAS/BRAF WT mCRC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Neoplasias Colorretais , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Capecitabina , Ensaios Clínicos Fase III como Assunto , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Estudos Prospectivos , Proteínas Proto-Oncogênicas B-raf/genética , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto
15.
J Biol Rhythms ; 38(2): 171-184, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36762608

RESUMO

The circadian timing system controls absorption, distribution, metabolism, and elimination processes of drug pharmacokinetics over a 24-h period. Exposure of target tissues to the active form of the drug and cytotoxicity display variations depending on the chronopharmacokinetics. For anticancer drugs with narrow therapeutic ranges and dose-limiting side effects, it is particularly important to know the temporal changes in pharmacokinetics. A previous study indicated that pharmacokinetic profile of capecitabine was different depending on dosing time in rat. However, it is not known how such difference is attributed with respect to diurnal rhythm. Therefore, in this study, we evaluated capecitabine-metabolizing enzymes in a diurnal rhythm-dependent manner. To this end, C57BL/6J male mice were orally treated with 500 mg/kg capecitabine at ZT1, ZT7, ZT13, or ZT19. We then determined pharmacokinetics of capecitabine and its metabolites, 5'-deoxy-5-fluorocytidine (5'DFCR), 5'-deoxy-5-fluorouridine (5'DFUR), 5-fluorouracil (5-FU), in plasma and liver. Results revealed that plasma Cmax and AUC0-6h (area under the plasma concentration-time curve from 0 to 6 h) values of capecitabine, 5'DFUR, and 5-FU were higher during the rest phase (ZT1 and ZT7) than the activity phase (ZT13 and ZT19) (p < 0.05). Similarly, Cmax and AUC0-6h values of 5'DFUR and 5-FU in liver were higher during the rest phase than activity phase (p < 0.05), while there was no significant difference in liver concentrations of capecitabine and 5'DFCR. We determined the level of the enzymes responsible for the conversion of capecitabine and its metabolites at each ZT. Results indicated the levels of carboxylesterase 1 and 2, cytidine deaminase, uridine phosphorylase 2, and dihydropyrimidine dehydrogenase (p < 0.05) are being rhythmically regulated and, in turn, attributed different pharmacokinetics profiles of capecitabine and its metabolism. This study highlights the importance of capecitabine administration time to increase the efficacy with minimum adverse effects.


Assuntos
Antimetabólitos Antineoplásicos , Ritmo Circadiano , Masculino , Camundongos , Ratos , Animais , Capecitabina/farmacocinética , Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/uso terapêutico , Camundongos Endogâmicos C57BL , Fluoruracila/metabolismo , Fluoruracila/uso terapêutico
16.
ESMO Open ; 8(1): 100782, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36791638

RESUMO

BACKGROUND: In 2020, the European Medicines Agency recommended testing patients for dihydropyrimidine dehydrogenase (DPD) deficiency before systemic treatment with fluoropyrimidines (FP). DPD activity testing identifies patients at elevated risk of severe FP-related toxicity (FP-TOX). The two most used methods for DPD testing are DPYD genotyping and DPD phenotyping (plasma uracil concentration). The primary objective of this study was to compare the overall frequency of overall grade ≥3 FP-TOX before and after the implementation of DPYD genotyping. PATIENTS AND METHODS: Two hundred thirty Danish, primarily gastrointestinal cancer patients, were DPYD-genotyped before their first dose of FP, and blood was sampled for post hoc assessment of P-uracil. The initial dose was reduced for variant carriers. Grade ≥3 FP-TOX was registered after the first three treatment cycles of FP. The frequency of toxicity was compared to a historical cohort of 492 patients with post hoc determined DPYD genotype from a biobank. RESULTS: The frequency of overall grade ≥3 FP-TOX was 27% in the DPYD genotype-guided group compared to 24% in the historical cohort. In DPYD variant carriers, DPYD genotyping reduced the frequency of FP-related hospitalization from 19% to 0%. In the control group, 4.8% of DPYD variant carriers died due to FP-TOX compared to 0% in the group receiving DPYD genotype-guided dosing of FP. In the intervention group, wild-type patients with uracil ≥16 ng/ml had a higher frequency of FP-TOX than wild-type patients with uracil <16 ng/ml (55% versus 28%). CONCLUSIONS: We found no population-level benefit of DPYD genotyping when comparing the risk of grade ≥3 FP-TOX before and after clinical implementation. We observed no deaths or FP-related hospitalizations in patients whose FP treatment was guided by a variant DPYD genotype. The use of DPD phenotyping may add valuable information in DPYD wild-type patients.


Assuntos
Deficiência da Di-Hidropirimidina Desidrogenase , Neoplasias Gastrointestinais , Humanos , Antimetabólitos Antineoplásicos/efeitos adversos , Capecitabina/efeitos adversos , Dinamarca , Deficiência da Di-Hidropirimidina Desidrogenase/induzido quimicamente , Deficiência da Di-Hidropirimidina Desidrogenase/tratamento farmacológico , Deficiência da Di-Hidropirimidina Desidrogenase/genética , Di-Hidrouracila Desidrogenase (NADP)/genética , Neoplasias Gastrointestinais/tratamento farmacológico , Genótipo , Uracila/uso terapêutico
17.
Cancer Rep (Hoboken) ; 6(2): e1704, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36806724

RESUMO

BACKGROUND: Fluoropyrimidines (FP) are among the most common class of prescribed anti-neoplastic drugs. This class has severe to moderate toxicity in around 10%-40% of those who take 5-fluorouracil (5-FU) or capecitabine for the treatment of cancer. In practice many patients with severe toxicities from FP use had dihydropyrimidine dehydrogenase (DPD) enzyme deficiency. Several studies have proposed DPD screening before treatment with 5-fluorouracil (5-FU) and capecitabine or other drugs belonging to the FP group. This study aims to assess the level of awareness and attitudes of oncology specialists in Saudi Arabia toward genetic screening for DPD prior to giving FP. This highlights the importance of health guidelines required for implementation in our health care system, as a framework to adopt testing as a regular practice in clinical care. Based on the findings in this study, guidelines have been suggested for the Middle East North Africa region. METHODS: A cross-sectional survey study was conducted during 2021 targeting oncologists and clinical pharmacists working in the oncology departments across Saudi Arabia. RESULTS: A total of 130 oncologists and pharmacists completed the questionnaire representing a response rate of 87%. Most of the respondents indicated that they prescribe FP in clinical practice, but 41% of respondents reported that they have never ordered a specific molecular test during their practice. Only 20% of respondents reported that they often screen for DPD deficiency prior to prescribing FP. Significantly higher rates of awareness of potential dihydropyrimidine dehydrogenase gene (DPYD) mutation were observed among respondents in governmental hospitals (81.1% vs. 47.4% in private hospitals), and among those with more years of practice (80.6% if 5 or more years of practice vs. 59.3% if less than 5 years of practice). Also, higher rates of observing the impact of DPD testing were present among respondents with a PharmD (35% vs. 11% for oncologists and 18% for other professions) and among those with 5 or more years of practice (24.6% vs. 7.7% among those with less than 5 years). CONCLUSION: While in some institutions there is a high level of awareness among oncology specialists in Saudi Arabia regarding the effect of the potentially serious DPD enzyme deficiency as a result of gene mutations, screening for these mutations prior to prescribing FP is not a routine practice in hospitals across the country. The findings of this study should promote personalized medicine with recognition of interpatient variability via DPD testing to manage the risks of FP prescribing more effectively in the Kingdom of Saudi Arabia.


Assuntos
Deficiência da Di-Hidropirimidina Desidrogenase , Di-Hidrouracila Desidrogenase (NADP) , Humanos , Di-Hidrouracila Desidrogenase (NADP)/genética , Capecitabina/efeitos adversos , Antimetabólitos Antineoplásicos/efeitos adversos , Arábia Saudita , Estudos Transversais , Fluoruracila/efeitos adversos , Deficiência da Di-Hidropirimidina Desidrogenase/diagnóstico , Deficiência da Di-Hidropirimidina Desidrogenase/tratamento farmacológico , Deficiência da Di-Hidropirimidina Desidrogenase/genética
18.
Zhonghua Yi Xue Za Zhi ; 103(4): 271-277, 2023 Jan 31.
Artigo em Chinês | MEDLINE | ID: mdl-36660788

RESUMO

Objective: To compare the efficacy and safety of short-course radiotherapy with total neoadjuvant therapy (SCRT-TNT) and neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced middle and low rectal cancer. Methods: A retrospective cohort study was carried out. A of 126 patients with locally advanced middle and low rectal cancer who were treated in the Department of Gastrointestinal Cancer Surgery of Fujian Cancer Hospital from September 2016 to March 2020 were enrolled, including 73 males and 53 females, with a mean age of (56.5±9.8) (23-77) years. Based on neoadjuvant regimen (nCRT treatment was performed before December 2018 and SCRT-TNT treatment was carried out after January 2019), patients were divided into nCRT group (n=68) and SCRT-TNT group (n=58). There were no statistically significant differences in age, sex, distance from tumor to anal verge, Eastern Cooperative Oncology Group (ECOG) performance status and clinical TNM stage between the two groups (all P>0.05). Patients in both groups received pelvic intensity-modulated radiotherapy (IMRT). The radiotherapy dose of nCRT group was 50Gy/25 times/5 weeks. Patients in nCRT group received oral capecitabine chemotherapy during radiotherapy and underwent surgery 6-8 weeks after chemoradiation. However, patients in SCRT-TNT group received CapeOX regimen (oxaliplatin+capecitabine) for 2 cycles of induction chemotherapy, followed by short-course radiotherapy (25Gy/5 times/5 days), then underwent a radical surgery two weeks after completion of consolidation chemotherapy (4 cycles). The adverse reactions, perioperative safety and efficacy of neoadjuvant therapy were compared and analyzed between the two groups. Results: Both groups completed neoadjuvant therapy as planned. Patients in nCRT group and SCRT-TNT group had similar incidence of adverse reactions to radiotherapy and chemotherapy, however, there were no statistically significant differences in the incidence of surgical complications, operation time, intraoperative blood loss and postoperative length of hospital stay (all P>0.05). A total of 119 patients underwent total mesenterectomy (TME), including 64 patients in the nCRT group and 55 patients in the SCRT-TNT group, all with R0 resection. The pathological complete response (pCR) rate was 10.9% (7/64) in the nCRT group and 25.5% (14/55) in the SCRT-TNT group, respectively, with a statistically significant difference (P=0.038). Two years after surgery, there was no statistically significant difference in local recurrence rate and overall survival rate between the two groups (both P>0.05). However, the clinical metastasis rate of SCRT-TNT group was significantly lower than that of nCRT group (20.3% vs 9.1%), with a statistically significant difference (P<0. 05). Conclusion: SCRT-TNT do not increase the adverse reactions of radio chemotherapy and perioperative risks in the treatment of locally advanced middle and low rectal cancer, and the tumor regression effect is good, which is worthy of clinical promotion.


Assuntos
Terapia Neoadjuvante , Neoplasias Retais , Masculino , Feminino , Humanos , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Capecitabina , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias Retais/cirurgia , Quimiorradioterapia , Estadiamento de Neoplasias , Protocolos de Quimioterapia Combinada Antineoplásica
19.
Medicine (Baltimore) ; 102(4): e32644, 2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36705379

RESUMO

RATIONALE: Pseudoprogression has been deemed as a rare clinical phenomenon during the treatment of immune checkpoint inhibitors in patients with advanced cancers, especially in periampullary carcinoma, however, leaving potential molecular mechanism remain unknown. PATIENT CONCERNS: Regular examination after radical pancreaticoduodenectomy because of periampullary carcinoma. DIAGNOSES: Recurrent periampullary carcinoma with metastasis in liver. INTERVENTIONS: Regimens of XELOX (oxaliplatin at a dose of 130 mg/m2, day 1 and oral capecitabine at a dose of 1000 mg/m2 twice a day, day 1-14, every 21 days), and tislelizumab at a dose of 200 mg, day 1, per 21 days, was prescribed as palliative treatment. OUTCOMES: Pseudoprogression and symptom of hair and mustache repigmentation were also observed, which resulted in partial response finally. LESSONS: Results of the present case suggested that pseudoprogression, along with hair and mustache repigmentation, possibly caused by anti-PD-1 inhibitors, may also happen in patients with periampullary carcinoma, which should be paid attention to. The potential mechanism should be further investigated.


Assuntos
Carcinoma , Inibidores de Checkpoint Imunológico , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Capecitabina , Oxaliplatina , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/tratamento farmacológico , Pancreaticoduodenectomia
20.
Curr Oncol ; 30(1): 663-672, 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36661700

RESUMO

Fluoropyrimidine chemotherapy is associated with interpatient variability in toxicity. A major contributor to unpredictable and severe toxicity relates to single nucleotide variation (SNV) in dihydropyrimidine dehydrogenase (DPYD), the rate-limiting fluoropyrimidine metabolizing enzyme. In addition to SNVs, a study of Finnish patients suggested that a DPYD exon 4 deletion was observed in their population. To better understand the potential generalizability of such findings, we investigated the presence of this exon 4 deletion in our Canadian patient population, using a TaqMan assay. We selected 125 patients who experienced severe fluoropyrimidine-associated toxicity, and 125 matched controls. One patient in the severe toxicity group harbored a haploid DPYD exon 4 deletion, and required a 35% dose reduction after their first fluoropyrimidine treatment cycle due to toxicity and required an additional 30% dose reduction before tolerating treatment. The predicted allele frequency was 0.2% in our cohort, much lower than the 2.4% previously reported. We also carried out a literature review of copy number variation (CNV) in the DPYD gene, beyond fluoropyrimidine toxicity and show that various types of CNV in DPYD are present in the population. Taken together, our findings suggest that CNV in DPYD may be an underappreciated determinant of DPYD-mediated fluoropyrimidine toxicity.


Assuntos
Di-Hidrouracila Desidrogenase (NADP) , Fluoruracila , Humanos , Di-Hidrouracila Desidrogenase (NADP)/genética , Fluoruracila/efeitos adversos , Capecitabina/efeitos adversos , Variações do Número de Cópias de DNA , Canadá , Éxons
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