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1.
Cancer Sci ; 111(2): 513-527, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31789476

RESUMO

The global, randomized NAPOLI-1 phase 3 trial reported a survival benefit with liposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (nal-IRI+5-FU/LV) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) after previous gemcitabine-based therapy. Median overall survival (OS) with nal-IRI+5-FU/LV was 6.1 vs 4.2 months with 5-FU/LV alone (unstratified hazard ratio [HR] = 0.67, P = .012). Herein, we report efficacy and safety results from a post-hoc subgroup analysis of Asian patients treated at Asian centers. Primary study endpoint was OS; secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. Patients receiving nal-IRI+5-FU/LV (n = 34) had significantly longer median OS versus 5-FU/LV (n = 35) (8.9 vs 3.7 months; unstratified HR = 0.51, P = .025). Patients had significantly increased median PFS with nal-IRI+5-FU/LV versus 5-FU/LV (4.0 vs 1.4; unstratified HR = 0.48, P = .011), and increased ORR (8.8% vs 0; P = .114). nal-IRI monotherapy (n = 50) numerically improved efficacy endpoints versus 5-FU/LV (n = 48): median OS was 5.8 versus 4.3 months (HR = 0.83, P = .423) and median PFS was 2.8 versus 1.4 months (HR = 0.69, P = .155). Grade ≥3 neutropenia was reported more frequently with nal-IRI+5-FU/LV versus 5-FU/LV (54.5% vs 3.4%), and incidence of grade ≥3 diarrhea was comparable between the two arms (3.0% vs 6.9%). This subgroup analysis confirms nal-IRI+5-FU/LV as an efficacious treatment option that improves survival in Asian patients with mPDAC that progressed after gemcitabine-based therapy, with a safety profile agreeing with previous findings. The nal-IRI+5-FU/LV regimen should represent a new standard of care for these patients in Asia. (Clinicaltrials.gov: NCT01494506).


Assuntos
Adenocarcinoma/tratamento farmacológico , Fluoruracila/administração & dosagem , Irinotecano/administração & dosagem , Leucovorina/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Grupo com Ancestrais do Continente Asiático , Determinação de Ponto Final , Feminino , Fluoruracila/uso terapêutico , Humanos , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Lipossomos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Análise de Sobrevida , Resultado do Tratamento
2.
Int J Radiat Oncol Biol Phys ; 106(1): 124-133, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31494181

RESUMO

PURPOSE: Preoperative therapy in borderline resectable pancreatic cancer (BRPC) is intended to increase R0 resection rates. An optimal approach in BRPC is yet to be defined. METHODS AND MATERIALS: Patients with BRPC, confirmed adenocarcinoma, performance status ≤1, and adequate organ function enrolled in a single-institution, phase 2 trial. Patients received FOLFIRINOX × 6 cycles, then radiation therapy (50 Gy in 25 fractions) concurrent with fixed-dose rate gemcitabine (1 g/m2 over 100 minutes) followed by 2 additional gemcitabine infusions. Computed tomography scans were performed at 2-month intervals during treatment. Patients without distant disease were offered surgical exploration. The primary objective was R0 resection rate with an alternate hypothesis of 55%. Secondary objectives included median progression-free survival (PFS), median overall survival (OS), response rate, and safety. The trial registration number is NCT01661088. RESULTS: Twenty-five patients with median age of 60 years (range, 47-77 years) enrolled from November 2011 through January 2017. Twenty-one (84%) completed FOLFIRINOX and 19 (76%) completed all protocol therapy. Treatment-related grade 3 to 4 toxicities included neutropenia (40%), nausea and vomiting (28%), diarrhea (16%), and fatigue (12%). Eighteen patients (72%) underwent laparotomy, 13 (52%) were resected (all R0). The median PFS and OS in 25 patients were 13.1 months (95% confidence interval [CI], 7.3-24.7) and 24.4 months (95% CI, 12.6-40.0), respectively. For resected patients, median PFS was 21.6 months (95% CI, 8.2-37.1) and OS was 37.1 months (95% CI, 15.4-not reached). CONCLUSIONS: Neoadjuvant therapy with FOLFIRINOX, followed by intensity modulated radiation therapy concurrent with fixed-dose-rate gemcitabine in BRPC is feasible and tolerated. Although the alternate hypothesis was not met, the OS of the resected cohort was favorable.


Assuntos
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Terapia Neoadjuvante/métodos , Neoplasias Pancreáticas/terapia , Radioterapia de Intensidade Modulada/métodos , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno CA-19-9/metabolismo , Quimiorradioterapia/métodos , Desoxicitidina/administração & dosagem , Fracionamento da Dose de Radiação , Estudos de Viabilidade , Feminino , Fluoruracila/administração & dosagem , Humanos , Irinotecano/administração & dosagem , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Neutropenia/induzido quimicamente , Oxaliplatina/administração & dosagem , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Intervalo Livre de Progressão , Radioterapia de Intensidade Modulada/efeitos adversos
3.
Chem Biol Interact ; 316: 108933, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31870839

RESUMO

Irinotecan is a chemotherapeutic drug used in the treatment of advanced colorectal cancer and elevated blood concentrations of its active metabolite, SN-38 leads to increased gastrointestinal (GI) toxicity and diarrhea in patients. In this study, we investigated the effects of inflammation on the pharmacokinetics (PK) of irinotecan (CPT-11) and its active metabolite, SN-38. Mice were i.p.-injected with either saline or lipopolysaccharide (LPS) to induce inflammation. After 16 h, irinotecan was administered orally. Blood was collected from the tail vein of mice from 0 to 24 h after dosing. Concentrations of irinotecan, SN-38 and SN-38G were analyzed using LC-MS/MS. The AUC, Cmax, and tmax were derived using WinNonlin® 5.2. A PK model was developed using Phoenix NLME® to describe the PK of irinotecan and SN-38 during inflammation. Results indicated a significant increase in the blood concentrations of irinotecan and SN-38 in mice during inflammation. The AUC of irinotecan and SN-38 in LPS group were 2.6 and 2-folds, respectively, of those in control saline-treated mice. The Cmax of irinotecan and SN-38 in LPS treated mice were 2.4 and 2.3-folds of those in saline-treated mice. The PK model was successfully developed and validated. The best-fit plots of individual PK analysis showed a good correlation between observed and predicted concentrations of irinotecan and SN-38. Together, this study reveals that SN-38 concentrations are elevated during inflammation, which may increase the GI toxicity and diarrhea in patients who receive irinotecan; and the developed PK model can quantitatively describe the PK of irinotecan and SN-38 during inflammation.


Assuntos
Inflamação/etiologia , Irinotecano/farmacocinética , Administração Oral , Animais , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Meia-Vida , Inflamação/metabolismo , Irinotecano/administração & dosagem , Irinotecano/sangue , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Teóricos , Curva ROC , Espectrometria de Massas em Tandem
4.
Medicine (Baltimore) ; 98(52): e18344, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31876708

RESUMO

BACKGROUND: Approximately 80% to 90% of patients with low-risk rhabdomyosarcoma can be cured. However, cured patients often face long-term complications associated with the treatment. An important factor in the treatment plan is the dose of cyclophosphamide administered because the dose can have both acute and long-term side effects. It is therefore essential to investigate whether the dose can be reduced without a negative effect on treatment outcome. The ARST0331 trial revealed that drastically reducing the cyclophosphamide dose to 4.8 g/m negatively affected treatment outcomes. The current study aims to determine whether reducing the cyclophosphamide dose to 10.8 g/m while introducing a new drug, irinotecan, can prevent the negative effect on treatment outcome. We also aim to investigate whether the reduced cyclophosphamide dose results in a decrease in infertility, one of the long-term complications of this treatment. METHODS: The subjects are patients with stage 1 group III rhabdomyosarcoma (excluding those with orbital group III N0 and NX) or patients with stage 3 group I and II low-risk subset B embryonal rhabdomyosarcoma who will alternately undergo VAC 1.2 treatment (vincristine, actinomycin D, cyclophosphamide 1.2 g/m) and VI treatment (vincristine, irinotecan). The effectiveness and safety of this treatment regimen will be assessed. Data will be presented at international conferences and will be published in peer-reviewed journals. DISCUSSION: This study is significant because it aims to establish that the use of irinotecan in patients with low-risk subset B embryonal rhabdomyosarcoma (aged 30 or younger) allows the dose of cyclophosphamide to be reduced and is associated with few short-term adverse effects and long-term complications. The open-label and single-arm design of this study may be a limitation. TRIAL REGISTRATION AND ETHICAL APPROVAL: The trial registration number is jRCTs051180200 (Japan Registry of Clinical Trials). The study protocol was approved by the institutional review board at each of the participating centers and the data will be presented at international conferences and published in peer-reviewed journals.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/administração & dosagem , Dactinomicina/administração & dosagem , Irinotecano/administração & dosagem , Rabdomiossarcoma/tratamento farmacológico , Vincristina/administração & dosagem , Adulto , Protocolos Clínicos , Ciclofosfamida/uso terapêutico , Dactinomicina/uso terapêutico , Humanos , Irinotecano/uso terapêutico , Estadiamento de Neoplasias , Rabdomiossarcoma/patologia , Resultado do Tratamento , Vincristina/uso terapêutico
5.
Medicina (B Aires) ; 79(Spec 6/1): 576-581, 2019.
Artigo em Espanhol | MEDLINE | ID: mdl-31864229

RESUMO

Locally advanced pancreatic cancer (LAPC) has several definitions, but it is essentially a non-metastatic tumor, in which the initial surgical resection is not considered beneficial due to the extensive vascular involvement and consequent high chance of a nonradical resection. The introduction of chemotherapy with calcium leucovorin, fluorouracil, irinotecan hydrochloride and oxaliplatin (FOLFIRINOX) and gemcitabine-nab (nanoparticle albumin-bound)-paclitaxel (gem-nab) had very important implications for the management of patients with LAPC. After 4 to 6 months of induction chemotherapy, a large proportion of them have stable disease or even tumor regression, allowing to rescue those who initially were not candidates for surgery, with 30-35 months overall survival after surgery.


Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Desoxicitidina/análogos & derivados , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Desoxicitidina/administração & dosagem , Fluoruracila/administração & dosagem , Humanos , Quimioterapia de Indução , Irinotecano/administração & dosagem , Leucovorina/administração & dosagem , Terapia Neoadjuvante , Estadiamento de Neoplasias , Oxaliplatina/administração & dosagem , Análise de Sobrevida
6.
Anticancer Res ; 39(11): 6097-6105, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704837

RESUMO

BACKGROUND/AIM: Colorectal cancer (CRC) is one of the most common in the world and its prevalence is rapidly increasing. Jagged-1-activated Notch signaling by apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1) promotes CRC, and high expression of Jagged-1 is associated with poor prognosis. However, its clinical implication is unknown. The aim of this study was to investigate the clinical role of Jagged-1-activated Notch signaling by APEX1. MATERIALS AND METHODS: The 5-dimethylthiazol-2-yl) 2, 5-diphenyltetrazolium bromide (MTT) assay was used to evaluate the anti-cancer efficacy of 5-fluorouracil (5-FU), oxaliplatin, and irinotecan. Tissue from CRC patients was analyzed to assess the clinical specificity of Jagged-1 activated by APEX1. RESULTS: The half-maximal inhibitory concentration (IC50) in cells co-expressing APEX1 and Jagged-1 cells was higher than that in cells expressing only APEX1. These results indicated that the simultaneous expression of APEX1 and Jagged-1 might be associated with chemoresistance toward 5-FU, oxaliplatin, and irinotecan. Analysis of tissue from CRC patients revealed that high expression of Jagged-1 was associated with a statistically significantly low response to chemotherapy. CONCLUSION: Overexpression of Jagged-1 by APEX1 might serve as a predictor of response to chemotherapy and of poor prognosis, and moreover may be a therapeutic target for chemotherapy of advanced CRC.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/patologia , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteína Jagged-1/metabolismo , Receptor Notch1/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Irinotecano/administração & dosagem , Proteína Jagged-1/genética , Masculino , Pessoa de Meia-Idade , Oxaliplatina/administração & dosagem , Prognóstico , Receptor Notch1/genética , Estudos Retrospectivos , Taxa de Sobrevida , Células Tumorais Cultivadas
7.
BMC Cancer ; 19(1): 990, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31646981

RESUMO

BACKGROUND: Biliary tract cancer (BTC) has a high mortality. Primary diagnosis is frequently delayed due to mostly unspecific symptoms, resulting in a high number of advanced cases at the time of diagnosis. Advanced BTCs are in principle chemotherapy sensitive as determined by improved disease control, survival and quality of life (QoL). However, median OS does not exceed 11.7 months with the current standard of care gemcitabine plus cisplatin. Thereby, novel drug formulations like nanoliposomal-irinotecan (nal-IRI) in combination with 5- fluorouracil (5-FU)/leucovorin may have the potential to improve therapeutic outcomes in this disease. METHODS: NIFE is an interventional, prospective, randomized, controlled, open label, two-sided phase II study. Within the study, 2 × 46 patients with locally advanced, non-resectable or metastatic BTC are to be enrolled by two stage design of Simon. Data analysis will be done unconnected for both arms. Patients are allocated in two arms: Arm A (experimental intervention) nal-IRI mg/m2, 46 h infusion)/5-FU (2400 mg/m2, 46 h infusion)/leucovorin (400 mg/m2, 0.5 h infusion) d1 on 14 day-cycles; Arm B (standard of care) cisplatin (25 mg/m2, 1 h infusion)/gemcitabine (1000 mg/m2, 0.5 h infusion) d1 and d8 on 21 day-cycles. The randomization (1:1) is stratified for tumor site (intrahepatic vs. extrahepatic biliary tract), disease stage (advanced vs. metastatic), age (≤70 vs. > 70 years), sex (male vs. female) and WHO performance score (ECOG 0 vs. ECOG 1). Primary endpoint of the study is the progression free survival (PFS) rate at 4 months after randomization by an intention-to-treat analysis in each of the groups. Secondary endpoints are the overall PFS rate, the 3-year overall survival rate, the disease control rate after 2 months, safety and patient related outcome with quality of life. The initial assessment of tumor resectability for locally advanced BTCs is planned to be reviewed retrospectively by a central surgical board. Exploratory objectives aim at establishing novel biomarkers and molecular signatures to predict response. The study was initiated January 2018 in Germany. DISCUSSION: The NIFE trial evaluates the potential of a nanoliposomal-irinotecan/5-FU/leucovorin combination in the first line therapy of advanced BTCs and additionally offers a unique chance for translational research. TRIAL REGISTRATION: Clinicaltrials.gov NCT03044587. Registration Date February 7th 2017.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Fluoruracila/uso terapêutico , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Sistema Biliar/patologia , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Irinotecano/administração & dosagem , Irinotecano/efeitos adversos , Irinotecano/química , Leucovorina/administração & dosagem , Masculino , Fosfolipídeos/química , Intervalo Livre de Progressão , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto
8.
Medicine (Baltimore) ; 98(39): e17384, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574891

RESUMO

BACKGROUND: Irinotecan (IRI)-based and oxaliplatin (OXA)-based regimens are available for the treatment of metastatic colorectal cancer (mCRC). Several studies have published inconsistent results in their comparisons of the efficacy and toxicity of IRI ±â€Šbevacizumab and OXA ±â€Šbevacizumab. This meta-analysis was performed to evaluate the efficacy and safety of these 2 regimens in patients with mCRC. METHODS: We searched several databases to identify relevant studies, including PubMed, EMBASE, and the Cochrane Controlled Trials Register. The primary endpoints were overall survival (OS) and time to progression (TTP). The secondary comparisons were overall response rate (ORR) and toxicity. In addition, the hazard ratio (HR) or risk ratio (RR) values with their corresponding 95% confidence intervals (CIs) were extracted from these studies. RESULTS: Pooled data of 13 studies demonstrated no significant differences in OS (HR = 0.96, 95% CI: 0.86-1.08, P = .53) and TTP (HR = 0.88, 95% CI: 0.72-1.08, P = .24) between the 2 groups. However, the ORR (RR = 0.87, 95% CI: 0.78-0.97, P = .02) was clearly improved in the OXA ±â€Šbevacizumab arm. Higher incidences of grade 3/4 nausea (RR = 1.63, 95% CI: 1.28-2.07, P < .001), vomiting (RR = 1.40, 95% CI: 1.09-1.81, P = .01), diarrhea (RR = 1.44, 95% CI: 1.23-1.70, P < .001), and anemia (RR = 4.13, 95% CI: 2.75-6.22, P < .001) were observed in the IRI group. However, the incidences of grade 3/4 neutropenia (RR = 0.75, 95% CI: 0.68-0.83, P < .001), thrombocytopenia (RR = 0.43, 95% CI: 0.26-0.73, P = .002), and paresthesia/neurological disturbances (RR = 0.04, 95% CI: 0.02-0.07, P < .001) were higher in the OXA group. CONCLUSION: This meta-analysis confirmed that the OXA ±â€Šbevacizumab regimen as a maintenance therapy significantly improved the ORR in patients with mCRC. Exhibiting strong efficacy and safety, the OXA and OXA plus bevacizumab regimens are preferred as first-line treatments for mCRC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Irinotecano/administração & dosagem , Oxaliplatina/administração & dosagem , Adulto , Idoso , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Resultado do Tratamento
9.
Khirurgiia (Mosk) ; (9): 93-98, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31532174

RESUMO

OBJECTIVE: To improve short- and long-term outcomes of locally advanced pancreatic body-tail cancer followed by major vessels invasion. MATERIAL AND METHODS: A case report of pure laparoscopic DP-CAR procedure with portal vein resection for locally advanced pancreatic body-tail cancer followed by severe abdominal pain in a 49-year-old patient is presented. RESULTS: Liver or stomach ischemia was not observed. Portal wall resection wasn't associated with any complication and resulted R0-resection. Postoperative period was complicated by Grade B pancreatic fistula. Preoperative abdominal pain completely disappeared after surgery. Surgery time was 330 min, intraoperative blood loss - 300 ml. The patient is currently undergoing FOLFIRINOX adjuvant chemotherapy. CT in 90 days after surgery confirmed no progression of disease or liver/stomach blood supply congestion. CONCLUSION: Modern technologies provide the opportunity to perform pure laparoscopic advanced surgical procedures with major vessels resection. Pure laparoscopic DP-CAR procedure with portal vein resection is effective and safe procedure that can be performed with all principles of open surgery and is associated with acceptable short- and long-term results.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Artéria Celíaca/cirurgia , Laparoscopia/métodos , Pancreatectomia/métodos , Neoplasias Pancreáticas/cirurgia , Veia Porta/cirurgia , Antineoplásicos/administração & dosagem , Fluoruracila/administração & dosagem , Humanos , Irinotecano/administração & dosagem , Leucovorina/administração & dosagem , Pessoa de Meia-Idade , Invasividade Neoplásica , Oxaliplatina/administração & dosagem , Pancreatectomia/efeitos adversos , Fístula Pancreática/etiologia , Neoplasias Pancreáticas/patologia , Veia Porta/patologia
10.
BMC Med Genet ; 20(1): 157, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31510946

RESUMO

BACKGROUND: X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disorder caused by germline mutations in the Bruton tyrosine kinase (BTK) gene on X chromosome. These mutations disturb B-cell development, decrease immunoglobulin levels, increase susceptibility to infection or neoplasms, and increase the risk of developing colorectal cancer (CRC). For occasional cases of CRC have been reported in XLA patients, low levels of B lymphocytes and immunoglobulins induced by congenital immune disorder make them more susceptible to drug-related toxicities (DRT). Therefore, gene sequencing, therapeutic drug monitoring and any possible measurement to predict DRT should be considered before determining the course of chemotherapy for XLA patients with CRC. CASE PRESENTATION: In this study, we reported a 21-year-old male who developed metastatic CRC in the context of XLA. Since the whole exome sequencing and therapeutic drug monitoring did not reveal any predictive markers of DRT, we applied standard first-line chemotherapy to the patient. However, progressive disease occurred after the fifth treatment cycle. Therefore, the administration of oxaliplatin was changed to irinotecan as second-line therapy. After that, the patient firstly suffered from severe hypocalcemia and eventually died due to metastatic CRC after the eighth treatment cycle. The overall survival time was 7.5 months. CONCLUSIONS: This study reported the first written record of a Chinese XLA patient with metastatic CRC and severe hypocalcemia. Whole exome sequencing and bioinformatic analysis indicated the somatic mutations in ABCA6, C6 and PAX3 genes might contribute to the early-onset and metastasis CRC. Besides, a number of germline mutations in genes related to calcium metabolism (CACNA2D4, CD36, etc.) and the administration of irinotecan were speculated to be the causes of severe hypocalcemia. We therefore suggested that in order to avoid severe DRT, clinicians should take genetic background and therapeutic drug monitoring into consideration while planning chemotherapy treatment for XLA patients with CRC.


Assuntos
Tirosina Quinase da Agamaglobulinemia/genética , Agamaglobulinemia/genética , Neoplasias Colorretais/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Predisposição Genética para Doença/genética , Hipocalcemia/complicações , Irinotecano/administração & dosagem , Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Agamaglobulinemia/diagnóstico por imagem , Grupo com Ancestrais do Continente Asiático , Linfócitos B , Canais de Cálcio Tipo L/genética , Capecitabina/administração & dosagem , Capecitabina/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Complemento C6/genética , Monitoramento de Medicamentos , Tratamento Farmacológico , Estudos de Associação Genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico por imagem , Humanos , Hipocalcemia/induzido quimicamente , Imunoglobulinas , Irinotecano/uso terapêutico , Masculino , Mutação , Oxaliplatina/uso terapêutico , Fator de Transcrição PAX3/genética , Sequenciamento Completo do Exoma , Adulto Jovem
11.
Int J Pharm ; 569: 118588, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31377406

RESUMO

The purpose of this study was to investigate the feasibility of an intravenously administered combinational therapy using lipid nanocapsules (LNCs) as a drug delivery carrier for the treatment of different cancers. Therefore, we encapsulated 6 anticancer drugs within LNCs. Their size was approximately 50 nm. Except for oxaliplatin, their encapsulation efficiency, which was measured by different analytical methods, varied between 75% for SN38 to 100% for regorafenib. The in vitro studies showed a nonsignificant difference between the cytotoxicity of free and encapsulated drugs and a significant decrease in haemolysis by encapsulation in LNCs. Finally, the in vivo experiment showed that a combinational regimen of SN38-LNCs and regorafenib-LNCs abates CT26 murine colorectal cancer growth and increases median survival time.


Assuntos
Antineoplásicos/administração & dosagem , Irinotecano/administração & dosagem , Nanocápsulas/administração & dosagem , Neoplasias/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , Animais , Linhagem Celular Tumoral , Combinação de Medicamentos , Eritrócitos/efeitos dos fármacos , Feminino , Hemólise/efeitos dos fármacos , Humanos , Lipídeos/administração & dosagem , Camundongos Endogâmicos BALB C
12.
Br J Surg ; 106(11): 1530-1541, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31436325

RESUMO

BACKGROUND: Tailored neoadjuvant treatment of locally advanced rectal cancer (LARC) may improve outcomes. The aim of this study was to determine early MRI prognostic parameters with which to stratify neoadjuvant treatment in patients with LARC. METHODS: All patients from a prospective, phase II, multicentre randomized study (GRECCAR4; NCT01333709) were included, and underwent rectal MRI before treatment, 4 weeks after induction chemotherapy and after completion of chemoradiotherapy (CRT). Tumour volumetry, MRI tumour regression grade (mrTRG), T and N categories, circumferential resection margin (CRM) status and extramural vascular invasion identified by MRI (mrEMVI) were evaluated. RESULTS: A total of 133 randomized patients were analysed. Median follow-up was 41·4 (95 per cent c.i. 36·6 to 45·2) months. Thirty-one patients (23·3 per cent) developed tumour recurrence. In univariable analysis, mrEMVI at baseline was the only prognostic factor associated with poorer outcome (P = 0·015). After induction chemotherapy, a larger tumour volume on MRI (P = 0·019), tumour volume regression of 60 per cent or less (P = 0·002), involvement of the CRM (P = 0·037), mrEMVI (P = 0·026) and a poor mrTRG (P = 0·023) were associated with poor outcome. After completion of CRT, the absence of complete response on MRI (P = 0·004), mrEMVI (P = 0·038) and a poor mrTRG (P = 0·005) were associated with shorter disease-free survival. A final multivariable model including all significant variables (baseline, after induction, after CRT) revealed that Eastern Cooperative Oncology Group performance status (P = 0·011), sphincter involvement (P = 0·009), mrEMVI at baseline (P = 0·002) and early tumour volume regression of 60 per cent or less after induction (P = 0·007) were associated with relapse. CONCLUSION: Baseline and early post-treatment MRI parameters are associated with prognosis in LARC. Future preoperative treatment should stratify treatment according to baseline mrEMVI status and early tumour volume regression.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Retais/mortalidade , Adolescente , Adulto , Idoso , Quimiorradioterapia Adjuvante/métodos , Intervalo Livre de Doença , Esquema de Medicação , Fluoruracila/administração & dosagem , Humanos , Infusões Intravenosas , Irinotecano/administração & dosagem , Laparoscopia/estatística & dados numéricos , Leucovorina/administração & dosagem , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Oxaliplatina/administração & dosagem , Medicina de Precisão/métodos , Estudos Prospectivos , Neoplasias Retais/patologia , Neoplasias Retais/terapia , Procedimentos Cirúrgicos Robóticos/estatística & dados numéricos , Carga Tumoral , Adulto Jovem
13.
Int J Pharm ; 568: 118499, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31299338

RESUMO

CPT-11 is a first-line chemotherapy for advanced or metastatic colorectal cancers. 7-Ethyl-10-hydroxycamptothecin (SN38), the active metabolite of CPT-11, has an anticancer efficacy 100-1000 folds more than CPT-11 in vitro. However, the drawbacks such as ultralow solubility and poor stability, greatly limit the clinical applications of SN38. Recently, SN38-based nanomedicines have greatly improved the pharmaceutical and therapeutic characteristics of SN38. In addition, these nanosized delivery systems can target tumor tissues via the EPR effect and/or active-targeting strategies, thereby significantly improving anticancer efficacy, reducing side effects and reversing drug resistance. This review focuses on the advances of nano-delivery systems for SN38. We categorize the published studies into two groups, physical encapsulation and chemical conjugation, for the development of SN38 nano-delivery systems, and particularly summarize those for active tumor targeting. The advantages and shortcomings of current SN38 nano-delivery systems, aiming to develop more potent SN38 nano-delivery systems, are also discussed.


Assuntos
Sistemas de Liberação de Medicamentos , Irinotecano/administração & dosagem , Nanoestruturas/administração & dosagem , Inibidores da Topoisomerase I/administração & dosagem , Animais , Humanos , Neoplasias/tratamento farmacológico
14.
Oncology ; 97(4): 211-216, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31266024

RESUMO

OBJECTIVES: The aim of this study was to determine the recommended dose (RD) of capecitabine combined with oxaliplatin and irinotecan (XELOXIRI) as a neoadjuvant chemotherapy in patients with locally advanced rectal cancer. METHOD: Patients received irinotecan and oxaliplatin (85 mg/m2) on day 1, and capecitabine (1,000 mg/m2 orally twice daily) on days 1-7 of a biweekly schedule. Three dose levels, ranging from 100 to 150 mg/m2, were explored for irinotecan in sequential cohorts of 6 patients. Dose-limiting toxicities (DLTs) were assessed in the first cycle to determine the RD. RESULTS: Six patients were enrolled. The DLT was grade 3 febrile neutropenia, which was observed in 2 of the 6 patients at dose level 1. The RD of irinotecan was defined as 150 mg/m2. Toxicity was manageable: the most common grade ≥3 toxicities were neutropenia (2 patients), anemia (1 patient), and anorexia (1 patient). Nodal downstaging (cN+ to ypN0) was detected in 2 patients and the T stage was downstaged in 3 patients. CONCLUSIONS: XELOXIRI is a feasible and active regimen for patients with locally advanced rectal cancer. Febrile neutropenia was the DLT, and the RD of irinotecan is 150 mg/m2.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/administração & dosagem , Irinotecano/administração & dosagem , Terapia Neoadjuvante , Oxaliplatina/administração & dosagem , Neoplasias Retais/tratamento farmacológico , Adulto , Idoso , Capecitabina/efeitos adversos , Quimioterapia Adjuvante , Progressão da Doença , Neutropenia Febril/induzido quimicamente , Feminino , Humanos , Irinotecano/efeitos adversos , Masculino , Pessoa de Meia-Idade , Oxaliplatina/efeitos adversos , Neoplasias Retais/patologia
15.
J Neurooncol ; 144(3): 501-509, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31325144

RESUMO

PURPOSE: The phase II GLARIUS trial assigned patients with newly diagnosed, O-6-methylguanine-DNA methyltransferase promoter non-methylated glioblastoma to experimental bevacizumab/irinotecan (BEV/IRI) or standard temozolomide (TMZ). To identify subpopulations with a particularly favorable course, we assessed the prognostic potential of magnetic resonance imaging (MRI) markers before treatment onset. METHODS: MRIs at baseline (before treatment onset) were analyzed for T1-hyperintense and diffusion-restricted lesions; as well as the presence of both hyperintense and diffusion-restricted (double positive) lesions. The MRI findings were correlated with overall and progression-free survival. RESULTS: MRI scans were evaluable in 71% of the GLARIUS modified intention-to-treat population (n = 121 of 170; 88 patients in the BEV/IRI arm, and 33 patients in the TMZ control arm). Diffusion-restricted and T1 hyperintense lesions were present in 60% and 65% of patients in BEV/IRI arm, while 57% and 63% were found in the TMZ arm, respectively. Double positive lesions were found in 37% of BEV/IRI patients and in 39% of TMZ patients. Neither the presence of T1-hyperintense, diffusion-restricted lesions, nor double positive lesions were associated with improved survival. CONCLUSIONS: Baseline T1-hyperintense and diffusion-restricted lesions are not suitable to predict progression-free or overall survival of patients treated with bevacizumab/irinotecan or temozolomide.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/mortalidade , Glioblastoma/mortalidade , Imagem por Ressonância Magnética/métodos , Adulto , Idoso , Bevacizumab/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Camptotecina/administração & dosagem , Dacarbazina/administração & dosagem , Feminino , Seguimentos , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Humanos , Irinotecano/administração & dosagem , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Temozolomida/administração & dosagem
16.
Expert Opin Investig Drugs ; 28(8): 667-673, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31353973

RESUMO

Introduction: A PEGylated form of irinotecan, a topoisomerase I inhibitor, is now available in commerce; its safety and efficacy have been tested in platinum resistant/refractory ovarian cancer (PROC) patients. This novel agent is known as Etirinotecan Pegol (EP). EP, like irinotecan, exerts its action through its principal metabolite SN-38. Areas covered: This drug evaluation article focuses on the most recent investigations and clinical progress regarding EP, a long-acting polymer conjugate of irinotecan for the treatment of PROC. Expert opinion: EP provides prolonged and continuous exposure of SN-38 in tumors, when compared to its parent drug irinotecan. Results from phase II studies are comparable in terms of efficacy to other agents of proven use in PROC. A limitation of the use of EP is the schedule-dependent toxicities (mainly diarrhea and dehydration). In the future, EP could be investigated in association with other agents, even in attempts to restore sensitivity to other treatments. PROC remains a very difficult setting and EP might be a valid agent for patients with good performance status that have exhausted therapeutic options. In such a setting, participation in clinical trials is strongly encouraged.


Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Inibidores da Topoisomerase I/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Irinotecano/administração & dosagem , Irinotecano/efeitos adversos , Recidiva Local de Neoplasia , Neoplasias Ovarianas/patologia , Polietilenoglicóis/efeitos adversos , Inibidores da Topoisomerase I/efeitos adversos , Inibidores da Topoisomerase I/farmacologia
17.
J Med Case Rep ; 13(1): 178, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31182138

RESUMO

BACKGROUND: Pancreatic cancers of the tail have an especially poor prognosis due to their late detection. An earlier diagnosis depends on a better understanding of the clinical course of the disease; however, much of the current literature focuses on pancreatic head adenocarcinomas owing to their higher incidence. Thus, we add our case report to the current literature of pancreatic tail cancers in the hope of aiding earlier detection. We present an interesting case of a patient who initially presented with innocuous abdominal pain and a single episode of vomiting who was subsequently diagnosed with metastatic pancreatic tail cancer. CASE PRESENTATION: A 56-year-old Hispanic man with a past medical history of alcohol and cocaine abuse was initially evaluated in our clinic after presenting to the emergency department with sudden onset of abdominal pain and one episode of emesis. On further questioning, he stated that he had been experiencing dull, intermittent left back pain for the past 2-3 years. Laboratory tests were performed, which showed that the patient had new-onset diabetes, and imaging revealed a pancreatic tail mass with metastases to the liver. Biopsy confirmed the diagnosis of stage IV metastatic pancreatic tail adenocarcinoma. During follow-up 1 month later, the patient reported that he had been largely asymptomatic since his hospital admission; however, his left back pain had increased in severity. He was then started on a FOLFIRINOX chemotherapy regimen (5-fluorouracil/leucovorin, irinotecan, and oxaliplatin). CONCLUSIONS: There are many pitfalls in the diagnosis of pancreatic cancer, especially pancreatic tail cancer due to its vague symptoms. Thus, pancreatic cancer of the tail often presents late with a very poor prognosis. Because there is currently no widespread screening for pancreatic cancer, it is often difficult for practitioners to identify pancreatic tail cancers. Current research suggests that there is a strong association between new-onset diabetes after the age of 50 and pancreatic cancer, and tumors detected at the onset of diabetes are favorable to resection. Pancreatic cancer has also been shown to be associated with certain risk factors, such as smoking, high body mass index, chronic pancreatitis, and a family history of pancreatic cancer. Thus, when patients with presentations similar to our patient's with new-onset diabetes after the age of 50, along with vague symptoms such as back or abdominal pain as well as the presence of risk factors, we suggest that it is beneficial for practitioners to maintain a high index of suspicion for pancreatic cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Hepáticas , Pâncreas , Neoplasias Pancreáticas , Dor Abdominal/diagnóstico , Dor Abdominal/etiologia , Antineoplásicos/administração & dosagem , Biópsia/métodos , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/etiologia , Diagnóstico Diferencial , Detecção Precoce de Câncer , Fluoruracila/administração & dosagem , Humanos , Irinotecano/administração & dosagem , Leucovorina/administração & dosagem , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Oxaliplatina/administração & dosagem , Pâncreas/diagnóstico por imagem , Pâncreas/patologia , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/fisiopatologia , Fatores de Risco
18.
World Neurosurg ; 130: e236-e243, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31203059

RESUMO

BACKGROUND: Bevacizumab plus irinotecan is a new beneficial chemotherapy strategy for patients with malignant glioma. The purpose of this systematic review and meta-analysis was to comprehensively assess the risk of adverse vascular events in adults with malignant glioma treated with bevacizumab plus irinotecan. METHODS: The Cochrane Library, Embase and PubMed were searched, and relevant trials were identified up to June 2018. Two investigators screened all titles and abstracts for possible inclusion and extracted data independently. Six studies were included, and 5 of them in the control group using bevacizumab alone or bevacizumab with temozolomide. Three systems were used to assess the quality of evidence and the level of recommendation. The Oxford Centre for Evidence-Based Medicine Levels of Evidence (2009) system was used to classify the evidence into 5 levels (classes I-V). The star system from the Newcastle-Ottawa Scale was used to assess methodological quality. The GRADE profiler was used to evaluate the overall body of evidence. RESULTS: Our data show that bevacizumab plus irinotecan therapy does not significantly affect the risk of systemic adverse events (odds ratio [OR], 1.17; 95% confidence interval [CI], 0.43-3.18). Patients treated with bevacizumab plus irinotecan had a similar risk of hematotoxicity (OR, 1.06; 95% CI, 0.26-4.38), thrombocytopenia (OR, 1.07; 95% CI, 0.25-4.63), and hypertension (OR, 1.34; 95% CI, 0.28-6.36) compared with the control group (those treated without irinotecan). Thrombosis occurred more frequently in patients treated with bevacizumab plus irinotecan compared with the control group (OR, 3.23; 95% CI, 1.47-7.12). CONCLUSIONS: The risk of systemic adverse events was not significantly different between patients with malignant glioma treated with bevacizumab plus irinotecan and the control group. The risks of hematotoxicity, thrombocytopenia, and hypertension were similar in the 2 groups. The risk of thrombosis was higher in patients treated with bevacizumab plus irinotecan. Monitoring for thrombosis and administering anticoagulant therapy as necessary merit promotion for patients with malignant glioma receiving treatment with bevacizumab plus irinotecan.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Trombose Intracraniana/induzido quimicamente , Irinotecano/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Neoplasias Encefálicas/diagnóstico por imagem , Glioma/diagnóstico por imagem , Humanos , Trombose Intracraniana/diagnóstico por imagem , Irinotecano/efeitos adversos , Fatores de Risco , Inibidores da Topoisomerase I/administração & dosagem , Inibidores da Topoisomerase I/efeitos adversos , Resultado do Tratamento
19.
Anticancer Res ; 39(6): 3071-3077, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177151

RESUMO

BACKGROUND: To compare outcomes for patients with colorectal cancer liver metastases (CRCLM) treated by drug-eluting bead chemoembolization (DEB-TACE) or radioembolization (TARE). PATIENTS AND METHODS: A single-center retrospective review was carried out on 202 patients with CRCLM, treated by DEB-TACE (n=47) or TARE (n=155) patients. Propensity-matching yielded 44 pairs. Paired statistical analysis was performed on matched pair demographics, treatment response, and survival. RESULTS: Patients treated with DEB-TACE had worse extra-hepatic metastasis (68.1 vs. 47.7%, p=0.014) and ≥10 liver lesions (42.2 vs. 68.8%, p=0.001). Matched patients treated with DEB-TACE had a trend towards worse toxicity (27% vs. 9.1% (p=0.057). Index DEB-TACE treatment was not a prognostic factor for overall survival (hazard ratio=0.94, 95% confidence intervaI=0.54-1.65; p=0.83). CONCLUSION: In the matched CRCLM cohort, there was a trend towards worse toxicity post-DEB-TACE treatment, but it was not an independent prognostic factor for survival.


Assuntos
Antineoplásicos/administração & dosagem , Quimioembolização Terapêutica/métodos , Neoplasias Colorretais/patologia , Doxorrubicina/administração & dosagem , Portadores de Fármacos , Irinotecano/administração & dosagem , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Compostos Radiofarmacêuticos/administração & dosagem , Idoso , Antineoplásicos/efeitos adversos , Quimioembolização Terapêutica/efeitos adversos , Quimioembolização Terapêutica/mortalidade , Neoplasias Colorretais/mortalidade , Progressão da Doença , Doxorrubicina/efeitos adversos , Feminino , Humanos , Irinotecano/efeitos adversos , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Compostos Radiofarmacêuticos/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo
20.
Gan To Kagaku Ryoho ; 46(4): 754-756, 2019 Apr.
Artigo em Japonês | MEDLINE | ID: mdl-31164525

RESUMO

Treatment containing FOLFIRINOX was planned to be administered to a 51-year-old man with locally advanced pancreatic cancer as second-line chemotherapy and to a 66-year-old woman with recurrent pancreatic cancer as third-line chemotherapy in their treatments. Since both patients were revealed to harbor UGT1A1 polymorphisms, which were highly associated with irinotecan-induced toxicity(the former: UGT1A1 *6/*28, the latter: UGT1A1*6/*6), there was no alternative hopeful treatment other than FOLFIRINOX for them. Therefore, FOLFIRINOX was administered very carefully. Although both patients showed Grade 4 neutropenia during the initial course, it was controllable with G-CSF administration and following stepwise reduction of the irinotecan dose. Severe diarrhea and other adverse events were not observed in both cases. Since the determined regimen of FOLFIRINOX for patients with high-risk UGT1A1 polymorphisms has not been developed yet, it would be critical to accumulate and review an experience of FOLFIRINOX administration for these patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Glucuronosiltransferase/genética , Neoplasias Pancreáticas , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina , Feminino , Fluoruracila/administração & dosagem , Humanos , Irinotecano/administração & dosagem , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Oxaliplatina/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Polimorfismo Genético
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