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1.
Nagoya J Med Sci ; 82(4): 725-733, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33311803

RESUMO

The standard chemotherapy regimen for unresectable or recurrent biliary tract cancer is gemcitabine combined with cisplatin (GC). To evaluate the effectiveness and safety of chemotherapy in patients with unresectable or recurrent biliary tract cancer in the real world, we retrospectively analyzed the clinical courses of patients who underwent chemotherapy with GC from January 2015 to November 2019. Forty-eight patients underwent the GC regimen. One patient (2.1%) achieved a complete response, seven patients (14.6%) achieved a partial response, 26 patients (54.2) achieved stable disease, 11 patients (22.9%) achieved progressive disease, and 3 patients (6.3%) were not evaluable. The overall response rate was 16.7%. The median overall survival was 14.2 months (95% CI: 13.8-14.6), and the median progression-free survival was 7.7 months (95% CI: 4.2-11.2). Thirty-nine patients (81.3%) experienced grade 3 or higher severe adverse events as follows: 54.2% experienced neutropenia, 20.8% experienced anemia, 12.5% experienced thrombocytopenia and 20.8% experienced biliary tract infection. As a second-line chemotherapy, S-1 was used in seventeen patients, and stable disease was achieved in three patients (17.6%). The GC regimen for biliary tract cancer is effective and safe for unresectable or recurrent biliary tract cancer in routine clinical practice.


Assuntos
Neoplasias do Sistema Biliar , Cisplatino , Desoxicitidina/análogos & derivados , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Recidiva Local de Neoplasia , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/normas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/epidemiologia , Neoplasias do Sistema Biliar/patologia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Padrões de Prática Médica/estatística & dados numéricos , Intervalo Livre de Progressão , Estudos Retrospectivos , Gencitabina
2.
Breast Cancer ; 23(2): 195-201, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25008867

RESUMO

BACKGROUND: Genetic risk factors for febrile neutropenia (FN), the major adverse event of perioperative chemotherapy for early breast cancer, remain unclear. METHODS: This study retrospectively explored pharmacogenetic associations of single nucleotide polymorphisms (SNPs) of the uridine glucuronosyltransferase 2B7 (UGT2B7, rs7668258), glutathione-S-transferase pi 1 (GSTP1, rs1695), and microcephalin 1 (MCPH1, rs2916733) genes with chemotherapy-related adverse events in 102 Japanese women who received epirubicin and cyclophosphamide as perioperative chemotherapy for early breast cancer. RESULTS: The allele frequencies for all of the SNPs were in concordance with the Hap-Map data of Japanese individuals. Among the 24 patients who had FN at least once during all courses of chemotherapy, 23 had the A/A genotype, and 1 had the A/G genotype of the GSTP1 polymorphism (rs1695, P = 0.001); 23 of the 70 patients with the A/A genotype had FN, as compared with only 1 of the 32 patients with the A/G and G/G genotypes. The genotype distributions of the UGT2B7 and MCPH1 polymorphisms did not differ between the patients who had FN or grade 3/4 neutropenia and those who did not. CONCLUSION: Among Japanese women who received epirubicin and cyclophosphamide as perioperative chemotherapy for early breast cancer, those with the A/A genotype of the GSTP1 polymorphism (rs1695) were more likely to have FN.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Neutropenia Febril/genética , Glutationa S-Transferase pi/genética , Farmacogenética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Neoplasias da Mama/complicações , Neoplasias da Mama/patologia , Ciclofosfamida/administração & dosagem , Epirubicina/administração & dosagem , Neutropenia Febril/induzido quimicamente , Neutropenia Febril/diagnóstico , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Genótipo , Humanos , Técnicas Imunoenzimáticas , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Estudos Retrospectivos
3.
Oncol Lett ; 10(4): 2662-2664, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26622908

RESUMO

FOLFIRINOX is a standard chemotherapeutic regimen for patients with advanced pancreatic cancer who have a good performance status. In this study, we present the case of a 64-year-old male who developed dysarthria following FOLFIRINOX treatment, and review all four cases of dysarthria encountered among the nine patients who received this treatment in our hospital. In all cases, dysarthria occurred during the infusion of irinotecan in the first course of treatment, persisted for several hours, and then resolved rapidly without any sequelae. Physical and neurological examinations at the onset of dysarthria revealed no other abnormalities. Imaging studies revealed no abnormal findings. Atropine was prophylactically administered in the second and subsequent courses of treatment and effectively prevented or alleviated dysarthria. This acute neurological symptom is surprising and uncommon in traditional cancer chemotherapy, and medical oncologists may initially suspect the onset of stroke or cerebrovascular disease. However, consistent with our experience, all reported cases resolved completely, with no need for dose reduction or treatment interruption.

4.
Cancer Chemother Pharmacol ; 73(4): 673-83, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24464355

RESUMO

PURPOSE: A phase 1 study of pazopanib alone or in combination with lapatinib was conducted to assess the safety, tolerability, and pharmacokinetics of these oral tyrosine kinase inhibitors in Japanese patients with solid tumors. METHODS: In part A (monotherapy), 7 patients initially received pazopanib 800 mg/day, the recommended dose for non-Japanese patients. Then, 3 patients received pazopanib 400 mg/day on day 1 followed by 800 mg/day from day 2 onward. Three other patients received pazopanib 1,000 mg/day. In part B (combination therapy), 17 patients received pazopanib plus lapatinib (pazopanib/lapatinib) at once-daily doses of 400/1,000 mg (4 patients), 800/1,000 mg (3 patients), 400/1,500 mg (3 patients), and then 600/1,250 mg (7 patients). RESULTS: There was no dose-limiting toxicity during the study. In part A, most drug-related adverse events were grade 2 or lower, including neutropenia/neutrophil count decreased, thrombocytopenia/platelet count decreased, diarrhea, hypertension, aspartate aminotransferase increased, and lipase increased. In part B, rash, decreased appetite, and serum thyroid-stimulating hormone increased also occurred. In all dose groups, the plasma concentrations after multiple doses of pazopanib exceeded the target trough concentration for inhibition of vascular endothelial growth factor receptor-2 activity (20 µg/mL). CONCLUSIONS: The pharmacokinetic profiles of pazopanib and lapatinib in Japanese patients were not apparently different from those reported in non-Japanese patients. There were no consistent trends in pharmacokinetic drug interactions between pazopanib and lapatinib. Pazopanib monotherapy at 800 and 1,000 mg once daily and pazopanib plus lapatinib once daily at any doses studied were well tolerated in Japanese patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Povo Asiático , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Humanos , Indazóis , Lapatinib , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Neoplasias/patologia , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Quinazolinas/farmacocinética , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética
5.
Cancer Sci ; 105(3): 347-53, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24405565

RESUMO

Buparlisib (BKM120) is an oral pan-phosphatidylinositol 3-kinase inhibitor, targeting all four isoforms of class I PI3K (α, ß, γ and δ). This open-label Phase I dose-escalation study was conducted to determine the maximum tolerated dose of continuous daily buparlisib in Japanese patients with advanced solid tumors. Secondary objectives included safety and tolerability, pharmacokinetics, antitumor activity and pharmacodynamic marker changes. Fifteen patients were treated at 25 mg/day (n = 3), 50 mg/day (n = 3) and 100 mg/day (n = 9) dose levels. One dose-limiting toxicity of Grade 4 abnormal liver function occurred at 100 mg/day. Considering the safety profile and the maximum tolerated dose in the first-in-man study of buparlisib in non-Japanese patients, further dose escalation was stopped and 100 mg/day was declared the recommended dose. The most common treatment-related adverse events were rash, abnormal hepatic function (including increased transaminase levels), increased blood insulin levels and increased eosinophil count. Hyperglycemia was experienced by two patients, one Grade 1 and one Grade 4, and mood alterations were experienced by three patients, two Grade 1 and one Grade 2. Pharmacokinetic results showed that buparlisib was rapidly absorbed in a dose-proportional manner. Best overall response was stable disease for six patients, including one unconfirmed partial response. In these Japanese patients with advanced solid tumors, buparlisib had a manageable safety profile, with similar pharmacokinetics to non-Japanese patients. The recommended dose of 100 mg/day will be used in future studies of buparlisib in Japanese patients.


Assuntos
Aminopiridinas/administração & dosagem , Antineoplásicos/administração & dosagem , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Morfolinas/administração & dosagem , Inibidores de Fosfoinositídeo-3 Quinase , Adulto , Idoso , Aminopiridinas/efeitos adversos , Aminopiridinas/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Área Sob a Curva , Carcinoma de Células Escamosas/patologia , Neoplasias Colorretais/patologia , Esquema de Medicação , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Japão , Metástase Linfática , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Morfolinas/farmacocinética , Resultado do Tratamento , Adulto Jovem
6.
Int J Clin Oncol ; 19(2): 391-6, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23609856

RESUMO

BACKGROUND: Nilotinib is a BCR-ABL kinase inhibitor approved for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia (CML). The UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphism UGT1A1*28 (*28)/*28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib. Beside *28, UGT1A1*6 (*6) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan, metabolized by UGT1A1. We retrospectively investigated the association between severe toxicity of nilotinib and UGT1A1 polymorphisms (*6 and*28) in Japanese patients with CML. PATIENTS AND METHODS: Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of UGT1A1 polymorphisms with severe nilotinib-related toxicity. Genotyping analyses were determined for *6 and *28. RESULTS: All 3 patients with the *6/*6 or *6/*28 genotype had severe toxicity, including QT interval prolongation (grade 3), elevated lipase levels (grade 3) plus hyperbilirubinemia (grade 2), and anemia (grade 3) plus hepatic cyst hemorrhage (grade 2) in 1 patient each. Among the 5 patients with the *6/*1 or *1/*1 genotype, 1 had elevated lipase levels (grade 3) and another had severe pain in the lower extremities (grade 3). CONCLUSION: These findings suggest that UGT1A1 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients.


Assuntos
Antineoplásicos/efeitos adversos , Glucuronosiltransferase/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Polimorfismo Genético , Pirimidinas/efeitos adversos , Adulto , Idoso , Cardiotoxicidade , Eletrocardiografia , Feminino , Genótipo , Humanos , Hiperbilirrubinemia/induzido quimicamente , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Pessoa de Meia-Idade
7.
Int J Clin Pharmacol Ther ; 51(6): 475-81, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23547850

RESUMO

OBJECTIVE: Pharmacogenomic associations between severe oxaliplatininduced chronic peripheral neurotoxicity (OXCPN) (Grade 2 lasting for > 7 days or Grade 3) and 9 single nucleotide polymorphisms (SNPs) in 8 genes (TAC1, FOXC1, ITGA1, ACYP2, DLEU7, BTG4, CAMK2N1, and FARS2) were reported by the genomewide association study (GWAS) in Korean patients. The present study was designed to explore reliable predictors of OXCPN and thereby improve the management of metastatic colorectal cancer (CRC). METHODS: We retrospectively investigated pharmacogenomic characteristics of OXCPN in 70 Japanese patients with CRC who received oxaliplatin-based chemotherapy and updated the results of our previous analysis of ERCC1 (C118T, rs11615 and C8092A, rs3212986) and GSTP1 (Ile105Val, rs1695) polymorphisms. RESULTS: Univariate analysis suggested potential associations of severe OXCPN with rs843748 in ACYP2 and rs17140129 in FARS2, as well as with the absence of diabetes mellitus (DM) (p = 0.056, 0.072, and 0.029, respectively). There was no association between severe OXCPN and any of the 7 other SNPs. Multiple logistic regression analysis showed that an increased risk of severe OXCPN was related to rs17140129 and the absence of DM (p = 0.034 and 0.030, respectively). On updated analysis, polymorphisms of ERCC1 (C118T, rs11615) and rs10486003 in TAC1 were associated with time to the onset of Grade 1 OXCPN (p = 0.024 and 0.049, respectively). CONCLUSIONS: Severe OXCPN is significantly related to rs17140129, found in the GWAS of Korean patients, in Japanese patients. Patients without DM are more likely to have OXCPN. The association between ERCC1 polymorphism and time to the onset of OXCPN was significant on updated analysis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Povo Asiático/genética , Neoplasias Colorretais/tratamento farmacológico , Compostos Organoplatínicos/efeitos adversos , Doenças do Sistema Nervoso Periférico , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética , Estudos Retrospectivos , Índice de Gravidade de Doença
8.
Cancer Chemother Pharmacol ; 71(4): 991-8, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23370664

RESUMO

PURPOSE: This phase I study was designed to determine the maximum tolerated dose (MTD) and the dose to be recommended for a future phase II study of tasisulam sodium in Japanese patients with advanced, refractory solid tumors. Safety, pharmacokinetics and preliminary anti-tumor activities were assessed. Due to high-affinity albumin binding, an albumin-tailored dose to reduce the variability in tasisulam exposure was also studied. METHODS: A dose escalation scheme of tasisulam was used over 4 dose levels. Dose levels 1-3 targeted the maximum plasma concentration (C max) of 300, 340, and 360 µg/mL. Dose level 4 used an albumin-tailored range of C max-targeted doses to achieve an albumin-corrected exposure (AUCalb) of 1,200-6,400 µg h/mL, the range chosen for global tasisulam studies. Tasisulam was administered intravenously on day 1 of each 21-day (dose levels 1 and 2) or 28-day (dose levels 3 and 4) cycle. RESULTS: The major adverse events were related to bone marrow suppression, particularly neutropenia and thrombocytopenia. Dose-limiting toxicities (DLTs) were not observed until dose level 4, where 3 out of 6 patients experienced DLT, despite a tendency toward lower AUCalb variability (CV %) in the albumin-tailored dose group (38 %) compared with the targeted C max groups (50-236 %). CONCLUSIONS: Tasisulam in doses up to dose level 3 (target C max 360 µg/mL) was well tolerated. Although albumin-tailored dosing provided less AUCalb variability, a MTD that aligns with other global tasisulam studies was not identified. A lower AUCalb range may be required for the Japan population.


Assuntos
Albuminas/administração & dosagem , Antineoplásicos/administração & dosagem , Benzamidas/administração & dosagem , Neoplasias/tratamento farmacológico , Sulfonamidas/administração & dosagem , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Área Sob a Curva , Hidrocarboneto de Aril Hidroxilases/fisiologia , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Medula Óssea/efeitos dos fármacos , Citocromo P-450 CYP2C19 , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética
9.
Cancer Chemother Pharmacol ; 71(2): 405-11, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23161411

RESUMO

PURPOSE: Bevacizumab, a monoclonal antibody that binds to VEGF, has a well-known toxic effect of hypertension. We studied possible associations between bevacizumab-related hypertension and gene polymorphisms to assure safer cancer therapy. METHODS: We retrospectively studied 60 Japanese patients with metastatic colorectal cancer who had received bevacizumab-based chemotherapy. Genotypes were determined for five well-known functional single-nucleotide polymorphism of the VEGF gene at positions C-2578A, T-1498C, G-1154A, G-634C, and C936T. Hypertension was graded according to CTCAE v4.0 on the basis of home blood pressure. RESULTS: The VEGF-2578 C/C and -1498 T/T genotypes were associated with significantly less hypertension during the first 2 months of bevacizumab-based chemotherapy (p = 0.004, p = 0.025, respectively). During the treatment period as a whole, the VEGF-2578 C/C and 936 C/C genotypes were associated with less hypertension (p = 0.031, p = 0.043, respectively). Preexisting hypertension was not associated with bevacizumab-related hypertension. CONCLUSIONS: This study demonstrated a significant relation between a lower incidence of grade 2 or higher bevacizumab-related hypertension and the VEGF-2578 C/C genotype for the entire treatment period in Japanese patients with metastatic colorectal cancer. This genotype might be useful for ensuring safer treatment of patients who receive bevacizumab-based chemotherapy.


Assuntos
Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Hipertensão/induzido quimicamente , Polimorfismo de Nucleotídeo Único , Fator A de Crescimento do Endotélio Vascular/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Bevacizumab , Neoplasias Colorretais/mortalidade , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/sangue
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