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1.
Transl Oncol ; 12(10): 1386-1394, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31382135

RESUMO

BACKGROUND: We conducted a phase I/II clinical trial to evaluate the efficacy of eribulin and olaparib in a tablet form (EO study) for triple-negative breast cancer (TNBC) patients. We hypothesized that somatic BRCA mutations and homologous recombination repair (HRR)-related gene alterations might affect efficacy. METHODS: Our analyses identified mutations in HRR-related genes and BRCA1/2, and we subsequently evaluated their association to response by the EO study participants. Tissue specimens were obtained from primary or metastatic lesion. Tissue specimens were examined for gene mutations or protein expression using a Foundation Medicine gene panel and immunohistochemistry. RESULTS: In the 32 tissue specimens collected, we detected 33 gene mutations, with the most frequent nonsynonymous mutations found in TP53. The objective response rates (ORRs) in patients with and without HRR-related gene mutation were 33.3% and 40%, respectively (P = .732), and the ORRs in patients with and without somatic BRCA mutations were 60% and 33.3%, respectively (P = .264), with the ORR numerically higher in the somatic BRCA-mutation group but not statistically significant. There was no correlation between immunohistochemistry status and response or between BRCA status or HRR-related gene mutation and survival. Immunohistochemical analysis indicated that EGFR-negative patients had a tendency for better progression-free survival (log-rank P = .059) and significantly better overall survival (log-rank P = .046); however, there was no correlation between the status of other immunohistochemistry markers and survival. CONCLUSION: These findings suggested somatic BRCA mutation and EGFR-negativity as a potential biomarker for predicting the efficacy of eribulin/olaparib combination therapy. (UMIN000018721).

2.
Eur J Cancer ; 109: 84-91, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30703739

RESUMO

BACKGROUND: We conducted a multicenter phase I/II trial of olaparib plus eribulin in Japanese patients with advanced or metastatic triple-negative breast cancer (TNBC) to determine the recommended phase II dose (RP2D) (phase I) and to examine the efficacy and safety (phase II) (UMIN00009498) of the combined therapy. PATIENTS AND METHODS: In phase I, olaparib tablet was orally administered twice daily from level 1:25 mg BID to level 7:300 mg BID, with 1.4 mg/m2 of eribulin on days 1 and 8. In phase II, patients were treated with RP2D to assess the response rate (independent review). The planned sample size was 24 with a threshold of 10%. RESULTS: One of the 24 patients enrolled in phase I experienced dose-limiting toxicity. The RP2D was established as 300 mg twice daily for olaparib and 1.4 mg/m2 for eribulin. Among the 24 patients in phase II, the median number of administered courses was 5.5 (range: 1-28). Grade ≥III adverse events included neutropenia (83.3%), leucopenia (83.3%), anaemia (41.7%), febrile neutropenia (33.3%) and thrombosis (8.3%). The response rate was 29.2% (independent; N = 7/24; 90% confidence interval [CI]; 14.6-47.9). Median progression-free survival and overall survival were 4.2 (95% CI, 3.0-7.4) and 14.5 (95% CI, 4.8-22.0) months, respectively. Germline BRCA1/2 mutation status was observed in three patients in phase I and 2 patients in phase II, respectively. The Cmax and area under the curve for olaparib increased in a dose-dependent manner, and these parameters for eribulin and olaparib were not influenced by each other. CONCLUSIONS: Combination therapy of olaparib with eribulin shows antitumour activity against advanced or metastatic TNBC, but caution must be exercised in the presence of febrile neutropenia.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Terapia de Salvação , Comprimidos/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antraciclinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Sob a Curva , Feminino , Seguimentos , Furanos/administração & dosagem , Humanos , Cetonas/administração & dosagem , Metástase Linfática , Dose Máxima Tolerável , Pessoa de Meia-Idade , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Prognóstico , Taxa de Sobrevida , Taxoides/administração & dosagem , Distribuição Tecidual , Neoplasias de Mama Triplo Negativas/patologia , Adulto Jovem
3.
Cancer Chemother Pharmacol ; 79(6): 1179-1186, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28447211

RESUMO

PURPOSE: Whether age and inter-individual variability of pharmacogenetics are risk factors for paclitaxel-induced peripheral neuropathy (PIPN) is inconclusive. This study was conducted to evaluate the influence of previously investigated single nucleotide polymorphisms (SNPs) and age, using genotype data from a prospective study of paclitaxel-related toxicity in Japanese patients with breast cancer. METHODS: Peripheral blood mononuclear cells from 127 Japanese women with breast cancer who received weekly adjuvant paclitaxel were used to genotypes SLCO1B3 T334G (rs4149117), CYP2C8 A1196G (rs10509681), ABCB1 C1236T (rs1128503), ABCB1 G2677T/A (rs2032582), and ABCB1 C3435T (rs1045642). Genotypic and clinical factors were investigated for associations with PIPN. RESULTS: Of the five SNPs evaluated, no SNPs were significantly associated with grade 2 or higher PIPN. However, ABCB1 1236 TT showed a trend to associate with grade 2 or higher PIPN compared to ABCB1 CT/CC (odds ratio 2.1, 95% CI 0.991-4.548, p = 0.051). In subgroup analysis, patients ≥60 years old with an ABCB1 1236 TT had a higher incidence of ≥grade 2 PIPN compared to patients with CT or CC genotype (p = 0.027). On multivariable analysis, age ≥60 years and the ABCB1 1236 TT showed a significant association with ≥grade 2 PIPN (p = 0.005 and p = 0.034, respectively). CONCLUSIONS: ABCB1 1236 TT genotype and older age might be a predictor of PIPN, which diminishes quality of life of cancer survivors.


Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/epidemiologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Envelhecimento/genética , Povo Asiático/estatística & dados numéricos , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Citocromo P-450 CYP2C8/genética , Feminino , Genótipo , Humanos , Incidência , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Farmacogenética , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Estudos Prospectivos , Células Receptoras Sensoriais , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto
4.
Oncologist ; 21(4): 508-13, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26975863

RESUMO

BACKGROUND: Bone-modifying agents (BMAs) reduce the incidence of skeletal-related events (SREs) and are thus recommended for breast cancer patients with bone metastases. However, the risk factors for SREs during BMA treatment are not well-understood. This study evaluated the number and timing of SREs from case studies to identify these factors. METHODS: The medical records of 534 women with breast cancer who developed bone metastases between 1999 and 2011 were reviewed. SREs were defined as a pathologic fracture, spinal cord compression, or the need for bone irradiation or surgery. Multiple variables were assessed and were analyzed by using the Cox proportional hazard analyses and the Andersen and Gill method. RESULTS: Multivariate analyses for both the time to the first SRE and the primary and subsequent SRE frequency demonstrated that significant baseline risk factors included luminal B type disease, a history of palliative radiation therapy, BMA treatment within 2 years, and elevated serum calcium levels at the time of the initial BMA dose. Additionally, for the time to the first SRE and for the primary and subsequent SRE frequency, the presence of extraskeletal metastases and BMA administration initiation ≥6 months after the detection of bone metastases were also significant risk factors, respectively. CONCLUSION: In breast cancer patients with bone metastases, more vigilant observation should be considered for patients with the identified risk factors. To reduce the risk for SRE, BMAs should be administered within 6 months of bone metastases diagnosis and before palliative radiation therapy. IMPLICATIONS FOR PRACTICE: Retrospectively, risk factors were identified for skeletal-related events (SREs) in breast cancer patients with bone metastasis who were treated with bone-modifying agents (BMAs). For the time to the first SRE and for the SRE frequency, presence of extraskeletal metastases and BMA initiation ≥6 months after the detection of bone metastases were risk factors, respectively. Luminal B type disease, a history of palliative radiation therapy, BMA treatment within 2 years, and elevated serum calcium levels at initial BMA dose were risk factors for both first SRE and SRE frequency. More vigilant observation should be considered for patients with these risk factors.


Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Neoplasias Ósseas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Difosfonatos/administração & dosagem , Adulto , Idoso , Conservadores da Densidade Óssea/efeitos adversos , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Difosfonatos/efeitos adversos , Feminino , Fraturas Espontâneas/induzido quimicamente , Fraturas Espontâneas/patologia , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Pessoa de Meia-Idade , Pamidronato , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Ácido Zoledrônico
5.
Breast Cancer ; 23(4): 624-32, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25962696

RESUMO

AIM: The aim of this study was to investigate gene expression in the peripheral blood mononuclear cells (PBMCs) of patients with HER2-positive breast cancer receiving trastuzumab. We also evaluated the effect of Fc-gamma receptor genotype on trastuzumab-driven gene expression. MATERIALS AND METHODS: Gene expression was assessed by microarray analyses before and after administration of single-agent trastuzumab in 34 patients with metastatic HER2-positive breast cancer who were genotyped for Fc-gamma receptor (FcGR) IIA H131R and FcGRIIIA V158F. Gene set enrichment analysis (GSEA) was used to identify the gene sets that were significantly enriched after administration of trastuzumab in patient cohorts categorized by FcGR variant. RESULTS: At baseline three non-immune-related gene sets were identified only in patient cohort of FcGRIIA non-H/H variant. Thirty gene sets were identified in the cohort of FcGRIIIA V/V variants, while no gene set was identified in FcGRIIIA non-V/V variants one week after starting trastuzumab. Eleven gene sets were identified in FcGRIIA H/H variants 8 week after starting trastuzumab, but none in non-H/H variants. Immune-related gene sets were significantly down-regulated after administration of trastuzumab. CONCLUSION: The response of PBMCs to trastuzumab markedly varied with polymorphisms in FcGRIIA and FcGRIIIA. These results indicate that FcGR polymorphisms contribute to the systemic immune reaction triggered by trastuzumab. Further investigations are needed to clarify the biological effects of FcGR variation on the mechanism of trastuzumab activity.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Polimorfismo Genético , Receptores de IgG/genética , Trastuzumab/uso terapêutico , Adulto , Idoso , Antineoplásicos/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/fisiologia , Pessoa de Meia-Idade , Receptor ErbB-2/metabolismo , Resultado do Tratamento
6.
Breast Cancer ; 23(1): 24-32, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25917108

RESUMO

Molecular imaging can visualize the biological processes at the molecular and cellular levels in vivo using certain tracers for specific molecular targets. Molecular imaging of breast cancer can be performed with various imaging modalities, however, positron emission tomography (PET) is a sensitive and non-invasive molecular imaging technology and this review will focus on PET molecular imaging of breast cancer, such as FDG-PET, FLT-PET, hormone receptor PET, and anti-HER2 PET.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Carcinoma Ductal de Mama/diagnóstico por imagem , Imagem Molecular/métodos , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Bevacizumab , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Cetuximab , Didesoxinucleosídeos , Receptores ErbB/metabolismo , Feminino , Radioisótopos de Flúor , Fluordesoxiglucose F18 , Humanos , Norprogesteronas , Receptor ErbB-2/metabolismo , Receptor IGF Tipo 1/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Trastuzumab
7.
EJNMMI Res ; 5: 8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25853014

RESUMO

BACKGROUND: The purpose of this study was to determine whether brain metastases from HER2-positive breast cancer could be detected noninvasively using positron emission tomography (PET) with (64)Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-trastuzumab. METHODS: PET was performed on five patients with brain metastases from HER2-positive breast cancer, at 24 or 48 h after the injection of approximately 130 MBq of the probe (64)Cu-DOTA-trastuzumab. Radioactivity in metastatic brain tumors was evaluated based on PET images in five patients. Autoradiography, immunohistochemistry (IHC), and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis were performed in one surgical case to confirm HER2 specificity of (64)Cu-DOTA-trastuzumab. RESULTS: Metastatic brain lesions could be visualized by (64)Cu-DOTA-trastuzumab PET in all of five cases, which might indicated that trastuzumab passes through the blood-brain barrier (BBB). The HER2 specificity of (64)Cu-DOTA-trastuzumab was demonstrated in one patient by autoradiography, immunohistochemistry, and LC-MS/MS. CONCLUSIONS: Cu-DOTA-trastuzumab PET could be a potential noninvasive procedure for serial identification of metastatic brain lesions in patients with HER2-positive breast cancer. TRIAL REGISTRATION: UMIN000004170.

8.
Jpn J Clin Oncol ; 45(1): 12-8, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25332421

RESUMO

OBJECTIVE: Trastuzumab emtansine (T-DM1), an antibody-drug conjugate composed of the cytotoxic agent DM1 conjugated to trastuzumab via a stable thioether linker, has shown clinical activity in human epidermal growth factor receptor 2-positive metastatic breast cancer patients. This study evaluated the maximum tolerated dose, toxicity and pharmacokinetics of trastuzumab emtansine in Japanese breast cancer patients. METHODS: Inoperable advanced or recurrent human epidermal growth factor receptor 2-positive breast cancer patients were administered trastuzumab emtansine intravenously at a dose of 1.8, 2.4 or 3.6 mg/kg every 3 weeks. The maximum tolerated dose was estimated using the continual reassessment method. RESULTS: This study enrolled 10 patients who were administered trastuzumab emtansine for a median of seven cycles. The dose-limiting toxicity was Grade 3 elevation of aspartate aminotransferase/alanine aminotransferase at the 2.4 mg/kg dose level. The maximum tolerated dose was estimated to be 3.6 mg/kg because at the point when dose-limiting toxicity was evaluable in 10 patients, the probability of dose-limiting toxicity estimated using the continual reassessment method was closest to 25% at a dose of 3.6 mg/kg and this was unchanged by the results for patients enrolled after that. The most frequent adverse events were nausea, arthralgia, fever, fatigue and decreased appetite. Adverse events were generally tolerable. The maximum concentration and area under the concentration-time curve increased linearly with the dose. CONCLUSIONS: Trastuzumab emtansine up to 3.6 mg/kg was well tolerated by Japanese breast cancer patients. Although thrombocytopenia and hepatotoxicity tended to be more severe than was seen in Western patients in previous trastuzumab emtansine trials, those adverse events recovered without special supportive treatment.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Biomarcadores Tumorais/análise , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Maitansina/análogos & derivados , Receptor ErbB-2/análise , Ado-Trastuzumab Emtansina , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/sangue , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Área Sob a Curva , Povo Asiático , Neoplasias da Mama/química , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Hipopotassemia/induzido quimicamente , Japão , Dose Máxima Tolerável , Maitansina/administração & dosagem , Maitansina/efeitos adversos , Maitansina/sangue , Maitansina/farmacocinética , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Trombocitopenia/induzido quimicamente , Trastuzumab
9.
Curr Drug Saf ; 9(3): 220-6, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24909577

RESUMO

This descriptive study used the Japanese spontaneous reporting data to investigate the time taken (TTILD) to development of interstitial lung disease (ILD) after initiation of chemotherapy and the death rates attributed in part to post-chemotherapy ILD (i.e., DR) for anticancer drugs. We evaluated TTILD and DR endpoints for 36 anticancer drugs, which are widely used for treating 11 solid and 3 hematological cancers, and are suspected of causing ILD, by using 8- year spontaneous reporting data recording for 2,553 patients in the reporting system of the relevant Japanese regulatory agency. The median TTILD and overall DR attributable to post-chemotherapy ILD for the drugs were 1.8 months and 29%, respectively. For most drugs, the median TTILDs were between 1 to 4 months, and the DRs attributable to postchemotherapy ILD were <40%; however, TTILDs were as long as 4 to 6 months and DRs attributable to postchemotherapy ILD were ≥40% for several other drugs. Of the 36 drugs, we identified those that may trigger postchemotherapy late-onset ILDs or result in high DRs. The anticancer drugs that may have triggered late-onset ILDs were defined as those that caused ILD development after approximately 4 months from the initial drug administration.


Assuntos
Doenças Pulmonares Intersticiais/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade
10.
J Nucl Med ; 54(11): 1869-75, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24029656

RESUMO

UNLABELLED: The purpose of this study was to determine the safety, distribution, internal dosimetry, and initial human epidermal growth factor receptor 2 (HER2)-positive tumor images of (64)Cu-DOTA-trastuzumab in humans. METHODS: PET was performed on 6 patients with primary or metastatic HER2-positive breast cancer at 1, 24, and 48 h after injection of approximately 130 MBq of the probe (64)Cu-DOTA-trastuzumab. Radioactivity data were collected from the blood, urine, and normal-tissue samples of these 6 patients, and the multiorgan biodistribution and internal dosimetry of the probe were evaluated. Safety data were collected for all the patients after the administration of (64)Cu-DOTA-trastuzumab and during the 1-wk follow-up period. RESULTS: According to our results, the best timing for the assessment of (64)Cu-DOTA-trastuzumab uptake by the tumor was 48 h after injection. Radiation exposure during (64)Cu-DOTA-trastuzumab PET was equivalent to that during conventional (18)F-FDG PET. The radioactivity in the blood was high, but uptake of (64)Cu-DOTA-trastuzumab in normal tissues was low. In 2 patients, (64)Cu-DOTA-trastuzumab PET showed brain metastases, indicative of blood-brain barrier disruptions. In 3 patients, (64)Cu-DOTA-trastuzumab PET imaging also revealed primary breast tumors at the lesion sites initially identified by CT. CONCLUSION: The findings of this study indicated that (64)Cu-DOTA-trastuzumab PET is feasible for the identification of HER2-positive lesions in patients with primary and metastatic breast cancer. The dosimetry and pharmacologic safety results were acceptable at the dose required for adequate PET imaging.


Assuntos
Anticorpos Monoclonais Humanizados , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/metabolismo , Compostos Organometálicos , Tomografia por Emissão de Pósitrons/métodos , Receptor ErbB-2/metabolismo , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Neoplasias da Mama/patologia , Estudos de Viabilidade , Humanos , Processamento de Imagem Assistida por Computador , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos Organometálicos/efeitos adversos , Tomografia por Emissão de Pósitrons/efeitos adversos , Segurança , Trastuzumab
11.
Cancer Chemother Pharmacol ; 71(5): 1369-74, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23558943

RESUMO

PURPOSE: To evaluate the feasibility of a cisplatin and S-1 combination regimen for the treatment for metastatic and recurrent cervical cancers, we performed this study prior to a randomized phase III trial to evaluate the clinical benefits of a cisplatin and S-1 combination regimen compared with cisplatin alone. METHODS: Cisplatin (50 mg/m(2), intravenously on day 1) and S-1 (80-120 mg/m(2), orally twice a day between days 1 and 14) were administered every 21 days for 6 cycles in patients with advanced or recurrent uterine cervical cancer. RESULTS: A total of 10 patients were enrolled in this trial. A total of 46 treatment cycles (median 6; range 1-6) were administered. All grade 3 or 4 hematologic toxicities were recorded in the 6 patients: 2 patients experienced anemia, 5 experienced neutropenia, 1 experienced thrombocytopenia, and 2 experienced febrile neutropenia. All grade 3 non-hematologic toxicities were recorded in the 6 patients, and no grade 4 non-hematologic toxicities occurred; the most frequent toxicities were hyponatremia in 3 patients, diarrhea in 2 patients, and infection in 2 patients. The patients with grade 3 diarrhea had received prior radiotherapy. All the patients recovered from the toxicities after receiving appropriate supportive care, and no treatment-related deaths occurred. Five patients (50 %) achieved a partial response, and 1 patient (10 %) had a stable disease. CONCLUSION: A cisplatin and S-1 combination regimen was feasible for patients with recurrent cervical cancer. Since patients who receive prior radiotherapy may experience severe diarrhea, these patients may require an S-1 dose reduction.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/administração & dosagem , Terapia Combinada , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Estudos de Viabilidade , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia , Ácido Oxônico/administração & dosagem , Projetos Piloto , Tegafur/administração & dosagem , Resultado do Tratamento , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/radioterapia
12.
Cancer Chemother Pharmacol ; 70(3): 391-7, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22806306

RESUMO

PURPOSE: The prognosis of adult rhabdomyosarcoma (RMS) has been considered dismal. The question is raised that vincristine, d-actinomycin, and cyclophosphamide (VAC) chemotherapy may not be administered as per schedule for adult RMS; consequently, low dose intensity (DI) leads to poor prognosis. Herein, we examined whether the administration of VAC chemotherapy for adults and children with RMS is feasible with regard to the DIs of VAC. METHODS: Chart review was retrospectively performed for all identified patients. The percentage of relative DI (RDI) was calculated according to the Children's Oncology Group D9803 protocol. Further, we examined the RDI in the first 6 cycles of VAC (induction phase) and the DI after the first 6 cycles of VAC (maintenance phase). RESULTS: We identified a total of 27 adults and 18 children with RMS, respectively. The mean RDIs of vincristine in total phase were significantly lower in adults than that in children (P = 0.04). In induction phase, the mean RDIs of vincristine and cyclophosphamide were similar for both groups; however, they were dropped significantly in adults during maintenance phase (P < 0.05). Mean RDIs of vincristine in elderly patients tended to become low. Low RDI was mainly attributable to hematologic toxicity, infection, and peripheral neuropathy. The prognosis of low versus high RDI was similar. CONCLUSIONS: The RDIs of vincristine and cyclophosphamide in the maintenance phase were significantly lower than that in children. VAC chemotherapy for adults was not feasible; these patients require a different regimen.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Rabdomiossarcoma/tratamento farmacológico , Adolescente , Adulto , Fatores Etários , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Ciclofosfamida/administração & dosagem , Dactinomicina/administração & dosagem , Relação Dose-Resposta a Droga , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Rabdomiossarcoma/patologia , Resultado do Tratamento , Vincristina/administração & dosagem , Adulto Jovem
13.
Breast Cancer Res Treat ; 132(3): 793-805, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21562709

RESUMO

The purpose of the present study was to identify histological surrogate predictive markers of pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC). Among 474 patients who received NAC and subsequent surgical therapy for stage II-III invasive breast carcinoma between 1999 and 2007, 102 (22%) had TNBC, and 92 core needle biopsy (CNB) specimens obtained before NAC were available. As controls, CNB specimens from 42 tumors of the hormone receptor-negative and HER2-positive (HR-/HER2+) subtype and 46 tumors of the hormone receptor-positive and HER2-negative (HR+/HER2-) subtype were also included. Histopathological examination including tumor-infiltrating lymphocytes (TIL) and tumor cell apoptosis, and immunohistochemical studies for basal markers were performed, and the correlation of these data with pathological therapeutic effect was analyzed. The rates of pCR at the primary site were higher for TNBC (32%) and the HR-/HER2+ subtype (21%) than for the HR+/HER2- subtype (7%) (P = 0.006). Expression of basal markers and p53, histological grade 3, high TIL scores, and apoptosis were more frequent in TNBC and the HR-/HER2+ subtype than in the HR+/HER2- subtype (P = 0.002 for TIL and P < 0.001 for others). In TNBC, the pCR rates of tumors showing a high TIL score and of those showing a high apoptosis score were 37 and 47%, respectively, and significantly higher or tended to be higher than those of the tumors showing a low TIL score and of the tumors showing a low apoptosis score (16 and 27%, respectively, P = 0.05 and 0.10). In a total of 180 breast cancers, the pCR rates of the tumors showing a high TIL score (34%) and of those showing a high apoptosis score (35%) were significantly higher than those of the tumors showing a low TIL score (10%) and those of the tumors showing a low apoptosis score (19%) (P = 0.0001 and 0.04, respectively). Histological grade and basal marker expression were not correlated with pCR. Although the whole analysis was exploratory, the degree of TIL correlated with immune response appear to play a substantial role in the response to NAC in TNBC.


Assuntos
Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Linfócitos/fisiologia , Terapia Neoadjuvante , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Adulto , Idoso , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Linfócitos/patologia , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Resultado do Tratamento , Adulto Jovem
14.
Cancer Chemother Pharmacol ; 69(2): 457-65, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21853310

RESUMO

PURPOSE: We conducted phase I and tolerability studies to determine the maximum tolerated dose (MTD) and recommended dose of nab-paclitaxel when administered weekly with solid tumors and to evaluate the tolerability of weekly administration at a dose of 150 mg/m(2) with metastatic breast cancer (MBC) as a first-line therapy in Japanese patients. METHODS: In this phase I study, patients with advanced solid tumors received nab-paclitaxel at dose levels of 80-125 mg/m(2) as 30-min infusions once a week for three weekly doses repeated every 4 weeks. In the tolerability study, patients received 150 mg/m(2) nab-paclitaxel. Blood samples at the first dose of nab-paclitaxel were collected for pharmacokinetic analysis. RESULTS: Fifteen patients were treated for a median of five cycles in the phase I study. The MTD was 125 mg/m(2); the dose-limiting toxicity was neutropenia requiring skipping of the second or third weekly administration in the first cycle. In the tolerability study, six patients were treated for a median of six cycles; no intolerable toxicities were observed in the first cycle. Grade 3 sensory and motor neuropathy was observed in four and one patients, respectively. Ocular toxicities were observed in two patients (keratopathy and macular hole). Maximum paclitaxel concentration and area under the curve increased linearly with the dose. CONCLUSIONS: Weekly administration of nab-paclitaxel was well tolerated up to 100 mg/m(2) by heavily pretreated patients. For MBC patients, 150 mg/m(2) nab-paclitaxel as a first-line therapy was well tolerated. Dose reduction due to neuropathy allows multiple cycles of treatment.


Assuntos
Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Paclitaxel/farmacocinética , Paclitaxel/uso terapêutico , Adulto , Idoso , Paclitaxel Ligado a Albumina , Albuminas/efeitos adversos , Albuminas/farmacocinética , Albuminas/uso terapêutico , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/uso terapêutico , Área Sob a Curva , Povo Asiático , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/etnologia , Neoplasias da Mama/metabolismo , Diarreia/induzido quimicamente , Relação Dose-Resposta a Droga , Esquema de Medicação , Exantema/induzido quimicamente , Feminino , Humanos , Japão , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Nanopartículas/administração & dosagem , Nanopartículas/efeitos adversos , Nanopartículas/uso terapêutico , Náusea/induzido quimicamente , Metástase Neoplásica , Neoplasias/etnologia , Paclitaxel/efeitos adversos , Resultado do Tratamento
15.
Eur J Obstet Gynecol Reprod Biol ; 159(2): 394-8, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21831511

RESUMO

OBJECTIVE: To examine the use of squamous cell carcinoma antigen (SCCA) as a biomarker of chemotherapy response in patients who underwent chemotherapy for metastatic cervical carcinoma. STUDY DESIGN: The study population consisted of patients who underwent first-line chemotherapy for metastatic cervical carcinoma between 1999 and 2009. SCCA levels were serially measured before, during and after chemotherapy. Radiographic responses were evaluated according to the criteria of the World Health Organization. A logistic model was used to determine the best prediction model, and internal and external validation of the prediction model were performed to compare the areas under the receiver operating characteristic curves (AUCs). RESULTS: In total, 55 patients were included in the analysis. Data for 32 patients enrolled in various clinical trials were used to develop the prediction model. Patients who achieved a radiographic response showed a significant decline in SCCA levels between the second and third cycles of chemotherapy, whereas patients who did not achieve a radiographic response showed constant SCCA levels over the same period. The prediction model was developed on the basis of changes in the SCCA level between the second and third cycles of chemotherapy (AUC=0.832) and the baseline SCCA level. The AUC after external validation, calculated using the data of the clinical practice population (n=22), was 0.871. CONCLUSIONS: A response to chemotherapy was possible for patients in whom SCCA levels declined between the second and third cycles of chemotherapy.


Assuntos
Antígenos de Neoplasias/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Carcinoma/sangue , Carcinoma/tratamento farmacológico , Serpinas/sangue , Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/tratamento farmacológico , Adulto , Idoso , Algoritmos , Antineoplásicos/uso terapêutico , Carcinoma/diagnóstico por imagem , Carcinoma/secundário , Colo do Útero/diagnóstico por imagem , Estudos de Coortes , Monitoramento de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Radiografia , Análise de Sobrevida , Neoplasias do Colo do Útero/diagnóstico por imagem
16.
J Cancer Res Clin Oncol ; 137(8): 1185-91, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21559815

RESUMO

PURPOSE: There are few existing reports on the efficacy of second-line chemotherapy in patients with cancer of unknown primary site (CUP). The aim of this study was to identify characteristics of CUP patients linked to a positive response to chemotherapy. METHODS: We retrospectively studied the clinical outcomes of second-line chemotherapy in patients with CUP who had previously been treated with platinum-based first-line chemotherapy. RESULTS: A total of 27 patients received second-line chemotherapy. Of these patients, 5 (19%) showed an objective response to second-line chemotherapy; 4 of these patients had shown a favorable response to first-line chemotherapy and had a chemotherapy-free interval (CFI) of more than 4.5 months. Among the 8 patients in whom the CFI was more than 4.5 months, 4 (50%) showed an objective response to platinum-based second-line chemotherapy, whereas among the 16 patients with a CFI of less than 4.5 months, only 1 (6%) showed a response to any chemotherapeutic regimen. CONCLUSIONS: The response to second-line chemotherapy in CUP patients who had received platinum-based first-line treatment seemed to be associated with the response to first-line chemotherapy and the CFI. Although it remains unclear whether second-line chemotherapy might contribute to a survival benefit in patients with CUP, patients who show a favorable response to first-line chemotherapy and also a relatively prolonged CFI appear to be likely to benefit from second-line chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Esquema de Medicação , Linfonodos/patologia , Neoplasias Primárias Desconhecidas/tratamento farmacológico , Neoplasias Primárias Desconhecidas/patologia , Adenocarcinoma/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Carboplatina/administração & dosagem , Carcinoma/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Intervalo Livre de Doença , Docetaxel , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Irinotecano , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Desconhecidas/mortalidade , Paclitaxel/administração & dosagem , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco , Taxoides/administração & dosagem , Fatores de Tempo , Falha de Tratamento , Resultado do Tratamento
17.
Med Oncol ; 28(2): 434-40, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20354821

RESUMO

This study aims at evaluating the impact of age on patterns of care in elderly patients with metastatic breast cancer (MBC) and their outcome. We identified 177 patients aged ≥ 65 treated for MBC at the National Cancer Center Hospital in Japan from 1999 to 2007. We evaluated the impact of age on the selection of best supportive care (BSC) only, chemotherapy as first-line treatment, and chemotherapy after first-line endocrine therapy. Fisher's exact test and a multivariate logistic regression analysis with variables of age, performance status (PS), hormone receptor (HR) status, human epidermal growth factor-2 (HER2), and life-threatening disease (LTD) were used. The median age of patients was 72, and 60 patients (33.9%) were aged ≥ 75. HR-negative patients and those whose PS was ≥ 2, regardless of age, were more likely to choose BSC without chemotherapy. Multivariate analysis revealed age ≥ 75 (P = 0.018), positive-HR status (P < 0.001), and absence of LTD (P < 0.001) were significantly correlated to choose endocrine therapy rather than chemotherapy. In patients who had previous endocrine therapy, age (P = 0.008) and absence of HER2 (P = 0.018) were related not to choose chemotherapy. Not age but HR-negative status or PS ≥ 2 were related to the selection of BSC. In selecting endocrine therapy rather than chemotherapy, age (≥ 75), HR-positive, and absence of LTD were significant factors. In patients failed to endocrine therapy, age and HER2 status were correlated to decision-making to choose chemotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Geriatria/normas , Cuidados Paliativos/estatística & dados numéricos , Fatores Etários , Idoso , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Humanos , Metástase Neoplásica , Padrões de Prática Médica , Receptor ErbB-2/genética , Estudos Retrospectivos
18.
Oncology ; 78(1): 34-9, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20185939

RESUMO

OBJECTIVES: The aim of this study was to analyze the prognostic impact of suboptimal treatment in patients with mediastinal primary nonseminomatous germ cell tumor (MNSGCT). METHODS: We retrospectively reviewed the clinical data of 23 consecutive MNSGCT patients who were referred to the National Cancer Center Hospital between 1999 and 2007. Optimal treatment was defined as a primary chemotherapy regimen comprising a standard dosage of bleomycin + etoposide + cisplatin or etoposide + ifosfamide + cisplatin with sufficient dose intensity according to the guidelines of the European Germ Cell Cancer Consensus Group. RESULTS: Ten and 13 patients received optimal and suboptimal treatment, respectively. The progression-free survival was statistically different between the patients who received optimal and suboptimal treatment (p = 0.01), and the hazard ratio of the optimal treatment group relative to the suboptimal treatment group was 0.19 (95% CI, 0.04-0.89). Although the overall survival was not statistically different between the 2 patient groups (p = 0.12), the hazard ratio in this regard was 0.36 (95% CI, 0.10-1.38). CONCLUSIONS: Patients who receive suboptimal treatment have poor clinical outcomes. Providing treatment after considering evidence-based guidelines may be important for improving the clinical outcomes of MNSGCT patients.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Mediastino/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Adolescente , Adulto , Humanos , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
19.
Oncology ; 75(3-4): 169-74, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18827494

RESUMO

OBJECTIVES: It was the aim of this study to investigate gender differences in the outcomes of carboplatin and paclitaxel chemotherapy in patients with unresectable stage IIIB-IV non-small cell lung cancer (NSCLC). METHODS: Gender, age, performance status, histology, hematological toxicity, tumor responses and survival parameters obtained retrospectively by medical chart review were analyzed. RESULTS: A total of 227 patients (147 males and 80 females) were included. The median lowest leukocyte count was 2,900 (range 1,200-12,400)/microl in males and 2,200 (range 600-6,500)/microl in females (p < 0.001). Grade 3-4 leukopenia was noted in 15% of male and in 39% of female patients (p < 0.001). In both genders, the response rate in evaluable patients was 39%. The median progression-free survival was 4.4 months for men and 5.3 months for women (p = 0.0081). After progression of the disease, gefitinib was administered in 64 (44%) male and 45 (56%) female patients, with a median treatment of 35 and 144 days, respectively. The median survival time was 11.9 months for men and 22.2 months for women (p < 0.001). CONCLUSION: Female gender was associated with a favorable prognosis in patients with NSCLC who received carboplatin and paclitaxel chemotherapy, although the response rates did not differ between the genders. Of note, hematological toxicity was more severe in female patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/secundário , Feminino , Humanos , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Fatores Sexuais , Taxa de Sobrevida , Resultado do Tratamento
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