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1.
Carcinogenesis ; 33(11): 2181-9, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22859269

RESUMO

Increasing evidence shows that estrogens are involved in lung cancer proliferation and progression, and most human lung tumors express estrogen receptor ß (ERß) as well as aromatase. To determine if the aromatase inhibitor anastrozole prevents development of lung tumors induced by a tobacco carcinogen, alone or in combination with the ER antagonist fulvestrant, ovariectomized female mice received treatments with the tobacco carcinogen 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK) along with daily supplements of androstenedione, the substrate for aromatase. Placebo, anastrozole and/or fulvestrant were administered in both an initiation and a promotion protocol of lung tumorigenesis. The combination of fulvestrant and anastrozole given during NNK exposure resulted in significantly fewer NNK-induced lung tumors (mean = 0.5) compared with placebo (mean = 4.6, P < 0.001), fulvestrant alone (mean = 3.4, P < 0.001) or anastrozole alone (mean = 2.8, P = 0.002). A significantly lower Ki67 cell proliferation index was also observed compared with single agent and control treatment groups. Beginning antiestrogen treatment after NNK exposure, when preneoplastic lesions had already formed, also yielded maximum antitumor effects with the combination. Aromatase expression was found mainly in macrophages infiltrating preneoplastic and tumorous areas of the lungs, whereas ERß was found in both macrophages and tumor cells. Antiestrogens, especially in combination, effectively inhibited tobacco carcinogen-induced murine lung tumorigenesis and may have application for lung cancer prevention. An important source of estrogen synthesis may be inflammatory cells that infiltrate the lungs in response to carcinogens, beginning early in the carcinogenesis process. ERß expressed by inflammatory and neoplastic epithelial cells in the lung may signal in response to local estrogen production.


Assuntos
Carcinógenos/toxicidade , Moduladores de Receptor Estrogênico/uso terapêutico , Neoplasias Pulmonares/prevenção & controle , Nicotiana/toxicidade , Nitrosaminas/toxicidade , Anastrozol , Animais , Inibidores da Aromatase/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Estradiol/análogos & derivados , Estradiol/uso terapêutico , Feminino , Fulvestranto , Técnicas Imunoenzimáticas , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Nitrilas/uso terapêutico , Receptores de Estrogênio/metabolismo , Triazóis/uso terapêutico
2.
Cancer ; 118(22): 5614-22, 2012 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-22569841

RESUMO

BACKGROUND: Neurotoxicity from adjuvant treatment with oxaliplatin has been studied in patients with colorectal carcinoma in short-term studies, but, to the authors' knowledge, the current article is the first long-term assessment which reports the National Surgical Adjuvant Breast and Bowel Project (NSABP) investigation of whether excess neurotoxicity persists beyond 4 years. METHODS: As part of a colorectal cancer long-term survivor study (LTS-01), long-term neurotoxicity was assessed in 353 patients on NSABP Protocol C-07 (cross-sectional sample). Ninety-two of these patients from LTS-01 also had longitudinal data and were reassessed 5 to 8 years (median, 7 years) after random assignment (longitudinal sample). Contingency tables compared cohorts, a mixed model compared neurotoxicity between treatments over time, and a Wilcoxon rank-sum test compared neurotoxicity between treatments (cross-sectional sample). RESULTS: In the cross-sectional sample, the increase in mean total neurotoxicity scores of 1.8 with oxaliplatin was statistically significant (P = .005), but not clinically significant (a minimally important difference of 4 was reported at the long-term assessment). Patients who received oxaliplatin had increased odds of numbness and tingling in hands (odds ratio, 2.00; P = .015) and feet (odds ratio, 2.78; P < .001) versus patients who did not receive oxaliplatin. The magnitude of the oxaliplatin effect varied with time (P < .001) in the longitudinal sample, such that the oxaliplatin-treated group did not have significantly greater total neurotoxicity scores by 7 years. CONCLUSIONS: At the long-term endpoint, there was no clinically significant increase in total neurotoxicity scores for patients who received oxaliplatin, but the specific neurotoxicities of numbness and tingling of the hands and feet remained significantly elevated for oxaliplatin-treated patients.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/efeitos adversos , Leucovorina/efeitos adversos , Síndromes Neurotóxicas/etiologia , Compostos Organoplatínicos/efeitos adversos , Adulto , Idoso , Quimioterapia Adjuvante/efeitos adversos , Feminino , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina
3.
Ann Thorac Surg ; 85(6): 1930-6; discussion 1936-7, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18498797

RESUMO

BACKGROUND: Effective systemic therapy is considered essential to improve the outcome for patients with surgically resectable locally advanced esophageal carcinoma. We report the long-term results of our phase II study of neoadjuvant chemotherapy, followed by esophagectomy and adjuvant chemotherapy for potentially resectable esophageal carcinoma. METHODS: Patients were staged with computed tomography scan (n = 70), endoscopic ultrasonography (n = 63), and laparoscopy with or without thoracoscopy (n = 70). The pretreatment stages were T2N0 (n = 1), T2N1 (n = 15), T3N0 (n = 13), and T3N1 (n = 41). Chemotherapy consisted of 2 or 3 cycles of cisplatin, 5-fluorouracil, and paclitaxel followed by esophagectomy and adjuvant chemotherapy. Patients were monitored for recurrence and survival. RESULTS: A total of 70 patients were enrolled (66 adenocarcinoma, 4 squamous cell carcinoma; 64 men and 6 women; median age, 60 years). Esophagectomy was performed in 63 patients. Operative mortality was 0%. The median overall survival of the entire group was 27.4 months. Seventeen patients were alive at a median follow-up of 62.8 months (range, 39.1 to 142). Fourteen patients were alive without recurrence at a median follow-up of 79 months (range, 39 to 138). Nodal status was an important predictor of overall survival. Patients who were downstaged experienced a significantly improved median survival of 63.4 months versus 21.5 months and overall survival (p = 0.005). CONCLUSIONS: This prospective study for esophageal carcinoma demonstrates encouraging long-term results. In particular, downstaging of the tumor with preoperative chemotherapy is predictive of better long-term outcome. Our results support the role for perioperative chemotherapy for locally advanced resectable esophageal cancer.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/cirurgia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/cirurgia , Esofagectomia , Terapia Neoadjuvante , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Estudos de Coortes , Terapia Combinada , Esquema de Medicação , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Seguimentos , Humanos , Técnicas In Vitro , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Prognóstico , Estudos Prospectivos
4.
J Clin Oncol ; 25(16): 2205-11, 2007 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-17470850

RESUMO

PURPOSE: The randomized, multicenter, phase III protocol C-07 compared the efficacy of adjuvant bolus fluorouracil and leucovorin (FULV) versus FULV with oxaliplatin (FLOX) in stage II or III colon cancer. Definitive analysis revealed an increase in 4-year disease-free survival from 67.0% to 73.2% in favor of FLOX. This study compares neurotoxicity between the treatments. PATIENTS AND METHODS: Neurotoxicity was recorded for all patients using standard adverse event reporting. Patients at select institutions completed a neurotoxicity questionnaire through 18 months of follow-up. RESULTS: A total of 2,492 patients enrolled onto C-07 and 400 patients enrolled onto the patient-reported substudy. Mean patient-reported neurotoxicity was higher with oxaliplatin throughout the 18 months of study (P < .0001). During therapy, patients receiving oxaliplatin experienced significantly more hand/foot toxicity (eg, "quite a bit" of cold-induced hand/foot pain 26% FLOX v 2.6% FULV) and overall weakness (eg, moderate weakness in 27.4% FLOX v 16.2% FULV). At 18 months, hand neuropathy had diminished, but patients who received oxaliplatin experienced continued foot discomfort (eg, moderate foot numbness and tingling for 22.1% FLOX v 4.6% FULV). Observer-reported neurotoxicity was low grade and primarily neurosensory rather than neuromotor. Sixty-eight percent in the FLOX group v 8% in the FULV group had neurotoxicity at their first on-treatment assessment. Time to resolution was significantly longer for those receiving oxaliplatin, and continued beyond 2 years for more than 10% in the oxaliplatin group. CONCLUSION: Oxaliplatin causes significant neurotoxicity. It is experienced primarily in the hands during therapy and in the feet during follow-up. In a minority of patients the neurotoxicity is long lasting.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Colo/tratamento farmacológico , Compostos Organoplatínicos/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Quimioterapia Adjuvante , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina
5.
J Clin Oncol ; 25(4): 424-30, 2007 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-17264338

RESUMO

PURPOSE: We compared health-related quality of life (HRQL), symptoms, and convenience of care (COC) in patients with stage II/III carcinoma of the colon who received either oral uracil/ftorafur (UFT) plus leucovorin (LV) or standard intravenous (IV) fluorouracil (FU) plus LV as adjuvant chemotherapy. PATIENTS AND METHODS: We measured HRQL with the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) questionnaire, Short Form-36 Vitality Scale (SF-36), and a Quality of Life Rating Scale (QLRS) at baseline, once during chemotherapy, and at 1 year. We used the Symptom Distress Scale (SDS) and treatment-specific Symptom Checklist (SCL) to assess symptoms and a modified Burden of Care form to assess COC at baseline, on day 1 of each treatment cycle, and at 1 year. Repeated measures analyses controlling for demographic variables and baseline scores were used for statistical comparisons. RESULTS: The study accrued 1,608 patients, 803 to the FU arm and 805 to the UFT arm. There were no differences between the arms in overall FACT-C scores, FACT-C scores within the subscales of colon-specific, physical, emotional, social, and functional health, or QLRS scores. Patients taking UFT reported substantially higher COC. Statistically significant but small differences were observed for SF-36, favoring FU, and for SDS and SCL, both favoring UFT. CONCLUSION: Patients perceive adjuvant treatment with UFT + LV as more convenient than standard IV treatment with FU + LV. Both regimens are well tolerated and do not differ in their impact on HRQL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Qualidade de Vida , Administração Oral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimioterapia Adjuvante , Neoplasias do Colo/cirurgia , Feminino , Fluoruracila/administração & dosagem , Nível de Saúde , Humanos , Infusões Intravenosas , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Tegafur/administração & dosagem , Uracila/administração & dosagem
6.
Breast Cancer Res Treat ; 86(2): 153-64, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15319567

RESUMO

PURPOSE: NSABP Protocol B-23 compared two chemotherapy regimens: (1) cyclophosphamide, methotrexate, and 5-fluorouracil (CMF); and (2) doxorubicin and cyclophosphamide (AC) in terms of relapse-free survival, event-free survival, and overall survival in node-negative and estrogen receptor-negative breast cancer patients. There are no previous data regarding the comparison of quality of life (QOL) between the two regimens in this population of breast cancer patients. QOL information was considered especially relevant given the possibility that the two chemotherapy regimens would prove equivalent in terms of clinical outcome. PATIENTS AND METHODS: One hundred and sixty patients participated in the NSABP B-23 QOL study. Patients in B-23 were randomly assigned to one of four arms: CMF plus 5 years of tamoxifen (TAM), CMF, Comparative health item and general health item plus placebo, AC plus TAM, or AC plus placebo. The questionnaires included the Functional Assessment of Cancer Therapy (FACT-B), the vitality scale from the Medical Outcomes Study 36-item Short Form Health Status Survey (MOS SF-36), a symptom checklist and additional items regarding overall QOL; and return to normal activity. Statistical comparisons between treatment arms were performed with area under the curve analyses, repeated measures analyses, and Fisher exact tests. RESULTS: Overall QOL as measured by the FACT-B did not significantly differ between chemotherapy treatment arms. However, the pattern of vitality over time during treatment differed between chemotherapy groups. The AC group vitality scores dropped more sharply during treatment and returned to baseline levels more quickly after treatment. Patients in the CMF arm were bothered by bladder problems and diarrhea significantly more often than were patients in the AC arm. Otherwise, no significant differences were found between AC and CMF for any of the QOL outcomes in terms of (1) overall QOL during the first 9 months after randomization, (2) the average QOL during treatment, or (3) the rate of recovery to baseline levels of QOL 1year after randomization. CONCLUSION: Overall QOL is equivalent between the two chemotherapy regimens, with some differences in symptoms and in patterns of vitality over time.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/psicologia , Qualidade de Vida , Tamoxifeno/uso terapêutico , Atividades Cotidianas , Administração Oral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Nível de Saúde , Humanos , Infusões Intravenosas , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Placebos , Receptores de Estrogênio
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