RESUMO
PURPOSE: To determine, in women with primary operable breast cancer, if preoperative doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan; AC) therapy yields a better outcome than postoperative AC therapy, if a relationship exists between outcome and tumor response to preoperative chemotherapy, and if such therapy results in the performance of more lumpectomies. PATIENTS AND METHODS: Women (1,523) enrolled onto National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 were randomly assigned to preoperative or postoperative AC therapy. Clinical tumor response to preoperative therapy was graded as complete (cCR), partial (cPR), or no response (cNR). Tumors with a cCR were further categorized as either pathologic complete response (pCR) or invasive cells (pINV). Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were estimated through 5 years and compared between treatment groups. In the preoperative arm, proportional-hazards models were used to investigate the relationship between outcome and tumor response. RESULTS: There was no significant difference in DFS, DDFS, or survival (P = .99, .70, and .83, respectively) among patients in either group. More patients treated preoperatively than postoperatively underwent lumpectomy and radiation therapy (67.8% v 59.8%, respectively). Rates of ipsilateral breast tumor recurrence (IBTR) after lumpectomy were similar in both groups (7.9% and 5.8%, respectively; P = .23). Outcome was better in women whose tumors showed a pCR than in those with a pINV, cPR, or cNR (relapse-free survival [RFS] rates, 85.7%, 76.9%, 68.1%, and 63.9%, respectively; P < .0001), even when baseline prognostic variables were controlled. When prognostic models were compared for each treatment group, the preoperative model, which included breast tumor response as a variable, discriminated outcome among patients to about the same degree as the postoperative model. CONCLUSION: Preoperative chemotherapy is as effective as postoperative chemotherapy, permits more lumpectomies, is appropriate for the treatment of certain patients with stages I and II disease, and can be used to study breast cancer biology. Tumor response to preoperative chemotherapy correlates with outcome and could be a surrogate for evaluating the effect of chemotherapy on micrometastases; however, knowledge of such a response provided little prognostic information beyond that which resulted from postoperative therapy.
RESUMO
Oltipraz is considered one of the most potent cancer chemoprevention agents, as shown in preclinical studies. Its pharmacological effects in humans have been associated with unusual toxicity affecting the fingers and toes. This study was designed to test intermittent dosing schedules using two dosage levels: 500 mg as a single weekly dose and 200 mg as a biweekly dose, each for 30 days. Fifteen men and women were studied in each dosing group. All were heavy smokers considered to be at high risk for developing lung cancer. Plasma, buccal mucosa cell, and lipoprotein concentrations were measured at different intervals corresponding to the time period when most of the adverse effects occur. No serious toxicities were observed using these doses and schedules. The plasma and buccal mucosa cell concentrations of Oltipraz showed substantial interindividual variations at each sampling. Some subjects had no detectable plasma or buccal mucosal cell Oltipraz concentrations. The distribution of Oltipraz incorporation into the lipid fractions and albumin was changed by the administration of different schedules of Oltipraz. The results of this study suggest that the intermittent dosing is well tolerated and does not result in steady state in plasma or buccal mucosa cells. The variation and lack of detectable Oltipraz concentration in plasma, buccal mucosa cells, and lipids may affect both the toxicity and the pharmacological effects when these doses and schedules are used.
Assuntos
Anticarcinógenos/farmacocinética , Metabolismo dos Lipídeos , Mucosa Bucal/metabolismo , Pirazinas/farmacocinética , Fumar , Administração Oral , Adulto , Anticarcinógenos/administração & dosagem , Anticarcinógenos/efeitos adversos , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Neoplasias Pulmonares/prevenção & controle , Masculino , Pessoa de Meia-Idade , Probabilidade , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Medição de Risco , Sensibilidade e Especificidade , Estatísticas não Paramétricas , Tionas , Tiofenos , Distribuição TecidualRESUMO
PURPOSE: Uncertainty about the relative worth of doxorubicin/cyclophosphamide (AC) and cyclophosphamide/methotrexate/fluorouracil (CMF), as well as doubt about the propriety of giving tamoxifen (TAM) with chemotherapy to patients with estrogen receptor-negative tumors and negative axillary nodes, prompted the National Surgical Adjuvant Breast and Bowel Project to initiate the B-23 study. PATIENTS AND METHODS: Patients (n = 2,008) were randomly assigned to CMF plus placebo, CMF plus TAM, AC plus placebo, or AC plus TAM. Six cycles of CMF were given for 6 months; four cycles of AC were administered for 63 days. TAM was given daily for 5 years. Relapse-free survival (RFS), event-free survival (EFS), and survival (S) were determined by using life-table estimates. Tests for heterogeneity of outcome used log-rank statistics and Cox proportional hazards models to detect differences across all groups and according to chemotherapy and hormonal therapy status. RESULTS: No significant difference in RFS, EFS, or S was observed among the four groups through 5 years (P =.96,.8, and.8, respectively), for those aged < or = 49 years (P =.97,.5, and.9, respectively), or for those aged > or = 50 years (P =.7,.6, and.6, respectively). A comparison between all CMF- and all AC-treated patients demonstrated no significant differences in RFS (87% at 5 years in both groups, P =.9), EFS (83% and 82%, P =.6), or S (89% and 90%, P =.4). There were no significant differences in RFS, EFS, or S between CMF and AC in patients aged < or = 49 or > or = 50 years. No significant difference in any outcome was observed when chemotherapy-treated patients who received placebo were compared with those given TAM. RFS in both groups was 87% (P =.6), 87% in patients aged < or = 49 (P =.9), and 88% and 87%, respectively (P =.4), in those aged > or = 50 years. CONCLUSION: There was no significant difference in the outcome of patients who received AC or CMF. TAM with either regimen resulted in no significant advantage over that achieved from chemotherapy alone.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Receptores de Estrogênio/metabolismo , Tamoxifeno/administração & dosagem , Fatores Etários , Protocolos de Quimioterapia Combinada Antineoplásica , Axila , Neoplasias da Mama/patologia , Cisplatino , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Fluoruracila , Humanos , Metástase Linfática , Metotrexato , Pessoa de Meia-Idade , Cooperação do Paciente , Placebos , Análise de SobrevidaRESUMO
BACKGROUND: The conviction that postoperative radiotherapy and chemotherapy represent an acceptable standard of care for patients with Dukes' B (stage II) and Dukes' C (stage III) carcinoma of the rectum evolved in the absence of data from clinical trials designed to determine whether the addition of radiotherapy results in improved disease-free survival and overall survival. This study was carried out to address this issue. An additional aim was to determine whether leucovorin (LV)-modulated 5-fluorouracil (5-FU) is superior to the combination of 5-FU, semustine, and vincristine (MOF) in men. PATIENTS AND METHODS: Eligible patients (n = 694) with Dukes' B or C carcinoma of the rectum were enrolled in National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol R-02 from September 1987 through December 1992 and were followed. They were randomly assigned to receive either postoperative adjuvant chemotherapy alone (n = 348) or chemotherapy with postoperative radiotherapy (n = 346). All female patients (n = 287) received 5-FU plus LV chemotherapy; male patients received either MOF (n = 207) or 5-FU plus LV (n = 200). Primary analyses were carried out by use of a stratified log-rank statistic; P values are two-sided. RESULTS: The average time on study for surviving patients is 93 months as of September 30, 1998. Postoperative radiotherapy resulted in no beneficial effect on disease-free survival (P =.90) or overall survival (P =.89), regardless of which chemotherapy was utilized, although it reduced the cumulative incidence of locoregional relapse from 13% to 8% at 5-year follow-up (P =.02). Male patients who received 5-FU plus LV demonstrated a statistically significant benefit in disease-free survival at 5 years compared with those who received MOF (55% versus 47%; P =.009) but not in 5-year overall survival (65% versus 62%; P =.17). CONCLUSIONS: The addition of postoperative radiation therapy to chemotherapy in Dukes' B and C rectal cancer did not alter the subsequent incidence of distant disease, although there was a reduction in locoregional relapse when compared with chemotherapy alone.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fluoruracila/uso terapêutico , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/radioterapia , Antimetabólitos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia Adjuvante , Terapia Combinada , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Retais/patologia , Neoplasias Retais/cirurgia , Semustina/administração & dosagem , Fatores Sexuais , Análise de Sobrevida , Fatores de Tempo , Vincristina/administração & dosagemRESUMO
PURPOSE: To compare the efficacy of leucovorin-modulated fluorouracil (FU+LV) with that of fluorouracil and levamisole (FU+LEV) or with the combination of FU+LV and levamisole (FU+LV+LEV). PATIENTS AND METHODS: Between July 1989 and December 1990, 2,151 patients with Dukes' B (stage II) and Dukes' C (stage III) carcinoma of the colon were entered onto National Surgical Adjuvant Breast and Bowl Project protocol C-04. Patients were randomly assigned to receive FU+LV (weekly regimen), FU + LEV, or the combination of FU+LV+LEV. The average time on study was 86 months. RESULTS: A pairwise comparison between patients treated with FU+LV or FU+LEV disclosed a prolongation in disease-free survival (DFS) in favor of the FU+LV group (65% v 60%; P =.04); there was a small prolongation in overall survival that was of borderline significance (74% v 70%; P =.07). There was no difference in the pairwise comparison between patients who received FU+LV or FU+LV+LEV for either DFS (65% v 64%; P =.67) or overall survival (74% v 73%; P =.99). There was no interaction between Dukes' stage and the effect of treatment. CONCLUSION: In patients with Dukes' B and C carcinoma of the colon, treatment with FU+LV seems to confer a small DFS advantage and a borderline prolongation in overall survival when compared with treatment with FU+LEV. The addition of LEV to FU+LV does not provide any additional benefit over and above that achieved with FU+LV. These findings support the use of adjuvant FU+LV as an acceptable therapeutic standard in patients with Dukes' B and C carcinoma of the colon.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma/mortalidade , Carcinoma/patologia , Quimioterapia Adjuvante , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Levamisol/administração & dosagem , Masculino , Pessoa de Meia-Idade , Recidiva Local de NeoplasiaRESUMO
BACKGROUND: We have shown previously that lumpectomy with radiation therapy was more effective than lumpectomy alone for the treatment of ductal carcinoma in situ (DCIS). We did a double-blind randomised controlled trial to find out whether lumpectomy, radiation therapy, and tamoxifen was of more benefit than lumpectomy and radiation therapy alone for DCIS. METHODS: 1804 women with DCIS, including those whose resected sample margins were involved with tumour, were randomly assigned lumpectomy, radiation therapy (50 Gy), and placebo (n=902), or lumpectomy, radiation therapy, and tamoxifen (20 mg daily for 5 years, n=902). Median follow-up was 74 months (range 57-93). We compared annual event rates and cumulative probability of invasive or non-invasive ipsilateral and contralateral tumours over 5 years. FINDINGS: Women in the tamoxifen group had fewer breast-cancer events at 5 years than did those on placebo (8.2 vs 13.4%, p=0.0009). The cumulative incidence of all invasive breast-cancer events in the tamoxifen group was 4.1% at 5 years: 2.1% in the ipsilateral breast, 1.8% in the contralateral breast, and 0.2% at regional or distant sites. The risk of ipsilateral-breast cancer was lower in the tamoxifen group even when sample margins contained tumour and when DCIS was associated with comedonecrosis. INTERPRETATION: The combination of lumpectomy, radiation therapy, and tamoxifen was effective in the prevention of invasive cancer.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Intraductal não Infiltrante/tratamento farmacológico , Tamoxifeno/uso terapêutico , Antineoplásicos Hormonais/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Carcinoma in Situ/tratamento farmacológico , Carcinoma in Situ/terapia , Carcinoma Intraductal não Infiltrante/mortalidade , Carcinoma Intraductal não Infiltrante/secundário , Carcinoma Intraductal não Infiltrante/terapia , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/terapia , Terapia Combinada , Método Duplo-Cego , Feminino , Humanos , Mastectomia Segmentar , Pessoa de Meia-Idade , Taxa de Sobrevida , Tamoxifeno/efeitos adversosRESUMO
PURPOSE: To determine, in women with primary operable breast cancer, if preoperative doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan; AC) therapy yields a better outcome than postoperative AC therapy, if a relationship exists between outcome and tumor response to preoperative chemotherapy, and if such therapy results in the performance of more lumpectomies. PATIENTS AND METHODS: Women (1,523) enrolled onto National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 were randomly assigned to preoperative or postoperative AC therapy. Clinical tumor response to preoperative therapy was graded as complete (cCR), partial (cPR), or no response (cNR). Tumors with a cCR were further categorized as either pathologic complete response (pCR) or invasive cells (pINV). Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were estimated through 5 years and compared between treatment groups. In the preoperative arm, proportional-hazards models were used to investigate the relationship between outcome and tumor response. RESULTS: There was no significant difference in DFS, DDFS, or survival (P = .99, .70, and .83, respectively) among patients in either group. More patients treated preoperatively than postoperatively underwent lumpectomy and radiation therapy (67.8% v 59.8%, respectively). Rates of ipsilateral breast tumor recurrence (IBTR) after lumpectomy were similar in both groups (7.9% and 5.8%, respectively; P = .23). Outcome was better in women whose tumors showed a pCR than in those with a pINV, cPR, or cNR (relapse-free survival [RFS] rates, 85.7%, 76.9%, 68.1%, and 63.9%, respectively; P < .0001), even when baseline prognostic variables were controlled. When prognostic models were compared for each treatment group, the preoperative model, which included breast tumor response as a variable, discriminated outcome among patients to about the same degree as the postoperative model. CONCLUSION: Preoperative chemotherapy is as effective as postoperative chemotherapy, permits more lumpectomies, is appropriate for the treatment of certain patients with stages I and II disease, and can be used to study breast cancer biology. Tumor response to preoperative chemotherapy correlates with outcome and could be a surrogate for evaluating the effect of chemotherapy on micrometastases; however, knowledge of such a response provided little prognostic information beyond that which resulted from postoperative therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/cirurgia , Terapia Combinada/efeitos adversos , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Taxa de SobrevidaRESUMO
PURPOSE: To estimate the prevalence of abnormalities in visual function and ocular structures associated with the long-term use of tamoxifen citrate. METHODS: A single-masked, cross-sectional study involving multiple community and institutional ophthalmologic departments was conducted with a volunteer sample of 303 women with breast cancer currently taking part in a randomized clinical trial to determine the efficacy of tamoxifen (20 mg/day) in preventing recurrences. Participants included women who had never been on drug (n=85); women who had taken tamoxifen for an average of 4.8 years, then been off the drug for an average of 2.7 years (n=140); and women who had been on tamoxifen continuously for an average of 7.8 years (n=78). Women were evaluated by questionnaire, psychophysical testing, and clinical examination to determine any abnormalities in visual function and the comparative prevalences of corneal, lens, retinal, and optic nerve pathology. RESULTS: There were no cases of vision-threatening ocular toxicity among the tamoxifen-treated participants. Compared with nontreated participants, the tamoxifen-treated women had no differences in the activities of daily vision, visual acuity measurements, or other tests of visual function except for color screening. Intraretinal crystals (odds ratio [OR]=3.58, P=.178) and posterior subcapsular opacities (OR=4.03, P=.034) were more frequent in the tamoxifen-treated group. CONCLUSIONS: Women should have a thorough baseline ophthalmic evaluation within the first year of initiating tamoxifen therapy and receive appropriate follow-up evaluations.
Assuntos
Antineoplásicos Hormonais/efeitos adversos , Oftalmopatias/induzido quimicamente , Tamoxifeno/efeitos adversos , Visão Ocular/efeitos dos fármacos , Idoso , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/prevenção & controle , Catarata/induzido quimicamente , Estudos Transversais , Feminino , Humanos , Cristalino/efeitos dos fármacos , Estudos Longitudinais , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/prevenção & controle , Prevalência , Retina/efeitos dos fármacos , Doenças Retinianas/induzido quimicamente , Método Simples-Cego , Tamoxifeno/uso terapêutico , Testes VisuaisRESUMO
BACKGROUND: The B-20 study of the National Surgical Adjuvant Breast and Bowel Project (NSABP) was conducted to determine whether chemotherapy plus tamoxifen would be of greater benefit than tamoxifen alone in the treatment of patients with axillary lymph node-negative, estrogen receptor-positive breast cancer. METHODS: Eligible patients (n = 2306) were randomly assigned to one of three treatment groups following surgery. A total of 771 patients with follow-up data received tamoxifen alone; 767 received methotrexate, fluorouracil, and tamoxifen (MFT); and 768 received cyclophosphamide, methotrexate, fluorouracil, and tamoxifen (CMFT). The Kaplan-Meier method was used to estimate disease-free survival, distant disease-free survival, and survival. Reported P values are two-sided. RESULTS: Through 5 years of follow-up, chemotherapy plus tamoxifen resulted in significantly better disease-free survival than tamoxifen alone (90% for MFT versus 85% for tamoxifen [P = .01]; 89% for CMFT versus 85% for tamoxifen [P = .001]). A similar benefit was observed in both distant disease-free survival (92% for MFT versus 87% for tamoxifen [P = .008]; 91% for CMFT versus 87% for tamoxifen [P = .006]) and survival (97% for MFT versus 94% for tamoxifen [P = .05]; 96% for CMFT versus 94% for tamoxifen [P = .03]). Compared with tamoxifen alone, MFT and CMFT reduced the risk of ipsilateral breast tumor recurrence after lumpectomy and the risk of recurrence at other local, regional, and distant sites. Risk of treatment failure was reduced after both types of chemotherapy, regardless of tumor size, tumor estrogen or progesterone receptor level, or patient age; however, the reduction was greatest in patients aged 49 years or less. No subgroup of patients evaluated in this study failed to benefit from chemotherapy. CONCLUSIONS: Findings from this and other NSABP studies indicate that patients with breast cancer who meet NSABP protocol criteria, regardless of age, lymph node status, tumor size, or estrogen receptor status, are candidates for chemotherapy.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Antagonistas de Estrogênios/uso terapêutico , Receptores de Estrogênio , Tamoxifeno/uso terapêutico , Antimetabólitos Antineoplásicos/administração & dosagem , Antineoplásicos Alquilantes/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Metástase Linfática , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Receptores de Estrogênio/efeitos dos fármacos , Risco , Análise de Sobrevida , Falha de Tratamento , Resultado do TratamentoRESUMO
PURPOSE: To determine whether preoperative doxorubicin and cyclophosphamide (AC) permits more lumpectomies to be performed and decreases the incidence of positive nodes in women with primary breast cancer. PATIENTS AND METHODS: Women (n = 1,523) were randomized to National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18; 759 eligible patients received postoperative AC and 747, preoperative AC. The clinical size of breast and axillary tumors was determined before each of four cycles of AC and before surgery. Tumor response to preoperative therapy was clinically complete (cCR), partial (cPR), stable (cSD), or progressive disease (cPD). Tissue from patients with a cCR was evaluated for a pathologic complete response (pCR). RESULTS: Breast tumor size was reduced in 80% of patients after preoperative therapy; 36% had a cCR. Tumor size and clinical nodal status were independent predictors of cCR. Twenty-six percent of women with a cCR had a pCR. Clinical nodal response occurred in 89% of node-positive patients: 73% had a cCR and 44% of those had a pCR. There was a 37% increase in the incidence of pathologically negative nodes. Before randomization, lumpectomy was proposed for 86% of women with tumors < or = 2 cm, 70% with tumors 2.1 to 5.0 cm, and 3% with tumors > or = 5.1 cm. Clinical tumor size and nodal status influenced the physician's decision. Overall, 12% more lumpectomies were performed in the preoperative group; in women with tumors > or = 5.1 cm, there was a 175% increase. CONCLUSION: Preoperative therapy reduced the size of most breast tumors and decreased the incidence of positive nodes. The greatest increase in lumpectomy after preoperative therapy occurred in women with tumors > or = 5 cm, since women with tumors less than 5 cm were already lumpectomy candidates. Preoperative therapy should be considered for the initial management of breast tumors judged too large for lumpectomy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Mastectomia Segmentar , Recidiva Local de Neoplasia/prevenção & controle , Antibióticos Antineoplásicos/administração & dosagem , Antineoplásicos Alquilantes/administração & dosagem , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Cuidados Pré-Operatórios , Resultado do TratamentoRESUMO
BACKGROUND: In 1982, the National Surgical Adjuvant Breast and Bowel Project initiated a randomized, double-blinded, placebo-controlled trial (B-14) to determine the effectiveness of adjuvant tamoxifen therapy in patients with primary operable breast cancer who had estrogen receptor-positive tumors and no axillary lymph node involvement. The findings indicated that tamoxifen therapy provided substantial benefit to patients with early stage disease. However, questions arose about how long the observed benefit would persist, about the duration of therapy necessary to maintain maximum benefit, and about the nature and severity of adverse effects from prolonged treatment. PURPOSE: We evaluated the outcome of patients in the B-14 trial through 10 years of follow-up. In addition, the effects of 5 years versus more than 5 years of tamoxifen therapy were compared. METHODS: In the trial, patients were initially assigned to receive either tamoxifen at 20 mg/day (n = 1404) or placebo (n = 1414). Tamoxifen-treated patients who remained disease free after 5 years of therapy were then reassigned to receive either another 5 years of tamoxifen (n = 322) or 5 years of placebo (n = 321). After the study began, another group of patients who met the same protocol eligibility requirements as the randomly assigned patients were registered to receive tamoxifen (n = 1211). Registered patients who were disease free after 5 years of treatment were also randomly assigned to another 5 years of tamoxifen (n = 261) or to 5 years of placebo (n = 249). To compare 5 years with more than 5 years of tamoxifen therapy, data relating to all patients reassigned to an additional 5 years of the drug were combined. Patients who were not reassigned to either tamoxifen or placebo continued to be followed in the study. Survival, disease-free survival, and distant disease-free survival (relating to failure at distant sites) were estimated by use of the Kaplan-Meier method; differences between the treatment groups were assessed by use of the logrank test. The relative risks of failure (with 95% confidence intervals [CIs]) were determined by use of the Cox proportional hazards model. Reported P values are two-sided. RESULTS: Through 10 years of follow-up, a significant advantage in disease-free survival (69% versus 57%, P < .0001; relative risk = 0.66; 95% CI = 0.58-0.74), distant disease-free survival (76% versus 67%, P < .0001; relative risk = 0.70; 95% CI = 0.61-0.81), and survival (80% versus 76%, P = .02; relative risk = 0.84; 95% CI = 0.71-0.99) was found for patients in the group first assigned to receive tamoxifen. The survival benefit extended to those 49 years of age or younger and to those 50 years of age or older. Tamoxifen therapy was associated with a 37% reduction in the incidence of contralateral (opposite) breast cancer (P = .007). Through 4 years after the reassignment of tamoxifen-treated patients to either continued-therapy or placebo groups, advantages in disease-free survival (92% versus 86%, P = .003) and distant disease-free survival (96% versus 90%, P = .01) were found for those who discontinued tamoxifen treatment. Survival was 96% for those who discontinued tamoxifen compared with 94% for those who continued tamoxifen treatment (P = .08). A higher incidence of thromboembolic events was seen in tamoxifen-treated patients (through 5 years, 1.7% versus 0.4%). Except for endometrial cancer, the incidence of second cancers was not increased with tamoxifen therapy. CONCLUSIONS AND IMPLICATIONS: The benefit from 5 years of tamoxifen therapy persists through 10 years of follow-up. No additional advantage is obtained from continuing tamoxifen therapy for more than 5 years.
Assuntos
Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Antagonistas de Estrogênios/administração & dosagem , Receptores de Estrogênio , Tamoxifeno/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Método Duplo-Cego , Neoplasias do Endométrio/etiologia , Antagonistas de Estrogênios/efeitos adversos , Feminino , Seguimentos , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Risco , Tamoxifeno/efeitos adversos , Fatores de TempoRESUMO
PURPOSE: To compare sequential methotrexate (M) and fluorouracil (F) (M-->F) with surgery (National Surgical Adjuvant Breast and Bowel Project [NSABP] B-13) and cyclophosphamide (C), M, and F with M-->F (NSABP B-19), in patients with estrogen receptor (ER)-negative tumors and negative axillary nodes. PATIENTS AND METHODS: A total of 760 patients were randomized to B-13; 1,095 patients with the same eligibility requirements were randomized to B-19. Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were determined using life-table estimates. RESULTS: A significant benefit in overall DFS (74% v 59%; P < .001) was demonstrated at 8 years in all B-13 patients who received M-->F (69% v 56% [P = .006] in those
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptores de Estrogênio/análise , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/química , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Leucovorina/administração & dosagem , Metástase Linfática , Mastectomia , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia , Taxa de SobrevidaRESUMO
The ability of human cells to regenerate ascorbic acid from dehydroascorbate is partially dependent on the glutathione redox status of the cell and the relative activity of dehydroascorbate reductases. Mammalian dehydroascorbate reductase activity is associated with two proteins known as thioltransferase (glutaredoxin) and protein disulfide isomerase. We compared the specific activity of thioltransferase, protein disulfide isomerase, and other GSH-related enzymes in Adriamycin-resistant human breast tumor cells, MCF-7 ADRR, and Adriamycin-sensitive, MCF-7 WT, tumor cells. MCF-7 ADRR cells had higher activities of glutathione peroxidase (34.7 fold), nonseleno-glutathione peroxidase (glutathione S-transferases; 5.3 fold), thioredoxin (2.3 fold), and thioltransferase (4.0 fold) compared with the WT Adriamycin-sensitive cell line. Thioltransferase was detected in Western blots in extracts of ADRR MCF-7 cells but not in WT MCF-7 cells. alpha-Tocopherol in the membrane and cytosolic fractions was 2.8 and 3.0 fold higher, respectively, in Adriamycin-resistant compared with Adriamycin-sensitive cells. Supplementation of MCF-7 cells with L-ascorbic acid 2-phosphate (2 and 10 mM) had no effect on WT cell viability after 5 days incubation with up to 0.33 microM Adriamycin. In contrast, supplementation of ADRR MCF-7 cells with L-ascorbic acid 2-phosphate resulted in enhanced resistance up to 3.4 microM Adriamycin over a 5-day incubation. Both lines of MCF-7 cells demonstrated the ability to utilize ascorbic acid as the 2-phosphate derivative. After 48 h incubation with 8.6 microM Adriamycin, the resistant cells maintained normal viability and ascorbate-dehydroascorbate levels, whereas drug-sensitive cells had significantly lower ascorbate with a higher percent dehydroascorbate and increased cell death as judged by cell protein levels (52% of controls).
Assuntos
Ácido Ascórbico , Neoplasias da Mama , Doxorrubicina/farmacologia , Oxirredutases , Animais , Western Blotting , Sobrevivência Celular , Células Cultivadas/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glutarredoxinas , Humanos , Proteínas , RatosRESUMO
Aminoglutethimide (Ag) is a potent aromatase-enzyme inhibitor used in the treatment of patients with breast cancer. In the past, it has been administered in doses of 1,000 mg/d (usually with 40 mg hydrocortisone). At these dose levels, the drug also affects multiple cytochrome P-450 enzymes, including enzymes for adrenal steroid biosynthesis. Recently, lower-dose regimens (500 mg/d) of Ag have been found to be just as effective for breast cancer therapy, but less toxic than the higher conventional dose. There is limited information on the adrenal effects at the lower dosages, and it is not known whether these effects are clinically significant. We measured basal and synthetic corticotropin (Cortrosyn)-stimulated levels of adrenal steroids in postmenopausal breast cancer patients before and during treatment with low-dose Ag (500 mg/d) administered without a glucocorticoid preparation. Basal levels of progesterone, 17-OH progesterone, and 11-deoxycortisol were higher after 2 months' treatment (P < .01). After ACTH injection, peak levels of progesterone and 17-OH progesterone were higher (P < .01), but in contrast, peak levels of 18-OH corticosterone were lower during treatment (P < .02). Basal and peak levels of cortisol, aldosterone, and all other adrenal steroids were unchanged during treatment. We conclude that low-dose Ag treatment leads to partial inhibition of the 21-hydroxylase, 11-hydroxylase, and 18-hydroxylase adrenal enzymes. Since cortisol and aldosterone secretion remained normal with minimal shunting to or accumulation of adrenal androgen compounds, we believe that the mild inhibition was compensated for by further endogenous ACTH stimulation.
Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Aminoglutetimida/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , 17-alfa-Hidroxiprogesterona , Idoso , Aldosterona/sangue , Neoplasias da Mama/fisiopatologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Hidrocortisona/sangue , Hidroxiprogesteronas/sangue , Pessoa de Meia-Idade , Pós-Menopausa , Progesterona/sangueRESUMO
The adriamycin sensitive and resistant human breast cancer cells (MCF-7) were investigated by computerized image analysis for establishment of characteristic cell nuclei-morphological differences. Using specially developed algorithms and a large set of subvisual parameters, morphological features characteristic for the resistant cell line were described. The most useful parameters for distinguishing the resistant from sensitive cells are related to chromatin structure and include integral optical density per micron 2, the average area of chromatin region, and the integral density of the chromatin region per micron 2. Besides the size of the nuclei, the two features with the most discriminatory power belonged to those characterizing patterns of chromatin condensation. The results of quantitative analysis suggest that drug resistance relates to specific chromatin patterns. Compared to sensitive cell line, the resistant MCF-7 cells show distinguished coarse chromatin pattern with enlarged condensed chromatin regions.
Assuntos
Neoplasias da Mama/ultraestrutura , Núcleo Celular/patologia , Doxorrubicina/uso terapêutico , Resistência a Medicamentos , Algoritmos , Nucléolo Celular/patologia , Cromatina/patologia , DNA de Neoplasias/análise , Humanos , Processamento de Imagem Assistida por Computador , Células Tumorais CultivadasRESUMO
The biological activities of vitamin E are related to the cellular functions and presence of sufficient tissue concentrations of this micronutrient. Most of the stored vitamin E is in the adipose tissue where it appears to be distributed equally. The breast adipose tissue has similar vitamin E concentrations as other parts of the body. The ductal systems also store vitamin E in sufficient concentrations to maintain cellular functions. The milk secreted from the ducts of the breast contains a high concentration of tocopherol. Whereas the normal breast tissue presumably utilizes vitamin E as an antioxidant, tumor tissue appears to handle vitamin E differently. Breast tumors possessing estrogen negative receptors and having poor histological differentiation have lower concentrations of vitamin E than tumors with positive estrogen receptors and well differentiated histology. Since vitamin E is considered the principal, if not sole, chain-breaking lipophilic antioxidant in plasma and tissue, its role as a potential chemopreventive agent in breast cancer should be further investigated. The combination of vitamin E with other cancer chemopreventive agents appears to be a reasonable procedure.
Assuntos
Neoplasias da Mama/prevenção & controle , Vitamina E/farmacocinética , Tecido Adiposo/química , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Administração Oral , Adulto , Idoso , Mama/química , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Leite Humano/química , Projetos Piloto , Distribuição Tecidual , Vitamina E/análise , Vitamina E/farmacologiaRESUMO
Pharmacological studies on Oltipraz [4-methyl-5(pyrazinyl-2)-1-2-dithiole-3-thione)] were conducted with normal healthy subjects using various doses and schedules. Administration of single doses (1, 2 and 3 mg/kg) resulted in detectable drug levels in the serum (mean peak serum concentrations 16, 61 and 205 ng, respectively) and urine. The t1/2 was short (4.4, 4.1 and 5.3 hours respectively) and no steady state was achieved after multiple daily doses for 12 days. Introduction of a loading dose during the first day produced a steady state when 1.5 and 2.0 mg/kg/day were used. Daily administration of Oltipraz sustained the steady state with insignificant variations. Consumption of a high fat diet increased the serum and urine concentrations of Oltipraz (30-60%) compared to the low fat diet. Two subjects experienced flatulence during the administration of the drug. One subject developed numbness and pain in the thumbs with occurrence of small purplish-black spots resembling those observed in subacute endocarditis. These changes disappeared 10 days after discontinuation of the drug. No changes in peripheral blood counts, biochemical profile or thyroid function tests were observed after four weeks of Oltipraz. Further studies with a larger number of healthy subjects are needed for clarification of the safety and biological efficacy of small doses of Oltipraz during chronic administration.
Assuntos
Anticarcinógenos/farmacologia , Pirazinas/farmacologia , Adulto , Anticarcinógenos/administração & dosagem , Anticarcinógenos/farmacocinética , Cromatografia Líquida de Alta Pressão , Gorduras na Dieta/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirazinas/administração & dosagem , Pirazinas/farmacocinética , Valores de Referência , Tionas , TiofenosRESUMO
Breast cancer metastatic to the eye is a common entity occurring in up to 30% of women with metastatic disease. The prevalence of this lesion is not appreciated because of the dominant clinical picture of metastases occurring in other organs. The diagnosis should be suspected in any women with a history of breast cancer and any visual symptoms, particularly metamorphopsia and scotomata. A thorough ophthalmologic evaluation, aided by ultrasonography, computed tomography, or magnetic resonance scanning, usually confirms the diagnosis. Early treatment with radiation therapy can alleviate symptoms and control local disease. The recognition and treatment of this disorder is important in maximizing the quality of life in patients with metastatic breast cancer, especially because newer treatment regimens prolong survival and thereby increase the chances for ocular metastasis.
Assuntos
Neoplasias da Mama/patologia , Neoplasias Oculares/secundário , Neoplasias Oculares/diagnóstico , Neoplasias Oculares/terapia , Feminino , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Prognóstico , Qualidade de Vida , Tomografia Computadorizada por Raios X , UltrassonografiaRESUMO
Common as well as unusual, heretofore unmentioned histopathologic features observed in 336 typical and 273 atypical medullary breast cancers from 6404 patients enrolled in various stage I and II protocols of the National Surgical Adjuvant Breast and Bowel Projects (NSABP) are presented. Both medullary types exhibited comparable pathologic findings, except for the infiltrative border and/or slight or absent tumor lymphoid infiltrate which by definition characterize the atypical form. Both also demonstrated a similar, high proclivity to be aneuploid, and to lack estrogen and progesterone receptors and nodal metastases. After appropriate statistical adjustments, survival (analyzed for 198 patients with typical and 149 with atypical medullary cancers) was found to be better for untreated, node-negative and node-positive patients treated with L-PAM + 5Fu who had typical medullary cancers than those with the NOS histologic type. The magnitude of this difference was 6% at 5 and 17% at 10 years post-operatively (cumulative odds = 1.81 with a 95% confidence interval of 1.08 - 3.3) for the former group, and 4% at 5 and 16% at 10 years (cumulative odds = 1.56 with a 95% confidence interval of 1.08 - 2.23) for the latter. Survival was comparable for patients with atypical medullary and NOS types in both situations. No clear difference in survival was found in untreated, positive node patients with the 3 histologic types examined, although the sample sizes in this subset were relatively small. This information as well as other pertinent considerations indicate that the prognosis of typical medullary cancer is not as 'good' as previously perceived. It is also concluded that there is insufficient evidence at present to exclude the atypical medullary variant as a histologic type of breast cancer.
Assuntos
Neoplasias da Mama/patologia , Carcinoma/patologia , Biomarcadores Tumorais/análise , Neoplasias da Mama/mortalidade , Carcinoma/mortalidade , Humanos , Tábuas de Vida , Linfonodos/patologia , Fenótipo , Ploidias , Prognóstico , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Taxa de Sobrevida , Estados UnidosRESUMO
The National Surgical Adjuvant Breast and Bowel Project (NSABP) implemented protocol B-15 to compare 2 months of Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) and cyclophosphamide (AC) with 6 months of conventional cyclophosphamide, methotrexate, and fluorouracil (CMF) in patients with breast cancer nonresponsive to tamoxifen (TAM, T). A second aim was to determine whether AC followed in 6 months by intravenous (IV) CMF was more effective than AC without reinduction therapy. Through 3 years of follow-up, findings from 2,194 patients indicate no significant difference in disease-free survival (DFS, P = .5), distant disease-free survival (DDFS, P = .5) or survival (S, P = .8) among the three groups. Since the outcome from AC and CMF was almost identical, the issue arises concerning which regimen is more appropriate for the treatment of breast cancer patients. AC seems preferable since, following total mastectomy, AC was completed on day 63 versus day 154 for conventional CMF; patients visited health professionals three times as often for conventional CMF as for AC; women on AC received therapy on each of 4 days versus on each of 84 days for conventional CMF; and nausea-control medication was given for about 84 days to conventional CMF patients versus for about 12 days to patients on AC. The difference in the amount of alopecia between the two treatment groups was less than anticipated. While alopecia was almost universally observed following AC therapy, 71% of the CMF patients also had hair loss and, in 41%, the loss was greater than 50%. This study and NSABP B-16, which evaluates the worth of AC therapy in TAM-responsive patients, indicate the merit of 2 months of AC therapy for all positive-node breast cancer patients.