RESUMO
BACKGROUND: MA17 showed improved outcomes in postmenopausal women given extended letrozole (LET) after completing 5 years of adjuvant tamoxifen. PATIENTS AND METHODS: Exploratory subgroup analyses of disease-free survival (DFS), distant DFS (DDFS), overall survival (OS), toxic effects and quality of life (QOL) in MA17 were performed based on menopausal status at breast cancer diagnosis. RESULTS: At diagnosis, 877 women were premenopausal and 4289 were postmenopausal. Extended LET was significantly better than placebo (PLAC) in DFS for premenopausal [hazard ratio (HR) = 0.26, 95% confidence interval (CI) 0.13-0.55; P = 0.0003] and postmenopausal women (HR = 0.67; 95% CI 0.51-0.89; P = 0.006), with greater DFS benefit in those premenopausal (interaction P = 0.03). In adjusted post-unblinding analysis, those who switched from PLAC to LET improved DDFS in premenopausal (HR = 0.15; 95% CI 0.03-0.79; P = 0.02) and postmenopausal women (HR = 0.45; 95% CI 0.22-0.94; P = 0.03). CONCLUSIONS: Extended LET after 5 years of tamoxifen was effective in pre- and postmenopausal women at diagnosis, and significantly better in those premenopausal. Women premenopausal at diagnosis should be considered for extended adjuvant therapy with LET if menopausal after completing tamoxifen.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Nitrilas/uso terapêutico , Pré-Menopausa , Triazóis/uso terapêutico , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Inibidores da Aromatase/efeitos adversos , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/diagnóstico , Quimioterapia Adjuvante , Intervalo Livre de Doença , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Letrozol , Pessoa de Meia-Idade , Nitrilas/efeitos adversos , Placebos , Pós-Menopausa , Qualidade de Vida , Sobrevida , Tamoxifeno/uso terapêutico , Resultado do Tratamento , Triazóis/efeitos adversosRESUMO
BACKGROUND: MA.17 evaluated letrozole or placebo after 5 years of tamoxifen and showed significant improvement in disease-free survival (DFS) for letrozole [hazard ratio (HR) 0.57, P = 0.00008]. The trial was unblinded and placebo patients were offered letrozole. PATIENTS AND METHODS: An intent-to-treat analysis of all outcomes, before and after unblinding, on the basis of the original randomization was carried out. RESULTS: In all, 5187 patients were randomly allocated to the study at baseline and, at unblinding, 1579 (66%) of 2383 placebo patients accepted letrozole. At median follow-up of 64 months (range 16-95), 399 recurrences or contralateral breast cancers (CLBCs) (164 letrozole and 235 placebo) occurred. Four-year DFS was 94.3% (letrozole) and 91.4% (placebo) [HR 0.68, 95% confidence interval (CI) 0.55-0.83, P = 0.0001] and showed superiority for letrozole in both node-positive and -negative patients. Corresponding 4-year distant DFS was 96.3% and 94.9% (HR 0.80, 95% CI 0.62-1.03, P = 0.082). Four-year overall survival was 95.1% for both groups. The annual rate of CLBC was 0.28% for letrozole and 0.46% for placebo patients (HR 0.61, 95% CI 0.39-0.97, P = 0.033). CONCLUSIONS: Patients originally randomly assigned to receive letrozole within 3 months of stopping tamoxifen did better than placebo patients in DFS and CLBC, despite 66% of placebo patients taking letrozole after unblinding.
Assuntos
Antineoplásicos/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Estrogênios , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Nitrilas/uso terapêutico , Progesterona , Triazóis/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/administração & dosagem , Intervalo Livre de Doença , Método Duplo-Cego , Humanos , Estimativa de Kaplan-Meier , Letrozol , Metástase Linfática , Segunda Neoplasia Primária/tratamento farmacológico , Segunda Neoplasia Primária/epidemiologia , Nitrilas/administração & dosagem , Aceitação pelo Paciente de Cuidados de Saúde , Placebos , Pós-Menopausa , Modelos de Riscos Proporcionais , Recidiva , Tamoxifeno/uso terapêutico , Triazóis/administração & dosagemRESUMO
BACKGROUND: Studies in animals and geographic correlations across populations suggest that fatty acid intake may have a positive relationship with breast cancer risk, but analytic epidemiologic studies of fat intake have been less supportive. Adipose tissue analysis provides a more objective assessment of intakes of fatty acids that are not endogenously synthesized than do the questionnaire survey methods used in many epidemiologic studies. PURPOSE: This case-control study of postmenopausal women was designed to examine the relationship between fatty acid composition of subcutaneous adipose tissue and risk of breast cancer and proliferative benign breast disease. In addition, we examined specific hypotheses that breast cancer risk is negatively associated with long-chain N-3 fatty acid intake, positively associated with trans fatty acid intake, and positively associated with increased intake of polyunsaturated fat together with low intake of antioxidants. METHODS: Aspirates of subcutaneous fat from the buttocks were obtained from 380 women with newly diagnosed stage I or II breast cancer and 176 with proliferative benign breast disease. A total of 397 women who were evaluated for breast abnormalities at the same institutions but did not require breast biopsy or whose biopsy revealed nonproliferative benign breast disease served as the control group. We examined associations between saturated, monounsaturated, polyunsaturated, trans, or long-chain N-3 fatty acids and breast cancer, atypical hyperplasia, or proliferative benign breast disease without atypia. RESULTS: We observed no consistent patterns of association between breast cancer risk and any of the categories of fatty acids or the individual constituent fatty acids in the adipose tissue. Saturated fatty acids were inversely associated with risk of proliferative benign breast disease without atypia but not with atypical hyperplasia or breast cancer. This association was not observed, however, when total fat intake was taken into account. Women with high levels of polyunsaturated fatty acids in adipose tissue and low serum or dietary levels of antioxidants were not observed to be at higher risk of breast cancer. CONCLUSIONS: Using an objective measure of intake, we observed no major associations between polyunsaturated fatty acids, including long-chain N-3 fatty acids and trans fatty acids, and risk of breast cancer or proliferative benign breast disease. IMPLICATIONS: These data do not support the hypothesis that intake of specific fatty acids, particularly polyunsaturated and trans fatty acids, is an important risk factor for malignant or benign breast disease.
Assuntos
Tecido Adiposo/química , Doenças Mamárias/etiologia , Neoplasias da Mama/etiologia , Gorduras na Dieta/efeitos adversos , Ácidos Graxos/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Gorduras na Dieta/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Fatores de Risco , Pele/químicaRESUMO
alpha-Interferon (IFN-alpha) enhances the activity of 5-fluorouracil in patients with advanced colorectal carcinoma. Preclinical evidence suggests a similar potential role for IFN-alpha combined with cyclophosphamide, doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH), and 5-fluorouracil (CAF) in advanced adenocarcinoma of the breast. To determine a maximum tolerated dose of IFN-alpha that could be combined with CAF and that did not compromise CAF dose intensity and to determine the effect of IFN-alpha on the pharmacokinetics of doxorubicin, a phase I study of IFN-alpha plus CAF was performed by the Eastern Cooperative Oncology Group. Nine patients with advanced breast cancer received CAF (cyclophosphamide at 100 mg/m2/day p.o. on days 1-14, doxorubicin at 30 mg/m2 and 5-fluorouracil at 500 mg/m2 i.v. bolus on days 1 and 8) plus IFN-alpha (1 milliunit/m2, n = 6, or 2 milliunits/m2, n = 3) given s.c. on days 1, 3, 5, and 8 (1 h prior to the doxorubicin and 5-FU injection on days 1 and 8) of each cycle every 28 or more days. Escalation of the IFN-alpha dose occurred in cohorts of 3-6 patients if a dose-limiting toxic event (neutropenic fever, platelet nadir of < 25,000/microliters, > 2-week treatment delay, or a > 50% dose reduction in day 8 CAF) occurred during the first two cycles in 0 of 3 or 1 of 6 patients. During cycle 1, IFN-alpha was omitted on day 1, and multiple plasma samples were drawn on day 1 (without IFN-alpha) and day 8 (with IFN-alpha) after each doxorubicin injection and were analyzed for plasma doxorubicin concentration. The maximum tolerated dose of IFN-alpha by our criteria was 1 milliunit/m2, and neutropenia was the predominant toxic effect that precluded IFN-alpha dose escalation. The dose intensity of CAF achieved with IFN-alpha was identical to that for CAF alone observed in prior studies. IFN-alpha had no significant effect on the pharmacokinetics of doxorubicin, although 3 of 7 patients studied had reduced doxorubicin clearance, ranging from 32% to 69%. Alternative CAF drug delivery schedules (all drugs given i.v. every 3-4 weeks) that are more amendable to hematopoietic growth factor support may be more suitable to combine with higher doses of IFN-alpha that may produce modulation.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Interferon-alfa/administração & dosagem , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Interferon alfa-2 , Pessoa de Meia-Idade , Proteínas RecombinantesRESUMO
In this pilot study of metastatic melanoma, interleukin-2 (IL-2) and cisplatin (CDDP) chemotherapy were combined using an alternating schedule designed to explore potential synergism between these modalities. Bolus IL-2 was given at a dose of 600,000 IU/kg intravenously (IV) every 8 hours, days 1 to 5 and 15 to 19, followed by high-dose CDDP administered by two different regimens: (A) 135 to 150 mg/m2 IV bolus over 30 minutes with the chemoprotectant WR-2721 910 mg/m2 or (B) 50 mg/m2 IV over 2 hours every day for 3 days. The trial design allowed an assessment of response to each phase of therapy. Among 27 assessable patients, there were 10 (37%) overall responses, including three (11%) complete responses (CRs) with durations of 9, 16, and 30+ months. Tumor regression was noted in seven patients (partial response [PR], four; minor response [MR], three; response rate [RR], four of 27 [15%]) after IL-2 administration and in 14 patients (PR, 12; MR, two; RR, 12 of 27 [44%]) after CDDP treatment, demonstrating noncrossresistance between the components of the regimen. Major PRs (greater than 90% reduction of tumor burden) or CRs were only seen in patients responding to IL-2. Toxicity during IL-2 therapy was typical for high-dose IL-2 protocols and was reversible. Among the first 20 patients treated with CDDP regimen A, there were eight episodes of grade IV nephrotoxicity (creatinine level greater than 5.0 mg/dL), including three of six patients treated with an initial CDDP dose of 135 mg/m2. This side effect was more frequent among patients with liver metastasis (P less than .05, Fisher's exact test). No significant nephrotoxicity was noted in seven patients treated on regimen B. Although ototoxicity was frequent, minimal bone marrow and neurologic toxicity was noted. There were no treatment-related deaths. This combination showed at least additive activity against melanoma, and the more protracted CDDP schedule was well tolerated. This regimen may serve as a model for future combined immunotherapy and chemotherapy trials in metastatic melanoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Adulto , Amifostina/administração & dosagem , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Sinergismo Farmacológico , Feminino , Humanos , Interleucina-2/administração & dosagem , Interleucina-2/efeitos adversos , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Projetos PilotoRESUMO
PURPOSE: To determine the response rate of postmenopausal breast cancer patients to the gonadotropin-releasing hormone (GN-RH) agonist, Zoladex (goserelin; ICI Pharma, Wilmington, DE). PATIENTS AND METHODS: A multi-institutional single-agent trial in postmenopausal patients was conducted. Serum levels of follicle-stimulating hormone (FSH), testosterone, and estradiol were requested before and after Zoladex treatment. RESULTS: For estrogen receptor-positive (ER+) patients, the response rate was 11%, with one complete response (CR) and three partial responses (PRs) among 36 eligible patients. Responses were of short duration. There were no responses among 16 estrogen receptor-negative (ER-) patients. CONCLUSION: GN-RH agonists have activity in ER+ postmenopausal patients, but response rates are not as high as with other available endocrine therapies and the duration of response is short.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Gosserrelina/uso terapêutico , Idoso , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Feminino , Hormônio Foliculoestimulante/sangue , Hormônios Esteroides Gonadais/sangue , Humanos , Menopausa , Pessoa de Meia-Idade , Metástase Neoplásica , Receptores de Estrogênio/metabolismo , Análise de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: The study was undertaken to assess the relationship among cosmesis and complications to factors related to disease presentation, surgical and radiotherapeutic technique, and adjuvant systemic therapy in conservative treatment for early-stage breast carcinoma. PATIENTS AND METHODS: Between 1982 and 1988, 234 women with stage I/II breast carcinoma were treated with conservation therapy by a highly standardized protocol of limited excision and radiotherapy. Radiation boost and/or reexcision were determined by careful quantitation of the normal tissue margin around the primary tumor. Boosts to 20 Gy were preferentially performed with interstitial iridium-192 (192Ir) implants. Axillary node dissections were performed in all patients aged less than 70 years. Adjuvant therapy consisted of cyclophosphamide, methotrexate, (doxorubicin), and fluorouracil (CM[A]F) six to eight times for node-positive premenopausal women and tamoxifen for node-positive or -negative postmenopausal women. Median follow-up was 50 months (range, 20 to 80 months). Cosmesis was graded by defined criteria, and complications were individually scored. RESULTS: Factors found to impact cosmesis adversely were palpable tumors (P = .046), volume of breast tissue resected (P = .027), reexcision of the tumor bed (P = .01), number of radiation fields (P = .03), radiation boost (P = .01), and chest wall separation (P = .01). There was a trend toward worse cosmesis (P = .062) in patients receiving tamoxifen. Cosmesis was not adversely affected by interstitial implant in spite of a higher prescribed dose. Factors influencing complication risk were axillary node dissection (P = .02), number of lymph nodes harvested (P = .05), and chemotherapy (P = .03). CONCLUSIONS: Optimal cosmesis and minimal complication risk require careful attention to the technical details of surgery and radiotherapy. The impact of systemic therapies needs to be more thoroughly examined.
Assuntos
Neoplasias da Mama/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/radioterapia , Quimioterapia Adjuvante , Terapia Combinada , Estética , Feminino , Humanos , Mamoplastia , Mastectomia Segmentar , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Radioterapia/efeitos adversos , Radioterapia/métodos , Resultado do TratamentoRESUMO
PURPOSE: A phase I dose-escalation trial of recombinant human interleukin-4 (IL-4) was performed to determine its toxicity, biologic activity, and potential antineoplastic effects. PATIENTS AND METHODS: Ten patients with refractory malignancies received IL-4 by bolus intravenous injection every 8 hours on days 1 to 5 and 15 to 19 (maximum, 28 doses) of a 31-day study period. Three patients received 10 micrograms/kg per dose and seven received 15 micrograms/kg per dose of IL-4. RESULTS: Toxic symptoms noted at the second dose level included nasal congestion, diarrhea, nausea and vomiting, fatigue, anorexia, headache, dyspnea, and capillary leak syndrome (median weight gain, 6.1%; range, 3.4% to 11.7%). Fever or sustained hypotension sufficient to require pressors did not occur. Decreases in lymphocyte count and serum bicarbonate, sodium, albumin, fibrinogen and immunoglobulin (Ig) levels, and increases in hematocrit, prothrombin time/partial thromboplastin time (PT/PTT), soluble CD23, and, occasionally, serum creatinine and transaminases occurred. All side effects resolved by day 31. Phenotypic analysis of peripheral-blood mononuclear cells (PBMC) showed a decrease in the percentage of circulating CD16 and CD14(+) cells. Plasma tumor necrosis factor (TNF) and IL-1 beta levels were unaffected, whereas serum C-reactive protein (CRP) concentrations increased slightly and plasma IL-1 receptor antagonist (IL-1RA) levels increased markedly. No tumor responses were observed. CONCLUSIONS: We conclude that 10 micrograms/kg per dose of IL-4 is the maximum-tolerated dose for this schedule, although 15 micrograms/kg per dose can be tolerated if more intensive, but still non-intensive care unit level care is provided. The results of this study should aid in the design of future phase II trials that involve IL-4 alone or phase I studies that combine IL-4 with other cytokines such as IL-2.
Assuntos
Interleucina-4/administração & dosagem , Interleucina-4/efeitos adversos , Neoplasias/tratamento farmacológico , Adulto , Idoso , Proteína C-Reativa/metabolismo , Esquema de Medicação , Feminino , Humanos , Imunofenotipagem , Injeções Intravenosas , Interleucina-4/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
PURPOSE: To determine the efficacy of a biweekly paclitaxel and cisplatin regimen in patients with advanced breast carcinoma, which has previously been reported to produce an 85% response rate in such patients. PATIENTS AND METHODS: Sixteen patients with metastatic breast carcinoma who had relapsed after prior doxorubicin-containing adjuvant chemotherapy were treated with paclitaxel (90 mg/m2) by intravenous (i.v.) infusion over 3 hours followed by cisplatin (60 mg/m2) given by i.v. infusion over 1 hour on an outpatient basis. Treatment was repeated every 2 weeks if the absolute neutrophil count was > or = 750/microL and platelet count > or = 75,000/microL. After a maximum of eight cycles of paclitaxel/cisplatin, patients received biweekly paclitaxel alone (90 mg/m2 with dose escalation). Thirteen patients were assessable for response and all for toxicity. Nine of 13 patients assessable for response (69%) had at least three sites of metastases and 10 patients (77%) had visceral-dominant disease. RESULTS: Partial response occurred in three of 13 assessable patients (23%; 90% confidence interval, 7% to 49%). All responders had two or fewer sites of metastases. The median time to progression was 4.3 months and the median survival duration was 11.4 months. Patients received a median of seven cycles of therapy (range, two to 21). Severe and/or life-threatening toxicity occurred in 50% and 38%, respectively, and consisted primarily of granulocytopenia, anemia, and neuropathy. The trial was terminated after the first interim analysis as per its two-stage design, since it was unlikely that the response rate would exceed 70%. CONCLUSION: Biweekly paclitaxel/cisplatin is not likely to produce a response rate greater than 70% in patients with metastatic breast cancer who have relapsed after prior doxorubicin-containing adjuvant chemotherapy and who have multiple sites of metastases and/or visceral-dominant disease.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Neoplasias da Mama/patologia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Análise de SobrevidaRESUMO
PURPOSE: Thrombocytopenia may compromise cancer treatment, causing chemotherapy dose reductions, schedule alterations, or the need for platelet transfusions. We evaluated the efficacy and safety of recombinant human interleukin-11 (rhIL-11; Neumega, Genetics Institute, Inc, Cambridge, MA), a novel thrombopoietic growth factor, in reducing the need for platelet transfusions in patients who undergo dose-intensive chemotherapy. PATIENTS AND METHODS: Women with advanced breast cancer received cyclophosphamide (3,200 mg/m2) and doxorubicin (75 mg/m2) plus granulocyte colony-stimulating factor (G-CSF; 5 microg/kg/d). Patients were randomized to blinded treatment with placebo or 50 microg/kg/d rhIL-11 subcutaneously for 10 or 17 days after the first two chemotherapy cycles. RESULTS: Seventy-seven patients were randomized and constitute the intent-to-treat (ITT) population. Sixty-seven patients (the assessable subgroup) either completed both cycles without a major protocol violation (n = 62) or received a platelet transfusion before treatment was discontinued after the first cycle. In the ITT population, rhIL-11 significantly decreased the requirement for platelet transfusions; 27 of 40 (68%) patients who received rhIL-11 did not require transfusions, compared with 15 of 37 (41%) in the placebo group (P = .04). Treatment with rhIL-11 significantly reduced the total number of platelet transfusions required in the assessable subgroup (P = .03) and the time to platelet recovery to more than 50,000/microL in the second cycle (P = .01). Most adverse events associated with rhIL-11 were reversible, mild to moderate in severity, and likely related to fluid retention. CONCLUSION: rhIL-11 is safe and effective in reducing treatment-associated thrombocytopenia and the need for platelet transfusions in patients who undergo dose-intensive chemotherapy, and thus may permit chemotherapy to be administered as planned at intended doses and thereby maximize the potential for a successful outcome.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Interleucina-11/uso terapêutico , Trombocitopenia/induzido quimicamente , Trombocitopenia/prevenção & controle , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Humanos , Interleucina-11/efeitos adversos , Pessoa de Meia-Idade , Transfusão de Plaquetas , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Trombocitopenia/terapiaRESUMO
PURPOSE: The identification of a subset of patients with axillary lymph node-positive breast cancer with an improved prognosis would be clinically useful. We report the prognostic importance of histologic grading and proliferative activity in a cohort of patients with axillary lymph node-positive breast cancer and compare these parameters with other established prognostic factors. PATIENTS AND METHODS: This Eastern Cooperative Oncology Group laboratory companion study (E4189) centered on 560 axillary lymph node-positive patients registered onto one of six eligible clinical protocols. Flow cytometric (ploidy and S-phase fraction [SPF]) and histopathologic analyses (Nottingham Combined Histologic Grade and mitotic index) were performed on paraffin-embedded tissue from 368 patients. RESULTS: Disease recurred in 208 patients; in 161 (77%), within the first 5 years. Mitotic index and grade were associated with both ploidy and SPF (P =.01). Within the first 5 years of follow-up, mitotic index (P =.004), grade (P =.004), ploidy (P =. 006), and SPF (P =.05) were associated with time to recurrence; there was also a significant association with survival. The effect of mitotic index was largely a result of the difference between 0 to 2 mitoses/10 high-power fields (HPF; 5-year recurrence of 31%) and more than 2 mitoses/10 HPF (5-year recurrence of 52%). The 0 to 2 mitoses/10 HPF group was independently associated with improved prognosis at 5 years (P =.002) in regression models that included other standard prognostic factors. CONCLUSION: A subset of axillary lymph node-positive patients with improved prognosis may be identified using a lower (< 3 mitoses/10 HPF) mitotic count than is usually performed.
Assuntos
Neoplasias da Mama/patologia , Adulto , Idoso , Axila , Estudos de Coortes , Feminino , Citometria de Fluxo , Humanos , Funções Verossimilhança , Metástase Linfática , Pessoa de Meia-Idade , Mitose , Recidiva Local de Neoplasia , Prognóstico , Modelos de Riscos Proporcionais , Análise de SobrevidaRESUMO
PURPOSE: Overexpression of the HER2 protein occurs in 25% to 30% of human breast cancers and leads to a particularly aggressive form of the disease. Efficacy and safety of recombinant humanized anti-HER2 monoclonal antibody as a single agent was evaluated in women with HER2-overexpressing metastatic breast cancer that had progressed after chemotherapy for metastatic disease. PATIENTS AND METHODS: Two hundred twenty-two women, with HER2-overexpressing metastatic breast cancer that had progressed after one or two chemotherapy regimens, were enrolled. Patients received a loading dose of 4 mg/kg intravenously, followed by a 2-mg/kg maintenance dose at weekly intervals. RESULTS: Study patients had advanced metastatic disease and had received extensive prior therapy. A blinded, independent response evaluation committee identified eight complete and 26 partial responses, for an objective response rate of 15% in the intent-to-treat population (95% confidence interval, 11% to 21%). The median duration of response was 9.1 months; the median duration of survival was 13 months. The most common adverse events, which occurred in approximately 40% of patients, were infusion-associated fever and/or chills that usually occurred only during the first infusion, and were of mild to moderate severity. These symptoms were treated successfully with acetaminophen and/or diphenhydramine. The most clinically significant adverse event was cardiac dysfunction, which occurred in 4.7% of patients. Only 1% of patients discontinued the study because of treatment-related adverse events. CONCLUSION: Recombinant humanized anti-HER2 monoclonal antibody, administered as a single agent, produces durable objective responses and is well tolerated by women with HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. Side effects that are commonly observed with chemotherapy, such as alopecia, mucositis, and neutropenia, are rarely seen.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias da Mama/terapia , Receptor ErbB-2/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Intervalos de Confiança , Progressão da Doença , Intervalo Livre de Doença , Feminino , Cardiopatias/etiologia , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Qualidade de Vida , Receptor ErbB-2/metabolismo , Fatores de TempoRESUMO
PURPOSE: To compare failure-free survival (FFS) and overall survival (OS) for patients with metastatic breast cancer treated with the gonadotropin-releasing hormone (GN-RH) agonist, goserelin versus surgical ovariectomy. PATIENTS AND METHODS: Between August 1, 1987 and July 15, 1995 138 (136 eligible) premenopausal patients with estrogen receptor (ER)- and/or progesterone receptor (PgR)-positive metastatic breast cancer were entered by the Southwest Oncology Group (SWOG), North Central Cancer Treatment Group (NCCTG), and Eastern Cooperative Oncology Group (ECOG). Prior chemotherapy or hormone therapy for metastatic disease was not allowed. Patients were randomly assigned to goserelin (3.6 mg subcutaneously every 4 weeks; (n = 69) versus surgical ovariectomy (n = 67). The study was initially designed as an equivalence trial with 80% power to rule out a 50% improvement in survival due to ovariectomy. However, accrual was slow and the study was terminated early, which resulted in a final power of 60% for the alternative hypothesis of equal survival distributions. RESULTS: FFS and OS were similar for goserelin and ovariectomy. The goserelin/ovariectomy death hazards ratio was .80 and the associated 95% confidence interval (CI) was .53 to 1.20. The test of 50% improvement in survival due to ovariectomy was rejected at P = .006. Goserelin lowered serum estradiol to postmenopausal levels. Hot flashes (75% v 46%) and tumor flare (16% v 3%) were more common with goserelin. CONCLUSION: Goserelin and ovariectomy resulted in similar FFS and OS. We can rule out a moderate advantage for ovariectomy. Goserelin was safe and well tolerated.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Gosserrelina/uso terapêutico , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias Hormônio-Dependentes/cirurgia , Ovariectomia , Adulto , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Hormônio-Dependentes/metabolismo , Neoplasias Hormônio-Dependentes/patologia , Pré-Menopausa , Receptores de Estrogênio/análise , Receptores de Progesterona/análiseRESUMO
Current practice in the management of patients who undergo a mastectomy does not usually include radiotherapy. Data from both meta-analyses and two randomized studies challenge this approach. Part of the skepticism about postmastectomy radiotherapy is what biological rationale would justify this intervention. Hellman has proposed the spectrum hypothesis, which explains the potential indication for additional local therapy for such patients. Another concern is the risk for increased toxicity, especially cardiotoxicity in patients who receive anthracycline-based adjuvant regimens. The addition of new agents (eg, Herceptin) also requires careful monitoring with regard to toxicity. Furthermore, the timing of radiation with chemotherapy is problematic. Overall, there is now evidence to support a role for postmastectomy radiotherapy, but further studies are needed on how best to incorporate this modality in multimodality treatment of early-stage breast cancer.
Assuntos
Neoplasias da Mama/radioterapia , Neoplasias da Mama/cirurgia , Mastectomia , Antineoplásicos/efeitos adversos , Quimioterapia Adjuvante , Feminino , Humanos , Metástase Linfática , Recidiva Local de Neoplasia , Radioterapia AdjuvanteRESUMO
Regional migratory osteoporosis is a disorder of unknown etiology, characterized by successive episodes of joint pain, accompanied by localized osteoporosis. The disorder affects the lower limbs, usually the region of the foot, knee, or hip, and each episode usually lasts several months and is followed by spontaneous recovery. This disorder has not previously been reported to cause episodes of vertebral osteoporosis. We describe three patients in whom regional osteoporosis, involving the lower limbs, was associated with simultaneous vertebral osteoporosis indistinguishable from idiopathic osteoporosis. These cases suggest that this disorder might be responsible for some cases of apparent idiopathic spinal osteoporosis.
Assuntos
Perna (Membro) , Osteoporose/etiologia , Doenças da Coluna Vertebral/etiologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteólise/complicações , Osteoporose/diagnóstico por imagem , Radiografia , Doenças da Coluna Vertebral/diagnóstico por imagemRESUMO
The association between dermatomyositis and Hodgkin's disease has been infrequently reported. A patient with advanced Hodgkin's disease and dermatomyositis is presented and an additional 11 cases obtained from the world literature are reviewed. The clinical features, response to treatment, and outcome of these diseases are discussed.
Assuntos
Dermatomiosite/complicações , Doença de Hodgkin/complicações , Adulto , Dermatomiosite/tratamento farmacológico , Dermatomiosite/patologia , Feminino , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , HumanosRESUMO
Between 1982 and 1985, 108 women with AJC Stage I and II invasive mammary carcinoma were treated to 115 breasts with conservative surgery and irradiation. The irradiation dose was adjusted to the histopathological normal tissue margin around the carcinoma in the tumor excision specimens. Margins were arbitrarily determined negative, close, and positive with normal tissue margins in the inked tumor excision specimens of greater than 5 mm, 2-5 mm, and less than 2 mm, respectively. Negative, close, and positive tumor margin patients were treated to radiation doses of 60, 65, and 70 Gy, respectively. The boost in excess of 50 Gy was directed to the tumor bearing quadrant of the breast using interstitial Ir-192 implants for doses greater than or equal to 70 Gy. The draining lymphatics were irradiated to 50 Gy except in patients with tumor in the lateral half of the breast and no axillary lymph node metastases. Histopathological evaluation of re-excision specimens revealed the difficulty of obtaining negative margins for tumors greater than 2 cm. By our criteria, 54% of the patients had a positive resection margin. None of the patients experienced a local recurrence at 60 months median follow-up. Three patients failed regionally, two in un-irradiated lymph node areas, one in the skin of the contralateral breast; five patients failed systemically. Overall and disease-free survival for Stages T1/N0, T1/N1, T2/N0 was 100 and 95%, respectively, and for T2/N1, 90 and 80%, respectively. The cosmesis was excellent in 66% of the patients with minimal treatment related complications. Carefully planned standardized irradiation with assessment of resection margins yields both excellent local control rates and cosmetic results.
Assuntos
Neoplasias da Mama/terapia , Axila , Neoplasias da Mama/patologia , Terapia Combinada , Seguimentos , Humanos , Excisão de Linfonodo , Masculino , Mastectomia , Estadiamento de Neoplasias , Dosagem RadioterapêuticaRESUMO
In 1977, tamoxifen, a nonsteroidal antiestrogen, was approved in the United States for the management of advanced breast cancer in postmenopausal women. Since that time, tamoxifen's therapeutic role has grown to include management of advanced breast cancer in premenopausal women, systemic adjuvant therapy for early breast cancer in premenopausal and postmenopausal women, and treatment of breast cancer in men; the drug is now being studied in chemoprevention trials for women at high risk for breast cancer. Tamoxifen therapy prolongs disease-free survival and reduces mortality in premenopausal, postmenopausal, node-positive, and node-negative patients. Positive objective responses are more frequent in patients with estrogen receptor-positive tumors. The role of tamoxifen in combination with chemotherapy needs to be further clarified with respect to the optimal regimen, sequential vs concomitant therapy, and appropriate patient selection. While the optimum duration of tamoxifen therapy has not yet been established, tamoxifen remains a major therapeutic agent in the medical management of breast cancer.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Antagonistas de Estrogênios/uso terapêutico , Tamoxifeno/uso terapêutico , Adjuvantes Farmacêuticos/uso terapêutico , Feminino , Humanos , Masculino , MenopausaRESUMO
Twenty previously untreated patients with advanced colorectal adenocarcinoma were entered on a Phase II trial of 3-day continuous infusion cisplatin (25 mg/m2/day) and 5-fluorouracil (800 mg/M2/day) with oral calcium leucovorin (30 mg/dose) every 6 hours. There were four partial responses (20%) and two complete responses (10%) for a total response rate of 30% (95% confidence limits +/- 20%). Patients received a median of 4.5 cycles of therapy (range 2-9 cycles). Three patients experienced neutropenia; one had a life-threatening infection. One developed neuropathy at 375 mg/M2 cumulative dose. Four patients developed mucositis. Treatment was stopped for one patient with stable disease after 5 cycles because of anorexia and nausea and vomiting; treatment was stopped for four patients because of excessive fatigue. The median duration of responses was 4 months (range 3-6 months). Although this regimen is active, the response rate, cumulative nature of the toxicity, and the requirement for hospitalization led us to conclude that this regimen does not warrant Phase III testing but might be a basis for further Phase II therapeutic trials.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Administração Oral , Adulto , Idoso , Cisplatino/administração & dosagem , Avaliação de Medicamentos , Feminino , Fluoruracila/administração & dosagem , Humanos , Infusões Intravenosas , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Indução de RemissãoRESUMO
Histologic evaluation and reporting of invasive breast cancer has effectively used Nottingham combined histologic grade (NCHG). This approach to predict outcome in invasive breast cancer has not been tested in multicenter cooperative trials. Histologic slides from selected breast cancer cases entered on node-negative Eastern Cooperative Oncology Group trials were assigned grades. Two pathologists evaluated cases for NCHG defined from differentiation, mitotic index, and nuclear grade. The study population consisted of separate samples from low- and high-risk strata, where low risk was estrogen receptor positive with a tumor size of less than 3 cm and high risk was estrogen receptor negative or tumor size greater than or equal to 3 cm. The rate of agreement was generally good, with 80% of cases classified the same for mitotic count and 76% of the cases classified the same for combined grade. There were no cases disagreeing from the lowest to the highest of the three categories. The median follow-up is 11.6 years, but for analysis of survival, this was truncated at 5 years. Mitotic index and combined grade as assessed by both pathologists showed significant associations with survival. High combined histologic grade was predictive for response to cyclophosphamide/methotrexate/5-fluorouracil (CMF) with survival differences at 5 years of 30% in the treated high-grade patients over the untreated patients. Overall, it is clear that pathologists can have close agreement in assignment of combined histologic grades, with highly significant prediction in univariate and borderline significance in multivariate analysis in prognostication of time to recurrence as well as survival. Thus, stratification used in these trials was highly prognostic as hoped, leaving a role for histologic grading in these relatively large tumors, more powerful than S-phase analysis in this series. In the subgroups of high-risk patients randomized between CMF and observation, there was a suggestion that the high-combined-grade group was predictive of treatment efficacy. We conclude that a combined histologic grade with defined criteria may be reliably assigned by practiced pathologists using readily available criteria, and that the measure may be of use in prognostication and prediction of therapeutic responsiveness when done in a technically ideal fashion.