RESUMO
BACKGROUND: SRC plays an important role in the pathogenesis of metastatic breast cancer (MBC). In preclinical models, paclitaxel and the oral SRC inhibitor dasatinib showed greater antitumor activity than either agent. To determine the maximum tolerated dose of this combination, we conducted a phase I study. PATIENTS AND METHODS: Patients with MBC; Eastern Cooperative Oncology Group performance status of zero to one; normal hepatic, renal and marrow function were eligible. Paclitaxel 80 mg/m(2) was given 3 weeks of 4. The starting dasatinib dose was 70 mg and was increased, using a standard 3 + 3 dose-escalation scheme. RESULTS: Fifteen patients enrolled (median age 54 years, range 35-74). No dose-limiting toxic effects (DLTs) occurred at dasatinib doses of 70-120 mg. One DLT (grade 3 fatigue) occurred in the dasatinib 150-mg cohort, which was expanded (six patients) with no further DLTs. However, due to cumulative toxic effects (rash, fatigue, diarrhea), the recommended phase II dose is dasatinib 120 mg. Of 13 assessable patients, a partial response was seen in 4 patients (31%), including 2 patients previously treated with taxanes; all received ≥120 mg dasatinib. An additional five patients (29%) had stable disease. CONCLUSION: In combination with weekly paclitaxel, the recommended phase II dose of dasatinib is 120 mg daily and preliminary activity has been seen in patients with MBC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama Masculina/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/patologia , Dasatinibe , Edema/induzido quimicamente , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Paclitaxel/administração & dosagem , Derrame Pleural Maligno/induzido quimicamente , Pirimidinas/administração & dosagem , Tiazóis/administração & dosagem , Resultado do TratamentoRESUMO
PURPOSE: We conducted a randomized Phase II trial to directly compare toxicity, feasibility, and delivered dose intensities of two adjuvant dose-intensive regimens containing doxorubicin, paclitaxel, and cyclophosphamide for patients with node-positive breast carcinoma. EXPERIMENTAL DESIGN: Forty-two patients with resected breast carcinoma involving one or more ipsilateral axillary lymph nodes, were randomized to receive two different schedules of adjuvant chemotherapy using 14-day dosing intervals: either (a) three cycles of doxorubicin 80 mg/m(2) as i.v. bolus followed sequentially by three cycles of paclitaxel 200 mg/m(2) as a 24-h infusion and then by three cycles of cyclophosphamide 3.0 g/m(2) as a 1-h infusion (arm A); or (b) the same schedule of doxorubicin followed by three cycles of concurrent cyclophosphamide and paclitaxel at the same doses (arm B). All cycles were supported by granulocyte colony-stimulating factor administration. RESULTS: Forty-one patients were assessable for toxicity and feasibility; 37 (90%) completed all planned chemotherapy. There was no treatment-related mortality; however, increased toxicity was observed on arm B compared with arm A, manifested by an increase in hospitalization for toxicity, mainly neutropenic fever, and an increased incidence of transfusion of packed RBCs transfusions for anemia. The mean delivered dose intensities for paclitaxel and cyclophosphamide were significantly greater for arm A compared with arm B (P =.01 and P =.05, respectively). There is no long-term, treatment-related toxicity, and no cases of acute myelogenous leukemia or myelodysplastic syndrome have been observed. CONCLUSIONS: Dose-dense sequential single-agent chemotherapy is more feasible than doxorubicin with subsequent concurrent paclitaxel and cyclophosphamide.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Ciclofosfamida/efeitos adversos , Doxorrubicina/efeitos adversos , Paclitaxel/efeitos adversos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Neoplasias da Mama/cirurgia , Terapia Combinada , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Esquema de Medicação , Feminino , Seguimentos , Hospitalização , Humanos , Metástase Linfática , Mamografia , Mastectomia Radical Modificada , Pessoa de Meia-Idade , Paclitaxel/administração & dosagemRESUMO
Gossypol has demonstrated in vitro effects on cell cycle regulation and anti-tumor activity against mammary carcinoma cell lines. This Phase I/II study assesses both the effect of gossypol on cell cycle regulatory proteins in vivo and the clinical effect. Twenty women with refractory metastatic breast cancer received oral gossypol at daily doses between 30 and 50 mg per day. Gossypol plasma levels were measured (n = 8) and the modulation of the retinoblastoma (Rb) gene protein and Cyclin D1 was assessed by serial biopsies (n = 4). Grade I-II toxicities with gossypol treatment included nausea in 30% of patients, fatigue 15%, emesis 15%, altered taste sensation 15% and diarrhea in 10% of patients. Two of the three patients receiving 50 mg/day experienced dose limiting dermatologic toxicity (grade III). One patient had a minor response and two patients had stable disease with > 50% decline in serial assessments of the serum tumor markers. Immunohistochemical analysis of cyclin D1 and Rb expression in serial biopsies of four patients revealed both a concurrent decrease in cyclin D1 expression and an increase in nuclear Rb expression in three patients. The maximal tolerated dose (MTD) of gossypol was 40 mg/day. Gossypol appears to affect the expression of Rb protein and cyclin D1 in breast cancer metastases at doses achievable, yet had negligible antitumor activity against anthracycline and taxane refractory metastatic breast cancer. The cell cycle regulatory effects of gossypol suggest a potential role for gossypol as a modulating agent in conjunction with other cell cycle specific compounds.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Ciclo Celular/efeitos dos fármacos , Gossipol/farmacologia , Administração Oral , Adulto , Idoso , Neoplasias da Mama/fisiopatologia , Ciclina D1/análise , Ciclina D1/biossíntese , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Fadiga/induzido quimicamente , Feminino , Gossipol/efeitos adversos , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Proteína do Retinoblastoma/biossíntese , Distúrbios do Paladar/induzido quimicamente , Resultado do TratamentoRESUMO
PURPOSE: This phase II study evaluated weekly trastuzumab and paclitaxel therapy in women with HER2-normal and HER2-overexpressing metastatic breast cancer. Efficacy was correlated with immunohistochemical and fluorescent in situ hybridization (FISH) assay results. PATIENTS AND METHODS: Eligible patients had bidimensionally measurable metastatic breast cancer. Up to three prior chemotherapy regimens, including prior anthracycline and taxane therapy, were allowed. Trastuzumab 4 mg/kg and paclitaxel 90 mg/m2 were administered on week 1, with trastuzumab 2 mg/kg and paclitaxel 90 mg/m2 administered on subsequent weeks. HER2 status was evaluated using four different immunohistochemical assays and FISH. RESULTS: Patients received a median of 25 weekly infusions (range, one to 85 infusions). Median delivered paclitaxel dose-intensity was 82 mg/m2/wk (range, 52 to 90 mg/m2/wk). The intent-to-treat response rate for all 95 patients enrolled was 56.8% (95% confidence interval, 47% to 67%). A response rate of 61.4% (4.5% complete response, 56.8% partial response) was observed in 88 fully assessable patients. In patients with HER2-overexpressing tumors, overall response rates ranged from 67% to 81% compared with 41% to 46% in patients with HER2-normal expression (ranges reflect the different assay methods used to assess HER2 status). Differences in response rates between patients with HER2-overexpressing tumors and those with normal HER2 expression were statistically significant for all assay methods, with CB11 and TAB250 antibodies and FISH having the strongest significance. Therapy was generally well tolerated, although three patients had serious cardiac complications. CONCLUSION: Weekly trastuzumab and paclitaxel therapy is active in women with metastatic breast cancer. Therapy was relatively well tolerated; however, attention to cardiac function is necessary.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Genes erbB-2/imunologia , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Neoplasias da Mama/genética , Neoplasias da Mama/secundário , Esquema de Medicação , Feminino , Amplificação de Genes , Humanos , Imunofenotipagem , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Trastuzumab , Resultado do TratamentoRESUMO
OBJECTIVE: We determined the pattern of spread of metastatic lobular carcinoma in the chest, abdomen, and pelvis on CT. MATERIALS AND METHODS: We identified 57 women (age range, 30-79 years; mean age, 57 years) with metastatic lobular carcinoma of the breast who underwent CT of the chest, abdomen, or pelvis between 1995 and 1998. Then two experienced oncology radiologists retrospectively reviewed 78 CT examinations of those patients to identify sites of metastatic disease and to identify complications caused by metastases. RESULTS: Metastases were identified in bone in 46 patients (81%), lymph nodes in 27 patients (47%), lung in 19 patients (33%), liver in 18 patients (32%), peritoneum in 17 patients (30%), colon in 15 patients (26%), pleura in 13 patients (23%), adnexa in 12 patients (21%), stomach in nine patients (16%), retroperitoneum in nine patients (16%), and small bowel in six patients (11%). Eighteen patients (32%) had gastrointestinal tract involvement that manifested as bowel wall thickening. Hydronephrosis was present in six patients (11%). CONCLUSION: Although lobular carcinoma metastasized to common metastatic sites of infiltrating ductal carcinoma, lobular carcinoma frequently metastasized to unusual sites, including the gastrointestinal tract, peritoneum, and adnexa. Gastrointestinal tract involvement was as frequent as liver involvement, appearing as bowel wall thickening on CT. Hydronephrosis was a complication of metastatic lobular carcinoma.
Assuntos
Neoplasias Abdominais/diagnóstico por imagem , Neoplasias Abdominais/secundário , Neoplasias da Mama/patologia , Carcinoma Lobular/diagnóstico por imagem , Carcinoma Lobular/secundário , Neoplasias Torácicas/diagnóstico por imagem , Neoplasias Torácicas/secundário , Tomografia Computadorizada por Raios X , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
PURPOSE: We conducted a phase II pilot study of dose-intensive adjuvant chemotherapy with doxorubicin followed sequentially by high-dose cyclophosphamide to determine the safety and feasibility of this dose-dense treatment and to estimate the disease-free and overall survival in breast cancer patients with four or more involved axillary lymph nodes. PATIENTS AND METHODS: Seventy-three patients received adjuvant treatment with four cycles of doxorubicin 75 mg/m(2) as an intravenous bolus every 21 days, followed by three cycles of cyclophosphamide 3,000 mg/m(2) every 14 days with granulocyte colony-stimulating factor support. RESULTS: Seventy-one patients were assessable, and all but two completed all planned chemotherapy. There was no treatment-related mortality. The most common toxicity was neutropenic fever, which occurred in 39% of patients. Median disease-free survival is 66 months (95% confidence interval, 34 to 98 months), and median overall survival has not yet been reached. At 5 years of follow-up, the disease-free survival is 51.7%, and overall survival is 60.0%. There is no long-term treatment-related toxicity, and no cases of acute myelogenous leukemia or myelodysplastic syndrome have been observed. CONCLUSION: Our pilot study of doxorubicin followed by cyclophosphamide demonstrates the safety and feasibility of the sequential dose-dense plan. Long-term follow-up, although noncomparative, is promising. However, this regimen is associated with a higher incidence of toxicity (and also higher costs) than the standard dose and schedule of doxorubicin and cyclophosphamide, and therefore it should not be used as conventional therapy in the absence of demonstrated improvement of outcome. Randomized trials testing the dose-dense approach have been completed but not yet reported. Because the sequential plan can decrease overlapping toxicities, it is an appropriate platform for the addition of newer active agents, such as taxanes or monoclonal antibodies.
Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Quimioterapia Adjuvante , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/efeitos adversos , Feminino , Humanos , Injeções Intravenosas , Metástase Linfática , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Projetos Piloto , Análise de SobrevidaRESUMO
The HER2/neu proto-oncogene is overexpressed in 25% to 30% of patients with breast cancer. Trastuzumab (Herceptin; Genentech, San Francisco, CA), a recombinant humanized monoclonal antibody with high affinity for the HER2 protein, inhibits the growth of breast cancer cells overexpressing HER2. In this phase II study the efficacy and toxicity of weekly administration of trastuzumab was evaluated in 46 patients with metastatic breast cancer whose tumors overexpressed HER2. A loading dose of 250 mg trastuzumab was administered intravenously, which was followed by 10 weekly doses of 100 mg each. Upon completion of this treatment period, patients with no disease progression could receive a weekly maintenance dose of 100 mg. Patients in this trial had extensive metastatic disease, and most had received prior anticancer therapy. Ninety percent of patients achieved adequate serum levels of trastuzumab. Toxicity was minimal, and no antibodies against trastuzumab could be detected. Objective responses were observed in 5 of the 43 evaluable patients, which included 1 complete remission and 4 partial remissions, for an overall response rate of 11.6%. Responses were seen in mediastinum, lymph nodes, liver, and chest wall lesions. Minor responses (seen in 2 patients) and stable disease (14 patients) lasted for a median of 5.1 months. These results demonstrate that trastuzumab is well tolerated and clinically active in patients with HER2-overexpressing metastatic breast cancers who have received extensive prior therapy. The regression of human cancer through the targeting of putative growth factor receptors such as HER2 warrants further evaluation of trastuzumab in the treatment of breast cancer.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/imunologia , Adulto , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Antineoplásicos/farmacocinética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Proto-Oncogene Mas , TrastuzumabRESUMO
PURPOSE: Dose-dense chemotherapy is predicted to be a superior treatment plan. Therefore, we studied dose-dense doxorubicin, paclitaxel, and cyclophosphamide (A-->T-->C) as adjuvant therapy. METHODS: Patients with resected breast cancer involving four or more ipsilateral axillary lymph nodes were treated with nine cycles of chemotherapy, using 14-day intertreatment intervals. Doses were as follows: doxorubicin 90 mg/m2 x 3, then paclitaxel 250 mg/m2/24 hours x 3, and then cyclophosphamide 3.0 g/m2 x 3; all doses were given with subcutaneous injections of 5 microg/kg granulocyte colony-stimulating factor on days 3 through 10. Amenorrheic patients with hormone receptor-positive tumors received tamoxifen 20 mg/day for 5 years. Patients treated with breast conservation, those with 10 or more positive nodes, and those with tumors larger than 5 cm received radiotherapy. RESULTS: Between March 1993 and June 1994, we enrolled 42 patients. The median age was 46 years (range, 29 to 63 years), the median number of positive lymph nodes was eight (range, four to 25), and the median tumor size was 3.0 cm (range, 0 to 11.0 cm). The median intertreatment interval was 14 days (range, 13 to 36 days), and the median delivered dose-intensity exceeded 92% of the planned dose-intensity for all three drugs. Hospital admission was required for 29 patients (69%), and 28 patients (67%) required blood product transfusion. No treatment-related deaths or cardiac toxicities occurred. Doxorubicin was dose-reduced in four patients (10%) and paclitaxel was reduced in eight (20%). At a median follow-up from surgery of 48 months (range, 3 to 57 months), nine patients (19%) had relapsed, the actuarial disease-free survival rate was 78% (95% confidence interval, 66% to 92%), and four patients (10%) had died of metastatic disease. CONCLUSION: Dose-dense sequential adjuvant chemotherapy with doxorubicin, paclitaxel, and cyclophosphamide (A-->T-->C) is feasible and promising. Several ongoing phase III trials are evaluating this approach.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Projetos PilotoRESUMO
Motivated by the observation of preclinical synergy, a Phase I dose escalation study of edatrexate in combination with a 3-h paclitaxel infusion was performed in patients with advanced breast cancer to determine the maximum tolerated dose (MTD) of edatrexate and the toxicities associated with this combination and to report preliminary observations of efficacy with this novel combination. Thirty-six patients were enrolled in this Phase I trial. Thirty-five eligible patients were treated every 21 days in cohorts of at least three patients and were assessable for toxicity. One patient was ineligible due to hyperbilirubinemia. Stepwise dose escalations of edatrexate were administered until grade >3 nonhematological dose-limiting toxicities were reported. The initial dose level of edatrexate was 180 mg/m2; subsequent cohorts were treated with escalating doses of edatrexate (210, 240, 270, 300, 350, and 400 mg/m2). Edatrexate was administered by i.v. infusion over 1 h. Paclitaxel was administered 24 h later at a fixed dose of 175 mg/m2 as a 3-h infusion with standard dexamethasone, diphenhydramine, and cimetidine premedication. The MTD of edatrexate was reached at the 350 mg/m2 level in this study. Grade 3 diarrhea was seen in one patient at the 300 and 400 mg/m2 dose levels, requiring dose reductions. Two patients experienced grade 4 stomatitis at the 400 mg/m2 dose level and also required dose reduction, establishing the MTD as 350 mg/m2. Grade 3 nausea and vomiting were noted in two of three patients at the highest dose level. Of 35 patients, 4 patients reported grade 3 myalgias and 1 patient reported grade 3 neurosensory complaints, which were seen mostly at the 350 and 400 mg/m2 dose levels; however, 1 patient reported grade 3 myalgias at 180 mg/m2. No cumulative neurotoxicity was observed, and no patient experienced an allergic reaction to paclitaxel. In 23 patients with bidimensionally measurable disease, there were four complete (17%) and seven partial responses, with an overall response rate of 48% (95% confidence interval, 27-69%). All of the responses were seen in patients who had not received prior chemotherapy for stage IV disease. The median duration of response was not assessable because many responding patients went on to receive high-dose chemotherapy treatment with stem cell support. The combination of edatrexate and paclitaxel for treatment of metastatic breast cancer is a feasible and safe regimen. The MTD of edatrexate was 350 mg/m2 when combined with a 3-h infusion of paclitaxel (175 mg/m2) given 24 h later. Activity was noted even among patients who had relapsed shortly after receiving methotrexate- and/or doxorubicin-containing adjuvant regimens. Additional studies evaluating the sequences and dosing schema for this combination are warranted to improve the response proportion and define the duration of the response.
Assuntos
Aminopterina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Paclitaxel/uso terapêutico , Adulto , Idoso , Aminopterina/administração & dosagem , Aminopterina/efeitos adversos , Aminopterina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Resultado do TratamentoAssuntos
Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/efeitos adversos , Coração/efeitos dos fármacos , Paclitaxel/efeitos adversos , Adulto , Doxorrubicina/administração & dosagem , Esquema de Medicação , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/diagnóstico , Humanos , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Fatores de Risco , Volume SistólicoRESUMO
CI-980 is a synthetic mitotic inhibitor that binds to the colchicine binding site of tubulin. It demonstrates broad activity against human and murine tumor models and shows no cross resistance with tumor models whose mechanism of resistance is mediated by P-glycoprotein (MDR-1). A phase I study was completed in 25 patients with solid tumors using a 24-hour infusion schedule, with courses repeated every 3 weeks. Eight dose levels were tested between 1.2 and 15.6 mg/m2. The maximum tolerated dose was 14.4 mg/m2. Neutropenia was dose-related but not dose-limiting; thrombocytopenia was infrequent. CNS toxicities were dose-limiting and consisted of dizziness, headache, loss of coordination, loss of consciousness, nervousness, and other symptoms. These events occurred near the end of the infusion and were reversible, usually within 24 hours. One patient who was to be treated at dose level 8 (intended dose was 19.2 mg/m2; actual dose was 15.6 mg/m2) became encephalopathic prior to completion of the infusion. Other adverse events included gastrointestinal toxicities (nausea, vomiting, anorexia, constipation, stomatitis, dyspepsia, bleeding, cheilitis), IV site erythema, fever, and fatigue. A partial response was observed in one patient with colon cancer and reductions in CA-125 levels were observed in 2 patients with ovarian cancer. Pharmacokinetics were linear and dose-proportional. Results indicate high systemic clearance and wide tissue distribution. Mean pharmacokinetic parameter values: T1/2 = 5.52 hours, plasma clearance 1163 mL/min/m2, and Vdss 376 L/m2.
Assuntos
Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Carbamatos/farmacocinética , Carbamatos/uso terapêutico , Neoplasias/tratamento farmacológico , Pirazinas/farmacocinética , Pirazinas/uso terapêutico , Piridinas/farmacocinética , Piridinas/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Área Sob a Curva , Disponibilidade Biológica , Carbamatos/efeitos adversos , Doenças do Sistema Nervoso Central/induzido quimicamente , Tolerância a Medicamentos , Feminino , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neutropenia/induzido quimicamente , Pirazinas/efeitos adversos , Piridinas/efeitos adversosRESUMO
The aim of this phase II study was to characterise the efficacy and toxicity of semisynthetic paclitaxel in patients with metastatic breast cancer. Eligible patients had measurable disease and had been treated with one prior chemotherapy regimen either as adjuvant or for metastatic disease. Semisynthetic paclitaxel was given at a dose of 175 mg/m2 over 3 h every 21 days with dexamethasone, cimetidine and diphenhydramine premedications. 31 patients were entered. All were evaluable for toxicity. 30 patients were evaluable for response because 1 patient was lost to follow-up after receiving one cycle. One patient achieved a complete response and 10 patients achieved partial responses for an overall response rate (CR + PR) of 37% (95% confidence interval 20-56%). 17 patients (55%) experienced at least one episode of grade 3 or 4 neutropenia. There were two episodes of febrile neutropenia complicating 155 cycles of therapy. One of these resulted in a treatment-related death in a patient with pulmonary metastasis. 3 patients required dose reductions for grade 3 sensory neuropathy. Our study shows that the antitumour activity and toxic effects of semisynthetic paclitaxel appear to be identical to the naturally occurring product.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Paclitaxel/uso terapêutico , Adulto , Idoso , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/síntese química , Neoplasias da Mama/patologia , Feminino , Doenças Hematológicas/induzido quimicamente , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Paclitaxel/efeitos adversos , Paclitaxel/síntese química , Resultado do TratamentoRESUMO
PURPOSE: Breast cancer frequently overexpresses the product of the HER2 proto-oncogene, a 185-kd growth factor receptor (p185HER2). The recombinant humanized monoclonal antibody (rhuMAb) HER2 has high affinity for p185HER2 and inhibits the growth of breast cancer cells that overexpress HER2. We evaluated the efficacy and toxicity of weekly intravenous administration of rhuMAb HER2 in patients with HER2-overexpressing metastatic breast cancer. PATIENTS AND METHODS: We treated 46 patients with metastatic breast carcinomas that overexpressed HER2. Patients received a loading dose of 250 mg of intravenous rhuMAb HER2, then 10 weekly doses of 100 mg each. Patients with no disease progression at the completion of this treatment period were offered a maintenance phase of 100 mg/wk. RESULTS: Study patients had extensive metastatic disease, and most had received extensive prior anticancer therapy. Adequate pharmacokinetic levels of rhuMAb HER2 were obtained in 90% of the patients. Toxicity was minimal and no antibodies against rhuMAb HER2 were detected in any patients. Objective responses were seen in five of 43 assessable patients, and included one complete remission and four partial remissions (overall response rate, 11.6%; 95% confidence interval, 4.36 to 25.9). Responses were observed in liver, mediastinum, lymph nodes, and chest wall lesions. Minor responses, seen in two patients, and stable disease, which occurred in 14 patients, lasted for a median of 5.1 months. CONCLUSION: rhuMAb HER2 is well tolerated and clinically active in patients with HER2-overexpressing metastatic breast cancers that had received extensive prior therapy. This is evidence that targeting growth factor receptors can cause regression of human cancer and justifies further evaluation of this agent.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias da Mama/terapia , Receptor ErbB-2/imunologia , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Pessoa de Meia-Idade , Metástase Neoplásica , Proto-Oncogene Mas , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismoRESUMO
Adjuvant chemotherapy has a real but modest impact on the disease-free and overall survival of patients with breast cancer. Recent attempts to improve its effectiveness have focused on dose intensity and new agents. Sequential therapy maximized dose intensity while limiting overlapping toxicity. Sequential therapy using doxorubicin followed by cyclophosphamide/methotrexate/5-fluorouracil (CMF) has been found superior in patients with high-risk resectable breast cancer. The novel chemotherapy agent paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is now known to be highly active in advanced breast cancer and appears to be clinically non-cross-resistant with doxorubicin. Therefore, this drug is being studied as a component of the next generation of adjuvant chemotherapy regimens. The most appropriate way to incorporate paclitaxel has not yet been defined, but its concurrent administration with other agents has, in some cases, been troublesome. Based on the demonstrated advantage of the sequential plan for doxorubicin and CMF, we conducted a series of pilot trials testing sequential high-dose therapy. Initially, we studied multiple cycles of doxorubicin followed by cyclophosphamide; we later added paclitaxel to this regimen. These phase II studies demonstrate the feasibility of sequential therapy with doxorubicin, paclitaxel, and cyclophosphamide, and early disease-free survival results are promising. Cooperative group projects are under way or planned to further define the activity of these regimens.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Neoplasias da Mama/patologia , Institutos de Câncer , Divisão Celular , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Humanos , Metotrexato/administração & dosagem , Cidade de Nova Iorque , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
The results of both retrospective and prospective studies suggest that the effectiveness of systemic adjuvant chemotherapy with doxorubicin and cyclophosphamide for breast cancer may be related to the dose intensity of these agents. Recent trials also have demonstrated the high activity of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) against metastatic breast cancer. Clinically, paclitaxel appears to be noncross-resistant with doxorubicin, but the unique and overlapping toxicities of these three agents might preclude concurrent adjuvant administration. A possible solution is sequential rather than concurrent administration, an approach that kinetic modelling predicts to be superior. A pilot study testing dose-intensive sequential administration of doxorubicin/paclitaxel/cyclophosphamide enrolled 42 patients with a median age of 42 years who had resected breast cancer metastatic to four or more ipsilateral axillary lymph nodes. Intravenous treatment, given at 14-day intervals, began with three cycles of doxorubicin 90 mg/m2, followed by three cycles of paclitaxel 250 mg/m2, given as a 24-hour infusion, and, finally, three cycles of cyclophosphamide 3 g/m2. Selected patients received radiotherapy. The median number of positive lymph nodes was eight (range, four to 25), and the median tumor size was 3.0 cm (range, 0 to 11.0 cm). Granulocyte colony-stimulating factor support was given. Both hematologic and non-hematologic toxicity were substantial but manageable. Hospital admission was necessary in 62 (17%) of 369 chemotherapy cycles in 29 patients (69%). As planned, the median intertreatment interval was 14 days through all nine cycles of therapy, and the median delivered dose intensity exceeded 98% for all three agents. The median follow-up from local control surgery in December 1994 was 448 days (range, 82 to 632 days). Three patients (7.2%) had disease relapses, one during the doxorubicin portion of treatment and two (4.9%) who had completed treatment with all three agents. Sequential dose-intensive therapy with doxorubicin/paclitaxel/cyclophosphamide has manageable toxicity and, with short follow-up, is a promising new regimen suitable for randomized testing.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/cirurgia , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Metástase Linfática , Paclitaxel/administração & dosagem , Adulto , Antibióticos Antineoplásicos/efeitos adversos , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Fitogênicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Axila , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/radioterapia , Quimioterapia Adjuvante , Ciclofosfamida/efeitos adversos , Doxorrubicina/efeitos adversos , Esquema de Medicação , Feminino , Seguimentos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Infusões Intravenosas , Injeções Intravenosas , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Paclitaxel/efeitos adversos , Admissão do Paciente , Projetos Piloto , Radioterapia AdjuvanteRESUMO
BACKGROUND: The contribution of classical conditioning processes to patients' distress before chemotherapy infusions (anticipatory distress) was compared to other potential sources of distress (e.g., trait anxiety). We hypothesized that posttreatment distress (putative unconditioned response) would become a stronger predictor of anticipatory distress as patients underwent more treatment infusions (putative conditioning trials). MATERIALS AND METHODS: Fifty women with early stage breast cancer, undergoing standard chemotherapy, completed questionnaires in the clinic prior to each of eight consecutive treatment infusions, as well as telephone interviews to assess side effects following infusions. RESULTS: Consistent with the conditioning hypothesis, posttreatment distress became significantly related to anticipatory distress at the fourth infusion and became the strongest predictor by the sixth. Path analysis indicated that posttreatment distress had a direct influence on anticipatory distress, and that trait anxiety had an indirect influence by influencing apprehension about chemotherapy which, in turn, directly predicted anticipatory distress. CONCLUSIONS: The results of the present study contribute to an emerging view of anticipatory distress as a conditioned response in chemotherapy patients. Results demonstrate that conditioning factors may be one of the strongest predictors of anticipatory distress in the later phases of chemotherapy treatment.
Assuntos
Neoplasias da Mama/psicologia , Estresse Psicológico/etiologia , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Ansiedade , Neoplasias da Mama/tratamento farmacológico , Condicionamento Clássico , Emoções , Feminino , Humanos , Infusões Intravenosas , Pessoa de Meia-Idade , Estresse Psicológico/psicologia , Vômito Precoce/etiologiaRESUMO
A case of spontaneous recurrent acute tumor lysis syndrome is presented in a woman with inflammatory breast cancer. The occurrence of tumor lysis syndrome in solid tumors is unusual, and spontaneous cases are rare. This and other unusual aspects of this case are discussed.
Assuntos
Adenocarcinoma/complicações , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/complicações , Síndrome de Lise Tumoral/etiologia , Doença Aguda , Adenocarcinoma/sangue , Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Pessoa de Meia-Idade , RecidivaRESUMO
Women diagnosed with primary breast or lung cancer and recorded between 1972 and 1989 in our tumor registry were identified. Of 4,123 lung cancer patients and 3,537 breast cancer patients, 42 patients with both diagnoses were identified. The two malignancies were diagnosed simultaneously in five patients, lung cancer was diagnosed first in six patients and breast cancer was diagnosed first in 31 (p < 0.001). Nineteen of those 31 patients received adjuvant radiotherapy for breast cancer and developed lung cancer a median of 17 years later. Of the 19 irradiated patients who subsequently developed lung cancer, 15 did so in the ipsilateral lung and only four had lung cancer contralateral to the previously irradiated site (p < 0.001). Adjuvant radiotherapy for breast cancer as delivered decades ago may be an etiologic factor for lung cancer.
Assuntos
Neoplasias da Mama/radioterapia , Neoplasias Pulmonares/etiologia , Neoplasias Induzidas por Radiação/etiologia , Segunda Neoplasia Primária/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Radioterapia Adjuvante/efeitos adversos , Sistema de Registros , Fatores de RiscoRESUMO
BACKGROUND: Pregnancy complicated by maternal human immunodeficiency virus (HIV) infection is increasing in frequency. This report describes a maternal malignancy associated with HIV infection that may complicate pregnancy. CASE: A 33-year-old primigravida was delivered by cesarean. Histologic examination of the placenta revealed the presence of metastatic non-Hodgkin lymphoma of B-cell origin. The patient was then found to be infected with HIV. Nine months postpartum, she was diagnosed with immunoblastic lymphoma. She is currently undergoing chemotherapy. CONCLUSION: Non-Hodgkin lymphoma of B-cell origin is an indication of AIDS. Pregnancies associated with maternal HIV infection may be complicated by this malignancy, which may metastasize to the products of conception. Careful examination of the placenta can detect metastases in women with non-Hodgkin B-cell lymphoma.
Assuntos
Síndrome da Imunodeficiência Adquirida/diagnóstico , Linfoma Relacionado a AIDS/diagnóstico , Doenças Placentárias/diagnóstico , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Neoplásicas na Gravidez/diagnóstico , Adulto , Feminino , Humanos , Recém-Nascido , GravidezRESUMO
CI-921, (9-[[2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino]- N,5-dimethyl-4-acridinecarboxamide 2-hydroxyethanesulfonate (1:1)), an anilinoacridine derivative with activity in experimental solid tumors was studied in a multicenter phase II trial in patients with solid tumors. Eligible tumor types included cancers of the breast, stomach, pancreas, nonsmall cell lung, small cell lung, colon, head and neck area, and melanoma. Prestudy requirements included an ECOG performance status of < or = 2, no CNS metastases, and measurable disease. CI-921 was administered intravenously over 1-2 hours on days 1, 8, and 15 of a 35-day course at an initial dose of 270 mg/M2, with modification in subsequent courses based upon tolerance. Principal toxicities included leukopenia, marked phlebitis, and mild nausea and vomiting. One hundred fifty patients were entered of whom 132 were evaluable for response. There was one complete and one partial response among 19 patients with breast cancer, and two partial responses, one each among 14 head and neck and 36 nonsmall cell lung cancer patients.