RESUMO
BACKGROUND: Acquired estrogen receptor alpha (ER/ESR1) mutations commonly cause endocrine resistance in ER+ metastatic breast cancer (mBC). Lasofoxifene, a novel selective ER modulator, stabilizes an antagonist conformation of wild-type and ESR1-mutated ER-ligand binding domains, and has antitumor activity in ESR1-mutated xenografts. PATIENTS AND METHODS: In this open-label, randomized, phase II, multicenter, ELAINE 1 study (NCT03781063), we randomized women with ESR1-mutated, ER+/human epidermal growth factor receptor 2 negative (HER2-) mBC that had progressed on an aromatase inhibitor (AI) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) to oral lasofoxifene 5 mg daily or IM fulvestrant 500 mg (days 1, 15, and 29, and then every 4 weeks) until disease progression/toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were safety/tolerability. RESULTS: A total of 103 patients received lasofoxifene (n = 52) or fulvestrant (n = 51). The most current efficacy analysis showed that lasofoxifene did not significantly prolong median PFS compared with fulvestrant: 24.2 weeks (â¼5.6 months) versus 16.2 weeks (â¼3.7 months; P = 0.138); hazard ratio 0.699 (95% confidence interval 0.434-1.125). However, PFS and other clinical endpoints numerically favored lasofoxifene: clinical benefit rate (36.5% versus 21.6%; P = 0.117), objective response rate [13.2% (including a complete response in one lasofoxifene-treated patient) versus 2.9%; P = 0.124], and 6-month (53.4% versus 37.9%) and 12-month (30.7% versus 14.1%) PFS rates. Most common treatment-emergent adverse events with lasofoxifene were nausea, fatigue, arthralgia, and hot flushes. One death occurred in the fulvestrant arm. Circulating tumor DNA ESR1 mutant allele fraction (MAF) decreased from baseline to week 8 in 82.9% of evaluable lasofoxifene-treated versus 61.5% of fulvestrant-treated patients. CONCLUSIONS: Lasofoxifene demonstrated encouraging antitumor activity versus fulvestrant and was well tolerated in patients with ESR1-mutated, endocrine-resistant mBC following progression on AI plus CDK4/6i. Consistent with target engagement, lasofoxifene reduced ESR1 MAF, and to a greater extent than fulvestrant. Lasofoxifene may be a promising targeted treatment for patients with ESR1-mutated mBC and warrants further investigation.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Fulvestranto/efeitos adversos , Pirrolidinas/uso terapêutico , Inibidores da Aromatase , Mutação , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismoRESUMO
BACKGROUND: Safety and efficacy of gemcitabine plus docetaxel (GD) and capecitabine plus docetaxel (CD) were compared in patients with metastatic breast cancer, where the alternate crossover monotherapy (GDâC or CDâG) was predetermined. PATIENTS AND METHODS: Patients were randomly assigned to 3-week cycles of either gemcitabine 1000 mg/m(2) on days 1 and 8 plus docetaxel 75 mg/m(2) on day 1 or capecitabine 1000 mg/m(2) twice daily on days 1-14 plus docetaxel 75 mg/m(2) day 1. Upon progression, patients received crossover monotherapy. Primary end point was time to progression (TtP). Secondary end points evaluated overall response rate (ORR), overall survival (OS), and adverse events (AEs). RESULTS: Despite over-accrual of 475 patients, the trial matured with only 324 of 385 planned TtP events due to patient discontinuations. Human epidermal growth factor receptor 2 status was not captured in this study. More CD patients (28%) discontinued due to AEs than GD patients (18.0%, P = 0.009). TtP [hazard ratio (HR) = 1.101, 95% confidence interval (CI) 0.885-1.370, P = 0.387] and OS (HR = 1.031, 95% CI 0.830-1.280, P = 0.785) were not significantly different comparing GD and CD. ORR was not statistically different (P = 0.239) comparing GD (72 of 207, 34.8%) and CD (78 of 191, 40.8%). TtP, OS, and ORR were not significantly different comparing crossover groups. GD caused greater fatigue, hepatotoxicity, neutropenia, and thrombocytopenia but not febrile neutropenia; CD caused more hand-foot syndrome, gastrointestinal toxicity, and mucositis. CONCLUSIONS: GD and CD produced similar efficacy and toxicity profiles consistent with prior clinical experience.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Capecitabina , Estudos Cross-Over , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Docetaxel , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Metástase Neoplásica , Taxoides/administração & dosagem , GencitabinaRESUMO
BACKGROUND: This phase II study evaluated the efficacy and safety of lapatinib in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic breast cancer that progressed during prior trastuzumab therapy. PATIENTS AND METHODS: Women with stage IIIB/IV HER2-overexpressing breast cancer were treated with single-agent lapatinib 1250 or 1500 mg once daily after protocol amendment. Tumor response according to RECIST was assessed every 8 weeks. HER2 expression was assessed in tumor tissue by immunohistochemistry and FISH. RESULTS: Seventy-eight patients were enrolled in the study. Investigator and independent review response rates [complete response (CR) or partial response (PR)] were 7.7% and 5.1%, and clinical benefit rates (CR, PR, or stable disease for >or=24 weeks) were 14.1% and 9.0%, respectively. Median time to progression was 15.3 weeks by independent review, and median overall survival was 79 weeks. The most common treatment-related adverse events were rash (47%), diarrhea (46%), nausea (31%), and fatigue (18%). CONCLUSIONS: Single-agent lapatinib has clinical activity with manageable toxic effects in HER2-overexpressing breast cancer that progressed on trastuzumab-containing therapy. Studies of lapatinib-based combination regimens with chemotherapy and other targeted therapies in metastatic and earlier stages of breast cancer are warranted.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Quinazolinas/uso terapêutico , Adulto , Idoso , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Neoplasias da Mama/patologia , Neoplasias da Mama/secundário , Progressão da Doença , Feminino , Humanos , Lapatinib , Pessoa de Meia-Idade , Receptor ErbB-2/biossíntese , Trastuzumab , Falha de Tratamento , Resultado do TratamentoRESUMO
Edrecolomab (monoclonal antibody 17-1A) is a murine monoclonal antibody that recognizes the human tumor-associated antigen Ep-CAM (otherwise known as 17-1A). It is being developed for the adjuvant treatment of colorectal cancer. In a study of 189 patients with resected stage III colorectal cancer, treatment with edrecolomab resulted in a 32% increase in overall survival compared with no treatment (P<0.01) and decreased the tumor recurrence rate by 23% (P<0.04). In terms of safety, edrecolomab was well tolerated. Based on these study results, edrecolomab is currently under investigation in large multicenter phase III studies both as monotherapy and in combination with 5-fluorouracil-based chemotherapy versus chemotherapy alone for the treatment of stage III colon cancer. Although these studies are still ongoing, an interim analysis of safety data indicated that the combination of edrecolomab with chemotherapy is well tolerated. In addition, edrecolomab monotherapy demonstrated a favorable safety profile compared with chemotherapy. Edrecolomab is also currently being tested in large multicenter adjuvant phase III studies in stage II/III rectal cancer and stage II colon cancer. Edrecolomab represents a novel therapeutic approach and has the potential to become a treatment of choice as monotherapy in stage II colon cancer and in combination with chemotherapy in stage II/III rectal and stage III colon cancer.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/toxicidade , Anticorpos Monoclonais Murinos , Antígenos de Neoplasias/imunologia , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Moléculas de Adesão Celular/imunologia , Neoplasias Colorretais/complicações , Neoplasias Colorretais/terapia , Molécula de Adesão da Célula Epitelial , HumanosRESUMO
We established short-term cell lines for 108/170 (64%) patients with metastatic melanoma. Tumor cell numbers were expanded to 10(8), then cells were irradiated, aliquoted, and cryopreserved for clinical use. Vaccines have been used to treat 69 patients with clinical follow up for 33 who had measurable metastatic disease at the time vaccine therapy was initiated (METS), and 33 who had no evidence of disease (NED) at the time of vaccine therapy following surgical resection of metastases. The protocol called for a baseline test of delayed tumor hypersensitivity (DTH), three weekly injections, a repeat of the DTH test, then monthly injections for an additional 5 months. Objective tumor responses were noted in 3/26 (12%) patients who received a minimum of three vaccinations, one complete, and two partial, with survivals of 36, 46+, and 78+ months. Only 6/64 (9.4%) had a positive DTH (>10 mm) at baseline, including three METS, all of whom progressed within 4 months and died within a year, and three who are still NED after more than 5 years. Conversion of DTH from negative to positive was documented in 18/44 (41%) patients who were tested at week 0 and 4. At a median follow up of greater than 5 years, the median overall survival (OS) was 40 months for "NED" with a 5-year survival rate of 39%, and 8.6 months with a 5-year survival rate of 10% for "METS" The 18 patients who had conversion of their DTH had a median event-free survival (EFS) of 15.8 months and 5-year EFS of 32% compared to 4.2 months and 9% for the 26 non-converters (P=0.012, two-tailed, log-rank test). Among patients who were NED when treatment started, the 12 patients whose DTH converted had a median overall survival of 61.4 months with 5-year survival of 63% compared to 9.7 months and 0% for the 13 non-converters (P=0.0026). This treatment approach is feasible, produces minimal toxicity, and is associated with long-term survival in a significant subset of patients.
Assuntos
Vacinas Anticâncer/administração & dosagem , Imunoterapia/métodos , Melanoma/terapia , Células Tumorais Cultivadas/imunologia , Adulto , Idoso , Feminino , Seguimentos , Humanos , Masculino , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Taxa de Sobrevida , Resultado do TratamentoRESUMO
This study was designed to determine the maximum tolerated dose (MTD) of high-dose melphalan (HDM), with peripheral blood stem cell support, that could be given twice within 90 days to patients with multiple myeloma. Twenty patients received tandem HDM at 160, 180 or 200 mg/m2 and a total of 55 were treated at the estimated MTD of 200 mg/m2. Seventeen of 55 (31%) did not receive cycle 2; six because of low CD34+ cell yields, three because of severe (n = 1) or fatal toxicities (n = 2) and eight for other reasons. The median interval between doses for 38 patients was 70 days (range 41-225). Three of 55 patients (5%) died of treatment-related causes. In patients completing two cycles of HDM, at any dose level, the complete remission rate improved from 15% following cycle 1 to 55% following cycle 2. The probabilities of survival, event-free survival and relapse or progression at 18 months for the 55 patients treated at the MTD were 0.84, 0.76 and 0.20, respectively, with a median follow-up of 19 months (range 9-36) from mobilization chemotherapy. It was concluded that two cycles of HDM, 200 mg/m2, could be administered to approximately 70% of patients under the age of 66 with multiple myeloma in a median interval of 70 days, with improvement in CR rates.
Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Melfalan/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/terapia , Adulto , Idoso , Antineoplásicos Alquilantes/toxicidade , Terapia Combinada , Esquema de Medicação , Tolerância a Medicamentos , Feminino , Humanos , Masculino , Melfalan/toxicidade , Pessoa de Meia-Idade , Transplante AutólogoRESUMO
The purpose of this study was to evaluate the frequency of detecting occult tumor cells in peripheral blood stem cell (PBSC) harvests and to determine the impact of infusing such cells on relapses after high-dose chemotherapy (HDC). Peripheral blood stem cell harvests from 223 patients with breast cancer were examined by an immunocytochemistry (ICC) method for detection of occult tumor cells, and infused after HDC without consideration of test results. Two hundred and four patients, 114 with stage II-III and 90 with stage IV disease who received only PBSC, that were tested by ICC were evaluated for time to relapse. Five hundred and eighty-one of 619 PBSC harvests (94%) from 223 patients were tested. Fifty-three of 581 harvests (9%), 8% from stage II-III and 10% from stage IV patients, were positive by ICC (P = 0.68). Forty-one of 223 patients (18%), 17/122 (14%) with stage II-III and 24/101 (24%) with stage IV disease, had positive harvests (P = 0.06). Eleven percent of patients who had 1-2 harvests tested were positive as compared to 32% of patients who had > or =3 PBSC harvests tested (P < 0.001). Nineteen patients who were infused with a mixture of ICC negative and untested PBSC harvests were excluded from analyses of relapse. The probabilities of relapse at 18 months for the 97 patients with stage II-III disease infused with ICC-negative and the 17 with ICC-positive PBSC were 0.19 and 0.13, respectively (P = 0.48). The probabilities of relapse at 18 months for patients achieving a CR or a CR in non-bone sites and improvement in bone lesions were 0.55 for the ICC-negative group (n = 30) and 0.45 for the ICC-positive group (n = 11) (P = 0.60). It was concluded that occult tumor cells were detected by ICC in PBSC harvests from a relatively small fraction of women with breast cancer, but were not associated with a significant increase in the probability of early relapse or progression when infused after HDC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/terapia , Transplante de Células-Tronco Hematopoéticas , Células Neoplásicas Circulantes , Adulto , Neoplasias da Mama/sangue , Terapia Combinada , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Prospectivos , Recidiva , Transplante AutólogoRESUMO
High-dose chemotherapy (HDC) with autologous peripheral blood progenitor cell (PBPC) is being increasingly utilized as a therapeutic modality for patients with chemotherapy-sensitive disease. Several published HDC regimens have become relatively widely used. The purpose of this analysis was to determine treatment-related mortality (TRM) following administration of five different HDC regimens in community cancer centers. A retrospective evaluation of 1000 consecutive patients with leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, sarcoma, ovarian cancer, or breast cancer who received one of five published HDC regimens followed by PBPC infusion over a 5-year period in community cancer centers was performed to determine TRM. Fifty-nine patients (5.9%) died within 100 days of PBPC infusion. Twenty-five patients (2.5%) died predominantly of causes related to disease progression. Thirty-four patients (3.4%) died of TRM, 15 patients (1.5%) died from infection and 19 (1.9%) died from regimen-related toxicities (RRT). In a logistic model, increasing age (P = 0.001) and lower numbers of CD34+ cells/kg (P = 0.003) were associated with an increased risk of 100-day TRM. High-dose cyclophosphamide, thiotepa, and carboplatin was associated with a lower risk of mortality than other regimens (P = 0.0001). High-dose chemotherapy and autologous PBPC support can be performed in community cancer centers with relative safety. Patient age, the type of preparative regimen and the number of CD34+ cells infused were important determinates of mortality.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Neoplasias/terapia , Fatores Etários , Terapia Combinada/mortalidade , Humanos , Neoplasias/mortalidade , Fatores de Risco , Resultado do TratamentoRESUMO
The purpose of this study was to develop a regimen of docetaxel, cyclophosphamide (CY) and filgrastim for mobilization of peripheral blood stem cells (PBSC) in patients with metastatic breast cancer (n = 66). A phase I trial of CY 2, 3 or 4 g/m2 with docetaxel 100 mg/m2, in consecutive cohorts of four patients each, did not reveal any dose-limiting toxicities and subsequent patients were randomized to receive 3 or 4 g/m2 of CY. The median yield of CD34+ cells from all patients was 11.06x10(6)/kg (range, 0.03-84.77) from a median of two aphereses (range, 1-7); 6.52x10(6) CD34+ cells/kg/apheresis (range, 0.01-52.07). Target CD34+ cell doses > or =2.5 and > or =5.0x10(6)/kg were achieved in 89% and 79%, respectively. There were no statistically significant differences in CD34+ cell yields or target CD34+ cell doses achieved following 3 or 4 g/m2 of CY. Patients with only one prior chemotherapy regimen yielded a median of 12.82x10(6) CD34+ cells/kg/apheresis compared to 5.85 for those receiving > or =2 regimens (P = 0.03). It was concluded that the combination of docetaxel, 100 mg/m2, CY 3 g/m2 without mesna could be administered with acceptable toxicity with collection of adequate quantities of PBSC from the majority of patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/terapia , Ciclofosfamida/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas , Paclitaxel/análogos & derivados , Taxoides , Adulto , Contagem de Células Sanguíneas/efeitos dos fármacos , Neoplasias da Mama/patologia , Terapia Combinada , Docetaxel , Feminino , Filgrastim , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/patologia , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Paclitaxel/administração & dosagem , Proteínas RecombinantesRESUMO
We investigated the outcomes of patients with breast cancer undergoing induction chemotherapy, mobilization of peripheral blood stem cells (PBSC) and high-dose chemotherapy (HDC) with PBSC infusion. One hundred and fourteen patients with untreated stage IV breast cancer, with a median age of 46 years (range 24-62), were entered on a phase II trial consisting of; (1) doxorubicin, 5-flurouracil, methotrexate (AFM) x 4 courses at 2 week intervals; (2) cyclophosphamide (4 g/m2), etoposide (600 mg/m2), cisplatin (105 mg/m2) (CEP), filgrastim (6 micrograms/kg/day) and PBSC collection; (3) cyclophosphamide (6 g/m2), thiotepa (500 mg/m2), carboplatin (800 mg/m2), (CTCb) followed by PBSC infusion. All patients received AFM, 107 (94%) received CEP, 93 (82%) received CTCb and PBSC as per protocol and 99 (87%) ultimately received HDC and PBSC. There was one infectious death after AFM and all other deaths were associated with progressive disease. Fifty-two patients (46%) are alive, 21 (18%) without progression, at a median 31 months (range 22-47). The probabilities of survival and progression-free survival at 3.5 years were 0.40 and 0.17, respectively. All 62 patients with visceral disease and/or a prior history of doxorubicin adjuvant therapy have relapsed or progressed. We conclude that the sequential administration of AFM, CEP and CTCb followed by PBSC resulted in long-term PFS only in patients who were NED, had bone-only disease or had lymph node or soft tissue disease with or without bone disease. Other strategies, aimed at improving responses to initial therapy, improving HDC regimens and/or developing immunomodulatory therapies, will be necessary to improve PFS for patients who fail doxorubicin adjuvant or who have visceral disease.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/terapia , Transplante de Células-Tronco Hematopoéticas , Adulto , Terapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Engraftment kinetics after high-dose chemotherapy (HDC) were evaluated in patients receiving autologous peripheral blood stem cell (PBSC) infusions with a low CD34+ cell content. Forty-eight patients were infused with < 2.5 x 10(6) CD34+ cells/kg; 36 because of poor harvests and 12 because they electively received only a fraction of their harvested cells. A median of 2.12 x 10(6) CD34+ cells/kg (range, 1.17-2.48) were infused following one of seven different HDC regimens. All patients achieved absolute neutrophil counts > or = 0.5 x 10(9)/l at a median of day 11 (range, 9-16). Forty-seven patients achieved platelet counts > or = 20 x 10(9)/l at a median of day 14 (range, 8-250). Nine of 47 (19%) had platelet recovery after day 21, 4/47 (9%) after day 100 and one died on day 240 without platelet recovery. Twenty-six patients (54%) died of progressive disease in 51-762 days; 22 (46%) are alive at a median of 450 days (range, 94-1844), 17 (35%) of whom are surviving disease-free at a median of 494 days (range, 55-1263). No patient died as a direct consequence of low blood cell counts. These data demonstrate that PBSC products containing 1.17-2.48 x 10(6) CD34+ cells/kg resulted in relatively prompt neutrophil recovery in all patients but approximately 10% had delayed platelet recovery.
Assuntos
Antígenos CD34/análise , Transplante de Células-Tronco Hematopoéticas , Neoplasias/terapia , Feminino , Humanos , Masculino , Neoplasias/sangue , Neutrófilos , Contagem de Plaquetas , Condicionamento Pré-Transplante , Transplante AutólogoRESUMO
The purpose of this trial was to determine the effects of paclitaxel in patients with newly diagnosed metastatic breast cancer scheduled to receive high-dose chemotherapy with peripheral blood stem cell support. Eighty-four patients received anthracycline-based induction and two doses of paclitaxel at 170 mg/m2 (n = 52) or 250 mg/m2 (n = 32). Eighty-two (98%) received cyclophosphamide and etoposide (n = 50) or paclitaxel and cyclophosphamide (n = 32) with granulocyte colony-stimulating factor for mobilization of peripheral blood stem cells, and 79 (94%) received cyclophosphamide, thiotepa, and carboplatin with peripheral blood stem cell support. One patient (1%) died of infection and 56 (67%) died of progressive disease. For patients with measurable disease, the complete response rate was 21% after induction and 29% after paclitaxel (p = 0.54). Results were compared with those of 125 patients who received the same sequence of therapy without paclitaxel. The complete response rate after high-dose chemotherapy was 54% for patients receiving paclitaxel and 62% for those not receiving paclitaxel (p = 0.60). The probabilities of overall survival and event-free survival at 3 years for patients receiving paclitaxel were 46% and 24%, respectively, compared with 54% and 22%, respectively, for patients not receiving paclitaxel (p = 0.62). Further trials evaluating this dose and schedule of paclitaxel in patients with metastatic breast cancer receiving high-dose chemotherapy are not warranted.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas , Paclitaxel/uso terapêutico , Adulto , Antraciclinas/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias da Mama/patologia , Carboplatina/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Paclitaxel/administração & dosagem , Modelos de Riscos Proporcionais , Análise de SobrevidaRESUMO
The purpose of this study is to determine outcomes for patients with high-risk nonmetastatic breast cancer undergoing high-dose chemotherapy with peripheral blood stem cell support. Forty-three patients with stage II-III disease, five to nine positive axillary lymph nodes, and a median age of 44 years (range, 27-60 years) were enrolled in a study that included: 1) standard dose doxorubicin, 5-fluorouracil, and methotrexate adjuvant therapy; 2) cyclophosphamide, etoposide, filgrastim, and peripheral blood stem cell harvest; and 3) high-dose cyclophosphamide, thiotepa, and carboplatin (CTCb) followed by peripheral blood stem cell infusion. All 43 patients received doxorubicin, 5-fluorouracil, and methotrexate, 42 (98%) received etoposide, and 41 (95%) received CTCb. Thirty-two patients (74%) are alive, 28 (65%) without relapse at a median of 55 months (range, 41-87 months). Two died (5%) of treatment-related causes, (subclavian catheter complication after etoposide and late radiation pneumonitis), and nine other deaths (21%) were associated with recurrent breast cancer. The probabilities of overall and event-free survival at 4 years were 0.77 and 0.67, respectively, compared with 0.82 and 0.69, respectively, for 72 similar patients with 10 or more positive axillary nodes receiving the same sequence of therapy. Thus, patients with five to nine positive axillary lymph nodes have a similar risk of failure after high-dose chemotherapy and peripheral blood stem cell support as patients with 10 or more positive axillary lymph nodes.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas , Adulto , Axila , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Quimioterapia Adjuvante , Doxorrubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas , Humanos , Metástase Linfática , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de SobrevidaRESUMO
The authors determined outcomes for patients with localized high-risk breast cancer undergoing sequential outpatient treatment with conventional-dose adjuvant therapy, chemotherapy, and growth factor mobilization of peripheral blood stem cells (PBSC) and high-dose chemotherapy (HDC) with PBSC support in community cancer centers. Ninety-six patients with stage II-IIIB noninflammatory breast cancer with 10 or more positive lymph nodes and a median age of 46 years (range, 22-60 years) were treated with: 1) doxorubicin, 5-fluorouracil, and methotrexate (AFM), four courses at 2-week intervals; 2) cyclophosphamide (4 g/m2) and etoposide (600 mg/m2) (CE), followed by filgrastim (6 microg/kg per day) and PBSC harvest; and 3) cyclophosphamide (6 g/m2), thiotepa (500 mg/m2), and carboplatin (800 mg/m2) (CTCb), followed by PBSC infusion. All 96 patients received AFM, 95 (99%) received CE, and 95 (99%) received CTCb with a median hospital stay of 12 days (5-34 days) for all phases of treatment. Sixty-nine patients (72%) are alive, 55 (57%) without relapse at a median follow-up of 53 months (range, 37-77 months). One patient (1%) died of acute myeloid leukemia and all other deaths were associated with recurrent breast cancer. The probabilities of event-free survival (EFS) at 4 years for patients with or without locally advanced disease were 0.37 and 0.69, respectively (p = 0.004), and 0.71 and 0.48 for patients who were estrogen/progesterone receptor (ER/PR) positive or ER/PR negative, respectively (p = 0.016). In multivariate analyses, locally advanced disease (relative risk, 2.3; p = 0.021) and ER/PR-negative hormone receptor status (relative risk, 2.2; p = 0.014) were the only adverse risk factors for EFS identified. Patients with zero, one, or two of these adverse risk factors had 4-year EFS of 0.80, 0.56, and 0.33, respectively. The sequential administration of AFM, CE, and CTCb followed by PBSC in an outpatient community setting was well tolerated in patients with high-risk stage II-III breast cancer. More intensive or more novel treatment strategies will be required to decrease relapses in patients who have ER/PR-negative tumors and/or have locally advanced disease.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/terapia , Transplante de Células-Tronco Hematopoéticas , Adulto , Assistência Ambulatorial , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Estudos de Viabilidade , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas Recombinantes , Análise de SobrevidaRESUMO
Because of their patient specificity and proliferative capacity, tumor cell lines established from autologous metastatic melanoma tumor samples may be an excellent immunogen for patient-specific vaccine therapy. Between October 1990 and July 1996, the Hoag Cancer Center cell biology laboratory received 136 fresh metastatic melanoma samples from 122 different patients. Tumor cell lines were successfully established for 92 of 136 samples (68%), for 87 of 122 patients (71%). Successful cultures were expanded to 10(8) cells (total culture time about 8 weeks), confirmed to be sterile, irradiated, and stored frozen in aliquots of 10(7) cells. Vaccines were prepared from 72 lines, and 62 vaccines were used in 57 different patients. Subcutaneous vaccination took place on weeks 1, 2 and 3, and then monthly for a total of 6 months. A delayed tumor hypersensitivity skin test (DTH) was administered at week zero and week 4. Various adjuvants were co-administered including BCG, alpha- or gamma-interferon, and GM-CSF. Patients were monitored for failure-free survival (FFS) and overall survival (OS) from the date of the first vaccination. Follow-up data is available for 52 patients, 27 who had no evident disease (NED) at the time of vaccination and 25 who had metastatic disease at the time of treatment. There were two partial responses which persisted 11.9 and 39.8+ months among the 25 patients who had detectable metastatic disease whün treatment was initiated (8%, 1 to 26%, 95%-Ci). Twenty patients had negative skin tests at week 0 and week 4; six were positive both times, and 13 converted their DTH from negative to positive, for a conversion rate of 13 of 33 (39%). Patients who received interferon-gamma and/or GM-CSF as an adjuvant had a higher rate of DTH conversion compared to patients who received other adjuvants (13 of 20 v 2 of 13, P = 0.003). For patients who were NED, nine of 19 (47%) converted their DTH test compared to four of 14 (29%) patients with metastatic disease (p = 0.33). For patients whose DTH converted from negative to positive after 3 weeks of vaccination, median FFS and OS were superior compared to patients whose DTH remained negative (19.4 v 4.0 months FFS, p = 0.0052 and 39.6 v 18.3 months OS, p = 0.0602). The autologous cell line approach to active specific immunotherapy is feasible for patients who have resectable foci of metastatic disease. Administration of such patient-specific vaccines improves survival for those patients who are NED at the time of vaccination and convert their DTH skin test, compared to those whose DTH test remains negative.
Assuntos
Vacinas Anticâncer , Melanoma/patologia , Melanoma/terapia , Vacina BCG/uso terapêutico , Vacinas Anticâncer/efeitos adversos , Técnicas de Cultura de Células/métodos , Linhagem Celular , Intervalo Livre de Doença , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Humanos , Hipersensibilidade Tardia , Interferons/uso terapêutico , Melanoma/imunologia , Melanoma/mortalidade , Taxa de Sobrevida , Células Tumorais CultivadasRESUMO
Cancer patients are at risk for profound derangements in the hemostatic mechanism due to multiple factors. Depending upon the dominant abnormality, bleeding, thrombosis or both, in conjunction with disseminated intravascular coagulation, may occur. Critical care physicians should have a high index of suspicion for underlying hemostatitic defects when a cancer patient presents with hemorrhage. Blood replacement therapy tailored to specific abnormalities coupled with effective treatment of the underlying malignancy will render the best result. Thrombosis in malignancy is a frequent occurrence and increasing in incidence due in part to the widespread use of indwelling venous catheters. Fibrinolytic therapy is effective and probably under-utilized in treating thrombosis but must be approached with care in these patients. A thorough understanding of diagnostic techniques, indications, and potential complications of anticoagulant therapy in cancer patients is essential.
Assuntos
Hemorragia/etiologia , Neoplasias/complicações , Trombose/etiologia , Cuidados Críticos , Fibrinolíticos/uso terapêutico , Hemorragia/tratamento farmacológico , Humanos , Flebografia , Embolia Pulmonar/diagnóstico por imagem , Fatores de RiscoAssuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/terapia , Transplante de Células-Tronco Hematopoéticas , Purging da Medula Óssea , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Ensaios Clínicos como Assunto , Terapia Combinada , Feminino , Fatores de Crescimento de Células Hematopoéticas/uso terapêutico , Humanos , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida , Transplante AutólogoRESUMO
The authors describe 12 episodes of severe chest pain suggesting acute cardiac or pulmonary events which occurred during infusions of bleomycin. The incidence of the syndrome was low, occurring in 2.8% of those receiving the drug. Typically, the chest pain was sudden in onset and described either as substernal pressure or pleuritic in character. Few associated symptoms were noted. Evaluations for the etiology of the pain were unrevealing except for electrocardiographic changes suggestive of pericarditis in two cases and radiographic evidence of a small pleural effusion in one. The syndrome was self-limited or relieved with analgesics. There were no long-term cardiac or pulmonary sequelae. Discontinuation of bleomycin was not necessary although improvement was seen when the infusions were stopped. Further courses of bleomycin did not lead to recurrent episodes in most patients and are not contraindicated. Chest pain during continuous bleomycin infusion should suggest the possibility of a drug effect.
Assuntos
Bleomicina/efeitos adversos , Dor no Peito/induzido quimicamente , Adulto , Bleomicina/administração & dosagem , Dispneia/induzido quimicamente , Eritema/induzido quimicamente , Feminino , Humanos , Infusões Intravenosas , Contagem de Leucócitos , Masculino , Fatores de TempoRESUMO
Peripheral blood stem cells (PBSC) are now used extensively to provide rapid and durable hematopoietic reconstitution following supralethal myeloablative therapies. A major clinical issue is the quantitation of the cells responsible for reconstitution. We review here published reports of transplants using the measurement of mononuclear cells and granulocyte-macrophage colony-forming units (CFU-GM) to quantitate PBSC. In addition, we present data from three institutions where hematopoietic recovery is correlated with doses of CFU-GM or CD34+ cells. These data suggest doses of 20 x 10(4) CFU-GM or 2 x 10(6) CD34+ cells/kg body weight that provide rapid engraftment of neutrophils and platelets.