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1.
Br J Cancer ; 107(9): 1481-7, 2012 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-23037712

RESUMO

BACKGROUND: Bevacizumab improves outcome for most recurrent glioblastoma patients, but the duration of benefit is limited and survival after initial bevacizumab progression is poor. We evaluated bevacizumab continuation beyond initial progression among recurrent glioblastoma patients as it is a common, yet unsupported practice in some countries. METHODS: We analysed outcome among all patients (n=99) who received subsequent therapy after progression on one of five consecutive, single-arm, phase II clinical trials evaluating bevacizumab regimens for recurrent glioblastoma. Of note, the five trials contained similar eligibility, treatment and assessment criteria, and achieved comparable outcome. RESULTS: The median overall survival (OS) and OS at 6 months for patients who continued bevacizumab therapy (n=55) were 5.9 months (95% confidence interval (CI): 4.4, 7.6) and 49.2% (95% CI: 35.2, 61.8), compared with 4.0 months (95% CI: 2.1, 5.4) and 29.5% (95% CI: 17.0, 43.2) for patients treated with a non-bevacizumab regimen (n=44; P=0.014). Bevacizumab continuation was an independent predictor of improved OS (hazard ratio=0.64; P=0.04). CONCLUSION: The results of our retrospective pooled analysis suggest that bevacizumab continuation beyond initial progression modestly improves survival compared with available non-bevacizumab therapy for recurrent glioblastoma patients require evaluation in an appropriately randomised, prospective trial.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Bevacizumab , Progressão da Doença , Esquema de Medicação , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
2.
AJNR Am J Neuroradiol ; 42(6): 1080-1086, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33737270

RESUMO

BACKGROUND AND PURPOSE: Despite high interest in machine-learning algorithms for automated segmentation of MRIs of patients with brain tumors, there are few reports on the variability of segmentation results. The purpose of this study was to obtain benchmark measures of repeatability for a widely accessible software program, BraTumIA (Versions 1.2 and 2.0), which uses a machine-learning algorithm to segment tumor features on contrast-enhanced brain MR imaging. MATERIALS AND METHODS: Automatic segmentation of enhancing tumor, tumor edema, nonenhancing tumor, and necrosis was performed on repeat MR imaging scans obtained approximately 2 days apart in 20 patients with recurrent glioblastoma. Measures of repeatability and spatial overlap, including repeatability and Dice coefficients, are reported. RESULTS: Larger volumes of enhancing tumor were obtained on later compared with earlier scans (mean, 26.3 versus 24.2 mL for BraTumIA 1.2; P < .05; and 24.9 versus 22.9 mL for BraTumIA 2.0, P < .01). In terms of percentage change, repeatability coefficients ranged from 31% to 46% for enhancing tumor and edema components and from 87% to 116% for nonenhancing tumor and necrosis. Dice coefficients were highest (>0.7) for enhancing tumor and edema components, intermediate for necrosis, and lowest for nonenhancing tumor and did not differ between software versions. Enhancing tumor and tumor edema were smaller, and necrotic tumor larger using BraTumIA 2.0 rather than 1.2. CONCLUSIONS: Repeatability and overlap metrics varied by segmentation type, with better performance for segmentations of enhancing tumor and tumor edema compared with other components. Incomplete washout of gadolinium contrast agents could account for increasing enhancing tumor volumes on later scans.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Algoritmos , Neoplasias Encefálicas/diagnóstico por imagem , Glioblastoma/diagnóstico por imagem , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Carga Tumoral
3.
Br J Cancer ; 101(12): 1986-94, 2009 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-19920819

RESUMO

BACKGROUND: We evaluated bevacizumab with metronomic etoposide among recurrent malignant glioma patients in a phase 2, open-label trial. METHODS: A total of 59 patients, including 27 with glioblastoma (GBM) and 32 with grade 3 malignant glioma, received 10 mg kg(-1) bevacizumab biweekly and 50 mg m(-2) etoposide daily for 21 consecutive days each month. The primary end point was a 6-month progression-free survival, and secondary end points included safety and overall survival. Vascular endothelial growth factor (VEGF), VEGFR-2, carbonic anhydrase 9 (CA9) and hypoxia-inducible factor-2alpha (HIF-2alpha) were assessed semiquantitatively in archival tumours using immunohistochemistry and were correlated with outcome. RESULTS: Among grade 3 and GBM patients, the 6-month progression-free survivals were 40.6% and 44.4%, the radiographic response rates were 22% and 37% and the median survivals were 63.1 and 44.4 weeks, respectively. Hypertension predicted better outcome among both grade 3 and GBM patients, whereas high CA9 and low VEGF were associated with poorer progression-free survival (PFS) among those with GBM. The most common grade > or = 3 adverse events included neutropaenia (24%), thrombosis (12%), infection (8%) and hypertension (3%). Two patients had asymptomatic, grade 1 intracranial haemorrhage and one on-study death occurred because of pulmonary embolism. CONCLUSION: Bevacizumab with metronomic etoposide has increased toxicity compared with previous reports of bevacizumab monotherapy. Its anti-tumour activity is similar to that of bevacizumab monotherapy or bevacizumab plus irinotecan. (ClinicalTrials.gov: NCT00612430).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Administração Oral , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Bevacizumab , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/mortalidade , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Glioma/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Falha de Tratamento , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
4.
Bone Marrow Transplant ; 37(11): 1009-15, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16633363

RESUMO

The prognosis for patients with metastatic breast cancer remains poor. Metastatic breast cancer confined to the bones may have a better prognosis, especially hormone receptor-positive disease. We performed a prospective, randomized clinical trial to compare immediate consolidation with high-dose chemotherapy and hematopoietic support versus observation with high-dose consolidation at the time of disease progression in women with metastatic breast cancer and only bone metastases. The patients received chemotherapy with doxorubicin, 5-fluorouracil and methotrexate before randomization. In all, 85 patients were enrolled and 69 were randomized. The median follow-up is 8.1 years from randomization. The median event-free survival (EFS) for the immediate transplant arm is 12 months and for the observation arm is 4.3 months (P<0.0001). The median overall survival for the immediate transplant arm is 2.97 years and for the observation arm 1.81 years, a difference that is not statistically significant. Immediate high-dose chemotherapy and radiation therapy as consolidation offers a clinically and statistically significant improvement in EFS compared with radiation therapy alone following induction chemotherapy for women with metastatic breast cancer confined to the bones.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/secundário , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/terapia , Transplante de Células-Tronco de Sangue Periférico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/terapia , Neoplasias da Mama/mortalidade , Terapia Combinada , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Metotrexato/administração & dosagem , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Fatores de Tempo , Transplante Autólogo
5.
J Natl Cancer Inst ; 85(13): 1080-5, 1993 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-8515495

RESUMO

BACKGROUND: Chemotherapy adjuvant to surgery in metastatic melanoma has been evaluated in only a few prospective randomized trials. In the treatment of metastatic melanoma, dacarbazine has response rates of 15%-25% and in several studies, when combined with other alkylating agents, has yielded even higher response rates. Among the highest response rates are those achieved by using high-dose chemotherapy regimens combined with autologous bone marrow support (transplantation). PURPOSE: We conducted a prospective randomized clinical trial to test the efficacy of high-dose alkylating agents in combination with autologous bone marrow support given as adjuvant therapy for high-risk stage II (World Health Organization) melanoma. METHODS: Thirty-nine patients with metastases involving five or more lymph nodes were randomly assigned to one of two treatment arms within 8 weeks of lymphadenectomy: immediate treatment or observation only. The immediate-treatment arm consisted of 19 patients who, immediately after random assignment, received high-dose chemotherapy with alkylating agents, followed 3 days later by reinfusion of autologous bone marrow. The observation arm consisted of 20 patients who were observed until relapse (confirmed by biopsy) and were then treated with the identical high-dose alkylating agent chemotherapy followed by reinfusion of autologous bone marrow. Bone marrow was harvested from the patients under general anesthesia 1-2 weeks prior to chemotherapy and was cryopreserved. Chemotherapy consisted of intravenous administration of cyclophosphamide (1875 mg/m2 as a 1-hour infusion daily for 3 days), cisplatin (55 mg/m2 per day by continuous infusion over the same 72-hour period), and carmustine (BCNU) (600 mg/m2) given immediately after cisplatin on the 4th day as a 2-hour infusion. The total doses of the three drugs were 5625, 165, and 600 mg/m2, respectively. All patients received medical evaluations every 6-12 weeks over the study period. Kaplan-Meier estimates were used to determine the time to disease progression on the basis of intent to treat. RESULTS: There was no statistically significant difference in overall survival or in time to disease progression between the two treatment arms. However, the median time to progression was 16 weeks in the observation arm and 35 weeks in the immediate-treatment arm. CONCLUSIONS: Immediate adjuvant high-dose chemotherapy with alkylating agents followed by autologous bone marrow support more than doubled the time to disease progression compared with observation alone, though the difference was not statistically significant. No differences in overall survival were noted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transplante de Medula Óssea , Melanoma/terapia , Adulto , Carmustina/administração & dosagem , Cisplatino/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Feminino , Humanos , Metástase Linfática , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Sobrevida , Transplante Autólogo , Resultado do Tratamento
6.
Cancer Res ; 50(22): 7216-20, 1990 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-2171759

RESUMO

The majority of patients with small cell carcinoma of the lung (SCCL) have bone marrow involvement detected by monoclonal antibodies (mAb). High dose chemotherapy followed by autologous bone marrow transplantation may improve treatment results for patients with SCCL, but the bone marrow may need to be purged of contaminating tumor cells. This study investigates the reactivity of a panel of mAb with two SCCL cell lines and normal bone marrow and the ability of the mAb and immunomagnetic beads to eliminate the SCCL cells from a mixture of 90% normal bone marrow cells and 10% SCCL cells. The mAb and immunomagnetic beads removed 4 to 5 log of SCCL cells in the model system. The immunomagnetic separation did not significantly adversely affect normal hematopoietic progenitor cells, as determined by bone marrow colony-forming units. The results suggest that the mAb and immunomagnetic beads could safely and effectively separate SCCL cells from the bone marrow for autologous bone marrow transplantation following high dose chemotherapy.


Assuntos
Anticorpos Monoclonais/imunologia , Células da Medula Óssea , Carcinoma de Células Pequenas/imunologia , Separação Celular/métodos , Anticorpos Antineoplásicos/imunologia , Antígenos de Neoplasias/imunologia , Citometria de Fluxo , Hematopoese , Células-Tronco Hematopoéticas/citologia , Humanos , Técnicas Imunológicas , Técnicas In Vitro , Neoplasias Pulmonares/patologia , Magnetismo
7.
Cancer Res ; 51(9): 2451-5, 1991 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-1673088

RESUMO

The CD15 carbohydrate antigen, lacto-N-fucopentaose III is expressed on a variety of human cancer cells including acute myeloid leukemia, small cell carcinoma of the lung, and colorectal carcinomas. We have found that cells from breast cancer cell lines and patient-derived tissue are strongly CD15 positive, as seen by binding to the PM-81 monoclonal antibody. In this report we show that monoclonal antibody PM-81 and immunomagnetic beads can remove breast cancer cells from bone marrow and thus be used as "purging" agents for autologous bone marrow transplantation. PM-81 and immunomagnetic beads removed up to 3 log of SK-BR-3 and MCF7 breast carcinoma cell line cells while minimally affecting normal hematopoietic progenitor cells. This technique may be useful for purging marrow for autologous bone marrow transplantation in breast cancer.


Assuntos
Anticorpos Monoclonais/imunologia , Antígenos de Diferenciação/imunologia , Antígenos de Neoplasias/imunologia , Células da Medula Óssea , Transplante de Medula Óssea , Neoplasias da Mama/terapia , Separação Celular/métodos , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Humanos , Antígenos CD15 , Magnetismo
8.
J Clin Oncol ; 11(6): 1132-43, 1993 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-8501500

RESUMO

PURPOSE: We studied high-dose cyclophosphamide, cisplatin, and carmustine (CPA/cDDP/BCNU) with autologous bone marrow support (ABMS) as consolidation after standard-dose adjuvant chemotherapy treatment of primary breast cancer involving 10 or more axillary lymph nodes. PATIENTS AND METHODS: One hundred two women with stage IIA, IIB, IIIA, or IIIB breast cancer involving 10 or more lymph nodes at surgery were registered; 85 were eligible, treated, and assessable. Patients were treated with four cycles of standard-dose cyclophosphamide, doxorubicin, and fluorouracil (CAF), followed by high-dose CPA/cDDP/BCNU with ABMS. RESULTS: Actuarial event-free survival for the study patients at a median follow-up of 2.5 years is 72% (95% confidence interval, 56% to 82%). Comparison to three historical or concurrent Cancer and Leukemia Group B (CALGB) adjuvant chemotherapy trials selected for similar patients showed event-free survival at 2.5 years to be between 38% and 52%. Therapy-related mortality was 12%; pulmonary toxicity of variable severity occurred in 31% of patients. Quality-of-life evaluations indicate that patients are functioning well without major impairments. CONCLUSION: High-dose consolidation with CPA/cDDP/BCNU and ABMS after standard-dose CAF results in a decreased frequency of relapse in patients with high-risk primary breast cancer compared with historical series at the median follow-up of 2.5 years. Evaluation in a prospective, randomized trial is warranted and currently underway.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea , Neoplasias da Mama/terapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Transplante de Medula Óssea/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Carmustina/administração & dosagem , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Pessoa de Meia-Idade , Taxa de Sobrevida , Transplante Autólogo
9.
J Clin Oncol ; 17(3): 887-93, 1999 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10071280

RESUMO

PURPOSE: To examine the impact of consolidation radiotherapy (RT) after high-dose chemotherapy with autologous bone marrow rescue (HDC) in patients with advanced breast cancer. PATIENTS AND METHODS: Between 1988 and 1994,425 patients with metastatic or recurrent breast cancer received doxorubicin, fluorouracil, and methotrexate (AFM) induction chemotherapy in a single-institution prospective trial. One hundred patients who achieved a complete response were randomized to receive HDC (cyclophosphamide, cisplatin, carmustine), with autologous bone marrow rescue immediately after AFM, or to observation, with HDC to be administered at next relapse. Seventy-four of the 100 became eligible for RT; 53 received consolidation RT (HDC RT+ and 21 did not (HDC RT-). The assignment of RT was not randomized. The RT+ and RT- groups were similar with regard to number of involved sites, the fraction of patients with only local-regional disease, age, and interval since initial diagnosis. Local control at previously involved sites and distant sites was assessed with extensive radiologic and clinical evaluations at the time of first failure or most recent follow-up. The impact of RT on failure patterns, event-free survival, and overall survival was evaluated. RESULTS: Sites of first failure were located exclusively at previously involved sites in 28% of RT+ patients versus 62% of RT- patients (P < .01). Event-free survival at 4 years was 31% and 21% in the RT+ and RT-groups, respectively (P = .02). Overall survival at 4 years was 30% and 16% in the RT+ and RT- groups, respectively (P = .20). CONCLUSION: Patients with advanced breast cancer who were treated with HDC without RT failed predominantly at the initial sites of disease. The addition of RT appeared to reduce the failure rate at initial disease sites and may improve event-free and overall survival. Our observations await verification in a trial in which assignment to RT is randomized.


Assuntos
Neoplasias da Mama/radioterapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Terapia Combinada , Humanos , Pessoa de Meia-Idade , Indução de Remissão , Transplante Autólogo
10.
J Clin Oncol ; 19(6): 1698-706, 2001 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-11250999

RESUMO

PURPOSE: HER-2 is overexpressed in 20% to 30% of human breast cancer and is associated with poor outcome. Studies suggest an association between HER-2 overexpression and resistance to alkylating agents. To further evaluate this relationship, we assessed the interaction of HER-2, measured by different methods, and outcome after dose intensification with alkylating agents in metastatic breast cancer. PATIENTS AND METHODS: From 1988 to 1995 at Duke University, 425 patients with metastatic breast cancer were enrolled in a study of high-dose alkylating agents (HDC) with autologous cellular support after doxorubicin-based therapy (AFM). HER-2 was measured in serum for shed extracellular domain (ECD) and in tissue by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). RESULTS: HER-2 ECD was positive in 29% (19 of 65) of patients pre-AFM and in 11.7% (34 of 290) pre-HDC. Higher pre-AFM and higher pre-HDC HER-2 ECD predicted worse overall survival (P =.045 and P =.0096, respectively). HER-2 overexpression by IHC and FISH showed no correlation with worse disease-free survival or overall survival. FISH and ECD were highly specific for IHC (97.3% and 97.7% respectively). However, ECD had a low sensitivity for IHC-only 22% of patients with HER-2 in the primary tumor shed ECD into the serum. CONCLUSION: These data suggest that the method of measuring HER-2 is important in predicting clinical outcome. HER2 ECD may identify a poor prognosis subgroup of HER-2-positive tumors. Lack of association of HER2 by IHC/FISH with worse outcome suggests that therapy with AFM and/or HDC therapy may be able to overcome the effect of this prognostic factor or it may not be a prognostic factor in this setting.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Genes erbB-2/genética , Receptor ErbB-2/biossíntese , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Receptor ErbB-2/análise , Estudos Retrospectivos
11.
J Clin Oncol ; 16(3): 1008-12, 1998 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-9508184

RESUMO

PURPOSE: To determine the incidence of myelodysplasia (MDS) and/or acute leukemia (AL) in breast cancer patients after high-dose chemotherapy (HDC) with a single conditioning regimen and autologous bone marrow transplant (ABMT), and analyze the cytogenetic abnormalities that arise after HDC. PATIENTS AND METHODS: We retrospectively reviewed the records of 864 breast cancer patients who underwent ABMT at Duke University Medical Center, Durham, NC, from 1985 through 1996 who received the same preparative regimen of cyclophosphamide 1,875 mg/m2 for 3 days, cisplatin 55 mg/m2 for 3 days, and BCNU 600 mg/m2 for 1 day (CPB). Pretransplant cytogenetics were analyzed in all patients and posttransplant cytogenetics were evaluated in four of five patients who developed MDS/AL. RESULTS: Five of 864 patients developed MDS/AL after HDC with CPB and ABMT. The crude cumulative incidence of MDS/AL was 0.58%. The Kaplan-Meier curve shows a 4-year probability of developing MDS/AL of 1.6%. Pretransplant cytogenetics performed on these five patients were all normal. Posttransplant cytogenetics were performed on four of five patients and they were abnormal in all four, although only one patient had the most common cytogenetic abnormality associated with secondary MDS/AL (chromosome 5 and/or 7 abnormality). CONCLUSION: Whereas MDS/AL is a potential complication of HDC with CPB and ABMT, the incidence in this series of patients with breast cancer was relatively low compared with that reported in patients with non-Hodgkin's lymphoma who underwent ABMT. The cytogenetic abnormalities reported in this group of breast cancer patients were not typical of those seen in prior reports of secondary MDS/AL and appear to have occurred after HDC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Transplante de Medula Óssea/efeitos adversos , Neoplasias da Mama/terapia , Leucemia/etiologia , Síndromes Mielodisplásicas/etiologia , Doença Aguda , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carmustina/administração & dosagem , Aberrações Cromossômicas , Cisplatino/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Feminino , Humanos , Cariotipagem , Leucemia/genética , Síndromes Mielodisplásicas/genética , Estudos Retrospectivos , Análise de Sobrevida , Transplante Autólogo
12.
J Clin Oncol ; 17(10): 3064-74, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10506601

RESUMO

PURPOSE: We performed a retrospective review to determine predictive and prognostic factors in patients with metastatic breast cancer who received induction therapy, and, if they responded to treatment, high-dose chemotherapy. PATIENTS AND METHODS: Patients with metastatic breast cancer received induction therapy with doxorubicin, fluorouracil, and methotrexate (AFM). Partial responders then received immediate high-dose chemotherapy, whereas those who achieved complete remission were randomized to immediate or delayed high-dose chemotherapy with hematopoietic stem-cell support. We performed a retrospective review of data from these patients and used Cox proportional hazards regression models for analyses. RESULTS: The overall response rate for the 425 patients enrolled was 74% (95% confidence interval, 70% to 78%). Multivariate analysis of data from all 425 patients revealed that positive estrogen receptor status (P =.0041), smaller metastatic foci ( 2 cm) (P =. 0165), a longer disease-free interval from initial diagnosis to diagnosis of metastases ( 2 years) (P =.0051), and prior treatment with tamoxifen (P =.0152) were good prognostic signs for overall survival. Patients who had received prior adjuvant therapy (P =.0001) and those who developed liver metastases (P =.0001) had decreased long-term survival. In the subgroup of responders to AFM induction, multivariate analysis showed that those with visceral metastases did less well (P =.0006), as did patients who had received prior adjuvant therapy (P =.0023). However, those who had received tamoxifen therapy in the adjuvant setting did better (P =. 0143). CONCLUSION: The chance for long-term remission with induction therapy with AFM and high-dose chemotherapy is increased for hormone receptor positive-patients with nonvisceral metastases who have not received prior adjuvant chemotherapy and have long disease-free intervals.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas , Adulto , Neoplasias da Mama/patologia , Terapia Combinada , Doxorrubicina/administração & dosagem , Antagonistas de Estrogênios/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Tamoxifeno/administração & dosagem , Resultado do Tratamento
13.
Clin Cancer Res ; 2(1): 81-6, 1996 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9816094

RESUMO

Peripheral blood progenitor cells (PBPCs) are being used increasingly to provide hematopoietic support after intensive chemotherapy. However, many investigators have detected tumor cells contaminating PBPC collections. Methods that eliminate the tumor cells and spare the normal hematopoietic progenitor cells may improve the number of long-term, disease-free survivors after intensive chemotherapy. We developed an effective method using anti-breast cancer murine monoclonal antibodies (MoAbs) and immunomagnetic beads to eliminate a low percentage of breast cancer cells from PBPCs. We identified optimal anti-breast cancer MoAbs that react with membrane glycoproteins and conditions for selective removal of tumor cells. Using three anti-breast cancer MoAbs (260F9, 317G5, and 520C9) at 0.8 microgram/ml, a cell concentration of 2 x 10(8) cells/ml and a bead:total cell ratio of 0.75 beads:1 cell, we eliminated 3.3-4.8 (mean, 4.1) logs of tumor cells consistently from a model system with 1% breast cancer cells and 99% normal PBPCs. Similar levels of tumor cell elimination were obtained with three breast cancer cell lines. Colony-forming units were not affected adversely, with a mean recovery of 200% compared with the control. A clinical trial has begun that uses immunomagnetically purged, autologous bone marrow and PBPCs to support patients with metastatic breast cancer receiving high-dose chemotherapy.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias da Mama/patologia , Células-Tronco Hematopoéticas/patologia , Separação Imunomagnética , Feminino , Humanos , Células Tumorais Cultivadas
14.
Semin Oncol ; 21(4 Suppl 7): 25-31, 1994 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-7916487

RESUMO

Recent studies have explored feasibility and cost considerations of administering high-dose chemotherapy with hematopoietic support in the outpatient setting. Between October 1991 and April 1993, we studied 110 women with primary metastatic breast cancer undergoing high-dose chemotherapy with hematopoietic support. Ninety-two patients were managed in an outpatient clinic after high-dose chemotherapy and autologous bone marrow transplantation and peripheral blood progenitor cells. The remaining 18 patients received the same high-dose treatment and hematopoietic support in the hospital and were discharged to a nearby hotel each night; these patients were the pilot group for this effort and also served as a control group. High-dose chemotherapy consisted of cyclophosphamide/cisplatin/carmustine. Chemotherapy was well tolerated, allowing 95% of 65 eligible patients enrolled since November 1992 to be discharged soon after chemotherapy for outpatient posttransplant support. Approximately 70% of these patients required either no hospital readmission or brief readmissions of 1 to 4 days. Median days of hospitalization required for historical groups of patients receiving high-dose chemotherapy plus bone marrow support as inpatient therapy, high-dose chemotherapy with colony-stimulating factor-primed peripheral blood progenitor cells and autologous bone marrow transplantation as inpatient therapy in a traditional transplant model, and outpatient management of autologous bone marrow transplantation patients were 37, 24.5, and 7 days, respectively, despite the same high-dose chemotherapy. Charges related to the transplant procedure were reduced by 50% over the last 2 to 5 years using the outpatient management approach. This procedure may be applicable to patients with other forms of cancer receiving intensive chemotherapeutic regimens. The use of outpatient management in a transplant setting is highly cost effective.


Assuntos
Assistência Ambulatorial/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea , Neoplasias da Mama/terapia , Transplante de Células-Tronco Hematopoéticas , Adulto , Transplante de Medula Óssea/economia , Terapia Combinada , Análise Custo-Benefício , Feminino , Preços Hospitalares , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Transplante Autólogo
15.
Int J Radiat Oncol Biol Phys ; 23(5): 1021-6, 1992.
Artigo em Inglês | MEDLINE | ID: mdl-1639635

RESUMO

Between 2/87 and 2/91, 49 women with operable breast cancer involving greater than or equal to 10 axillary nodes were treated following mastectomy, with four cycles of Cyclophosphamide, Adriamycin, 5FU, followed by high doses of Cyclophosphamide, Cisplatin, Carmustine (HDCT) with autologous bone marrow transplant support. Forty patients received local-regional radiotherapy (generally to the chest wall, internal mammary, supraclavicular, +/- axillary nodal areas; minimum 44-50 Gy, 1.8-2 Gy/fraction, +/- 10-15 Gy scar boost; standard radiation techniques). The first nine patients did not receive local-regional radiotherapy. Three developed a local-regional failure (6-12 months after HDCT); six are without evidence of disease. Local-regional radiotherapy (LR XRT) was delivered to the subsequent 40 patients following HDCT+autologous bone marrow transplant. Six received less than 44 Gy of the planned local-regional radiotherapy due to significant toxicity and one of these failed locally. Only one local failure was observed among the 34 patients who received greater than or equal to 44 Gy. Two additional patients developed distant metastases. None of these 40 patients have failed in the axilla despite the fact that the axilla was irradiated in only 18 cases. Overall, 36/40 (90%) of these patients are without evidence of disease 4-30 months following HDCT (approximately 10-36 months after mastectomy, median 22 months). Radiotherapy was interrupted or discontinued because of progressive dyspnea, thrombocytopenia, or neutropenia in nine patients. Further studies to determine the roles of local-regional radiotherapy and HDCT in the development of these toxicities are underway. These encouraging results suggest that HDCT + autologous bone marrow transplant+local-regional radiotherapy may improve the survival rate in these high risk patients. A national randomized study to test the efficacy of this HDCT regimen is currently underway (Cancer and Leukemia Group B#9082 and Southwest Oncology Group #9114).


Assuntos
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea , Neoplasias da Mama/terapia , Mastectomia , Adenocarcinoma/epidemiologia , Adenocarcinoma/radioterapia , Adulto , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/radioterapia , Carmustina/administração & dosagem , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Transplante Autólogo
16.
Bone Marrow Transplant ; 8(1): 35-40, 1991 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-1655139

RESUMO

Immunomagnetic beads can be used to remove subpopulations of cells from a mixed cell suspension in a flow-through system. One application of this process is the removal of tumor cells from bone marrow prior to its use in autologous bone marrow transplantation (ABMT). Based on preliminary data showing that three monoclonal antibodies (MoAb) (SCCL 175, HNK-1, and TFS-4) gave optimal separation in small-scale experiments, we have designed a large-scale separator suitable for clinical use. In our separator, the cell suspension flows through a 150 ml baffled transfer pack which is held over an array of permanent magnets. Direct (one MoAb only) and indirect (MoAb and anti-mouse antibody) methods of binding beads to cells were investigated as were the effects of temperature, bead to cell ratio, and medium additives on tumor cell removal and normal cell recovery. We determined the optimal separation conditions to be the indirect method of binding at 22 degrees C using a bead to tumor cell ratio of 25:1. Testing of the device on DMS-273 small cell lung cancer (SCCL) cells mixed with normal human bone marrow mononuclear cells resulted in a mean tumor cell removal of 3.64 logs (99.977%) with a concomitant mean normal granulocyte-monocyte colony forming unit (CFU-GM) recovery of 61.3%. These experiments form the basis to use the immunomagnetic beads to purify bone marrow from patients with SCCL for use in ABMT.


Assuntos
Purging da Medula Óssea/métodos , Carcinoma de Células Pequenas/patologia , Neoplasias Pulmonares/patologia , Magnetismo , Microesferas , Anticorpos Monoclonais/imunologia , Transplante de Medula Óssea/patologia , Adesão Celular/efeitos dos fármacos , Desoxirribonucleases/farmacologia , Heparina/farmacologia , Humanos , Soroalbumina Bovina/farmacologia , Temperatura
17.
Bone Marrow Transplant ; 13(4): 495-6, 1994 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-7517261

RESUMO

Clostridium septicum bacteremia is frequently associated with hematologic and colonic malignancies and neutropenia. It frequently produces 'metastatic' gangrene with excessive mortality. Standard therapy usually includes surgical debridement and antibiotics. We present a patient with metastatic breast cancer treated with high-dose chemotherapy and bone marrow transplantation. She was treated successfully with antibiotics alone despite developing Cl. septicum bacteremia and gas in hepatic metastases. The pathophysiology of this infection is reviewed.


Assuntos
Infecções por Clostridium/complicações , Quimioterapia Combinada/uso terapêutico , Abscesso Hepático/complicações , Neoplasias Hepáticas/secundário , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Carmustina/administração & dosagem , Ceftazidima/uso terapêutico , Cisplatino/administração & dosagem , Clindamicina/uso terapêutico , Infecções por Clostridium/tratamento farmacológico , Infecções por Clostridium/fisiopatologia , Terapia Combinada , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Gases , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Imipenem/uso terapêutico , Hospedeiro Imunocomprometido , Abscesso Hepático/tratamento farmacológico , Abscesso Hepático/microbiologia , Abscesso Hepático/fisiopatologia , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/tratamento farmacológico , Metotrexato/administração & dosagem , Neutropenia/etiologia , Neutropenia/terapia , Sepse/complicações , Sepse/diagnóstico , Sepse/microbiologia
18.
Bone Marrow Transplant ; 14(2): 287-91, 1994 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-7994244

RESUMO

High-dose cyclophosphamide (CY) is associated with a high risk of hemorrhagic cystitis. The reported frequency ranges from 6.5 to 52% despite the use of hydration protocols. The current study reports a hyperhydration and continuous bladder irrigation protocol which resulted in a very low incidence of microscopic hematuria and no reported cases of visible hematuria. Patients received baseline fluids at 200 ml/m2/h during chemotherapy. Additional fluid boluses were given if urine output fell below 200 ml/h. Bladder irrigation was performed at a rate of 1 l/h during and for 24 h after high-dose CY. Three hundred three evaluable patients with solid tumors received high-dose chemotherapy with CY at a dose of 5625 mg/m2 over 3 days. Patients also received cisplatin 165 mg/m2 and carmustine 600 mg/m2. Some patients received thiotepa 300-750 mg/m2 instead of carmustine. The overall incidence of microscopic hematuria (> 15 RBCs per high power field) was 19%, with only 11% of patients experiencing more than 50 RBCs per high power field. No patient developed visible hematuria or symptomatic hematuria requiring intervention. These results using aggressive hyperhydration and high volumes of continuous bladder irrigation are among the best reported following high-dose CY chemotherapy.


Assuntos
Transplante de Medula Óssea/efeitos adversos , Ciclofosfamida/efeitos adversos , Cistite/prevenção & controle , Hematúria/prevenção & controle , Humanos , Transplante Autólogo
19.
Bone Marrow Transplant ; 22(2): 153-9, 1998 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-9707023

RESUMO

High-dose chemotherapy (HDC) with hematopoietic support appears promising in the treatment of breast cancer, although reinfusion of contaminating tumor cells may contribute to disease relapse. Ex vivo expansion may reduce tumor cell content through use of a small inoculum volume and by passive purging during culture. We assessed the ex vivo expansion potential of tumor cell positive bone marrow (BM) from breast cancer patients and the effect of ex vivo expansion on tumor cell content. Cryopreserved/thawed mononuclear cell (C/T MNC) BM harvests with known tumor cell contamination (n = 7) were assessed for tumor cells pre- and post-expansion using immunocytochemical (ICC) staining. Pre-expansion inoculum samples contained a range of 6-2128 tumor cells per 5.0 x 10(6) nucleated cells. Ex vivo expansion resulted in fold expansions of 6.67 and 11.37 for total cells and CFU-GM, respectively. Tumor cells were undetectable in four of the seven post-expansion samples and were reduced in the remaining three samples. The data demonstrate passive purging of breast cancer cells during ex vivo expansion, with hematopoietic progenitor cell expansion comparable to that of normal BM. Reduction in tumor cell number contained in the small volume culture inoculum combined with passive purging during the ex vivo expansion process suggest a potential 2-4+ log reduction in tumor cell content in the reinfused cell product.


Assuntos
Purging da Medula Óssea , Transplante de Medula Óssea , Neoplasias da Mama/terapia , Células-Tronco Hematopoéticas , Adulto , Medula Óssea , Técnicas de Cultura de Células/métodos , Criopreservação , Feminino , Humanos , Pessoa de Meia-Idade , Transplante Autólogo
20.
Bone Marrow Transplant ; 6(4): 277-80, 1990 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-1982228

RESUMO

Although monoclonal antibodies (MoAbs) to CD15, especially PM-81, react with leukemic blasts from the majority of patients with acute myeloid leukemia (AML), a small subset of patients have cells that are CD15 negative or dim. We determined previously that neuraminidase will increase the reactivity of PM-81 with AML blasts, as well as blasts from many patients with acute lymphoblastic leukemia (ALL). In this report, we describe the laboratory results and clinical course of the first patient with AML whose harvested bone marrow was treated with neuraminidase prior to MoAbs and complement treatment. Neuraminidase increased the percentage of the patient's leukemia cells that reacted with PM-81 from 18% to 90% and more than doubled the percentage of AML blasts that were lysed by PM-81 and complement. The patient suffered no acute toxicity, engrafted rapidly, and was transfusion independent by day 21 post-ABMT. This report demonstrates the probable safety and efficacy of pretreatment of bone marrow with neuraminidase, and increases the number of patients with AML or ALL who may benefit from ABMT using marrow purging with MoAb to CD15.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Transplante de Medula Óssea , Leucemia Mieloide/tratamento farmacológico , Neuraminidase/uso terapêutico , Doença Aguda , Anticorpos Monoclonais/imunologia , Antígenos de Diferenciação/imunologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Proteínas do Sistema Complemento/uso terapêutico , Humanos , Leucemia Mieloide/imunologia , Leucemia Mieloide/cirurgia , Antígenos CD15 , Masculino , Pessoa de Meia-Idade , Transplante Autólogo
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