RESUMEN
Ovarian cancer is leading cause of gynecologic cancer mortality in Canada. To date, overall survival (os) has been the most-used endpoint in oncology trials because of its relevance and objectivity. However, as a result of various factors, including the pattern of sequential salvage therapies, measurement of os and collection of os data are becoming particularly challenging. Phase ii and iii trials have therefore adopted progression-free survival (pfs) as a more convenient surrogate endpoint; however, the clinical significance of pfs remains unclear. This position paper presents discussion topics and findings from a pan-Canadian meeting of experts that set out to evaluate the relevance of pfs as a valid endpoint in ovarian cancer;reach a Canadian consensus on the relevance of pfs in ovarian cancer; andtry to address how pfs translates into clinical benefit in ovarian cancer.Overall, the findings and the group consensus posit that future studies should ensure that trials are designed to evaluate pfs, os, and other clinically relevant endpoints such as disease-related symptoms or quality of life;incorporate interim futility analyses intended to stop accrual early when the experimental regimen is not active;stop trials early to declare superiority only when compelling evidence suggests that a new treatment provides benefit for a pre-specified, clinically relevant endpoint such as os or symptom relief; anddiscourage early release of secondary endpoint results when such a release might increase the frequency of crossover to the experimental intervention.
RESUMEN
BACKGROUND: In the early 1990s, the role of adjuvant tamoxifen in premenopausal women with early breast cancer (EBC) was not established. Similarly, optimum timing relative to adjuvant chemotherapy and efficacy of tamoxifen in hormone receptor-negative tumors were unclear. PATIENTS AND METHODS: Premenopausal women with EBC, any hormone receptor status, after surgery received standard adjuvant chemotherapy [doxorubicin (adriamycin)/cyclophosphamide, cyclophosphamide/methotrexate/5-fluorouracil, or cyclophosphamide/epirubicin/5-fluorouracil] followed by randomization to tamoxifen or placebo for 5 years. Outcomes were overall survival (OS), disease-free survival (DFS), toxicity, and compliance with therapy. RESULTS: Median follow-up for 672 women was 9.7 years. Multivariate analysis showed improved DFS [78.2% versus 71.3% at 5 years; hazard ratio (HR) 0.77; P = 0.056] and a trend for improved OS (86.6% versus 82.1% at 5 years; HR 0.78; P = 0.12). There was no evidence of greater benefit for the receptor-positive subgroup. Compliance with treatment was suboptimal in both arms, with 103 (31%) women on tamoxifen and 70 (21%) on placebo-stopping therapy early because of toxicity, refusal, or other choices. CONCLUSIONS: Adjuvant tamoxifen, given after chemotherapy to premenopausal women with EBC, improved 5-year DFS. Poor compliance may have reduced treatment efficacy.
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Neoplasias de la Mama/tratamiento farmacológico , Premenopausia , Tamoxifeno/administración & dosificación , Academias e Institutos , Adulto , Antineoplásicos/administración & dosificación , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Canadá , Quimioterapia Adyuvante , Progresión de la Enfermedad , Esquema de Medicación , Femenino , Humanos , Escisión del Ganglio Linfático , Mastectomía/métodos , Persona de Mediana Edad , Placebos , Premenopausia/efectos de los fármacos , Análisis de Supervivencia , Factores de TiempoRESUMEN
Malignant wounds, caused by the direct invasion of cancer into the skin, occur in cancer patients with primary skin tumours and as cutaneous metastasis in approximately 10% of patients with metastatic internal malignancies. Malignant wounds have a profound impact on patients, family members and health care providers. The assessment of the patient with malignant wounds can be complex and there is no widely accepted, consistent approach. Valid, descriptive survey research methods were used to develop the Malignant Wound Assessment Tool (MWAT). The authors developed two versions of the MWAT: a brief clinical version (MWAT-C) and a more detailed research version (MWAT-R). Domains include clinical wound features, physical effects and emotional and social impacts of the wound. The two tools underwent content and construct validity testing using a Delphi process. An international panel of professionals with clinical or research expertise related to malignant wounds was formed. Panelists participated in two rounds of review for each tool. Development and face validity testing of the MWAT-C and MWAT-R tools through the Delphi process have resulted in tools ready for clinical application and will support clinical and research activities to improve care for patients with this devastating condition.
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Técnica Delphi , Cuidados Paliativos , Proyectos de Investigación , Neoplasias Cutáneas/patología , Heridas y Lesiones/patología , Humanos , Neoplasias Cutáneas/clasificación , Neoplasias Cutáneas/secundario , Encuestas y Cuestionarios/normas , Heridas y Lesiones/clasificaciónRESUMEN
BACKGROUND: Dose-dense and dose-intensive regimens have improved the outcome of breast cancer in high-risk women with operable disease. PATIENTS AND METHODS: Sixty-three premenopausal women with Stage 2, 3 breast cancer and > or =4 positive axillary nodes were treated in three successive cohorts with 70 mg/m(2) of epirubicin, 500 mg/m(2) of 5-fluorouracil and G-CSF every 14 days for 12 cycles. Cyclophosphamide (C) was given at 700 mg/m(2), 900 mg/m(2), and 1100 mg/m(2) doses. Patients were evaluated for dose-limiting toxicities (DLTs) in the first four cycles, the primary endpoint of the trial. RESULTS: No DLTs were seen at C 700 mg/m(2); at C 900 mg/m(2) two of 16 patients experienced febrile neutropenia and poor performance status; at C 1100 mg/m(2), 1 of 31 patients experienced poor performance status. Over 6 months, febrile neutropenia, grade 4 thrombocytopenia, grade 3 anemia and severe fatigue were observed. Clinical congestive heart failure occurred in three patients over 4 years. CONCLUSION: A dose-intense and dose-dense regimen of cyclophosphamide, epirubicin and 5-fluorouracil was delivered with G-CSF without apparent increase in acute toxicity. Cyclophosphamide could be increased to more than twice the standard dose at the cost of more anemia and fatigue.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Epirrubicina/administración & dosificación , Epirrubicina/efectos adversos , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Humanos , Metástasis Linfática , PremenopausiaRESUMEN
PURPOSE: This pilot phase II study investigated the efficacy and toxicity of docetaxel with doxorubicin and cyclophosphamide (TAC) as first-line chemotherapy for anthracycline-naive patients with metastatic breast cancer. PATIENTS AND METHODS: Fifty-four patients received a total of 359 courses consisting of docetaxel 75 mg/m2 given intravenously (IV) over 1 hour, preceded by IV doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 for a maximum of eight 3-week cycles. RESULTS: After an independent panel review, the overall objective response rate was 77% (complete response, 6%). Overall objective response rates in patients with visceral, bone, and liver involvement were 82%, 82%, and 80%, respectively. Median duration of response was 52 weeks, and median time to progression was 42 weeks. With a median follow-up of 32 months, the median survival had not yet been reached, whereas the 2-year survival was 57%. The main toxicities were hematologic (neutropenia grade 3/4 in 100% of patients and 95% of cycles; febrile neutropenia in 34% of patients and 9% of cycles). Documented grade 3 infection was seen in one patient (2%) in one cycle, and no toxic death was reported. Severe acute or chronic nonhematologic adverse events were infrequent, and docetaxel-specific toxicities (such as fluid retention and nail changes) were mild, with only one patient being discontinued for fluid retention. Congestive heart failure was seen in two patients (4%). CONCLUSION: TAC is an active and manageable regimen that has been chosen as the basis of five randomized phase III trials, including two pivotal studies comparing TAC to fluorouracil plus doxorubicin and cyclophosphamide in the metastatic and adjuvant treatment of breast cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Paclitaxel/análogos & derivados , Taxoides , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/patología , Ciclofosfamida/administración & dosificación , Docetaxel , Doxorrubicina/administración & dosificación , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Paclitaxel/administración & dosificación , Proyectos Piloto , Inducción de Remisión , Análisis de SupervivenciaRESUMEN
Considering the single-agent activity of docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) and doxorubicin in breast cancer and their potential non-cross-resistance, several docetaxel/anthracycline-based combination chemotherapies were developed in phase I and II programs for metastatic breast cancer patients. The rationale for these combinations was also reinforced by the fact that docetaxel showed significant activity in phase III trials in patients previously exposed or having failed anthracycline chemotherapy. In a pivotal randomized phase III study of doxorubicin plus docetaxel versus doxorubicin plus cyclophosphamide as first-line chemotherapy for 429 patients with metastatic breast cancer, doxorubicin/docetaxel emerged as the more effective regimen. Despite a lower-dose intensity of doxorubicin, patients receiving doxorubicin/docetaxel experienced a higher response rate as well as a significantly longer time to progression and time to treatment failure. This difference was seen even in patients with poor-prognosis disease. Febrile neutropenia was more common in doxorubicin/docetaxel-treated patients. However, there were no septic deaths among 213 patients receiving doxorubicin/ docetaxel. Extrahematologic toxicity appeared mild for both regimens and the combination docetaxel/doxorubicin did not increase the cardiac toxicity expected for an anthracycline-containing regimen. Docetaxel plus doxorubicin is the first regimen, involving a newly developed agent, proven superior to a standard anthracycline-containing combination in metastatic breast cancer and its potential is now being investigated in the adjuvant setting.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Taxoides , Antibióticos Antineoplásicos/administración & dosificación , Antineoplásicos Fitogénicos/administración & dosificación , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Ensayos Clínicos como Asunto , Docetaxel , Doxorrubicina/administración & dosificación , Femenino , Humanos , Paclitaxel/administración & dosificación , Paclitaxel/análogos & derivadosRESUMEN
Among the novel chemotherapeutic drugs introduced in the last decade, taxanes have emerged as the most powerful compounds and results available to date suggest that they will be remembered in the future as the breast cancer chemotherapy of the 1990s. The two taxanes (paclitaxel, Taxol, Bristol-Myers Squibb and docetaxel, Taxotere, Rhône-Poulenc Rorer) share some characteristics, but are also significantly different both in preclinical profile and, most importantly, in clinical characteristics. The main clinical differences are related to their different efficacy-toxicity ratio in relation to dose and schedule; the differing integrability of paclitaxel and docetaxel in anthracycline-taxane containing regimens, secondary to major differences in pharmacokinetic interactions between each taxane and the anthracyclines, and; the potential differences in level of synergism between each taxane and herceptin (HeR2Neu antibody/trastuzumab, Genentech/Roche). In clinical practice, the taxanes are now standard therapy in metastatic breast cancer after prior chemotherapy, in particular anthracyclines, has failed. Their role in combination with anthracyclines in first-line therapy of advanced breast cancer is emerging and sheds new light on the potential role of taxanes in the adjuvant setting. However, the impact of taxanes on the natural history of breast cancer is yet to be defined, despite the trend of results suggesting that these agents have the potential for significant improvements in advanced and, most importantly, adjuvant therapy of breast cancer. The results of all completed or ongoing Phase III trials in first-line metastatic and the adjuvant setting will help determine if taxanes will further improve the outcome of breast cancer or not.
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Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Taxoides , Animales , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama/patología , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Femenino , HumanosRESUMEN
OBJECTIVE: To determine the feasibility and the economic impact of tumour EGFR, erbB-2 and cathepsin-D measurements in women with node-negative breast cancer. DESIGN: Consecutive tumour samples received at a regional steroid receptor laboratory from patients with node-negative breast cancer were evaluated with commercially available kits to determine EGFR, erbB-2 and cathepsin-D levels. SETTING: All node-negative patients whose tumours were submitted to the steroid receptor laboratory from November 1992 to March 1994 were included (n = 142). A control group of concurrent node-negative breast cancer patients from the London Regional Cancer Centre (LRCC) database were also evaluated to determine the representativeness of our sample. MAIN OUTCOME MEASURE: To determine the proportion of patients who were positive for the 3 newer prognostic factors relative to their risk of relapse. RESULTS: We found 75 positive values in 69 patients (48.6%). We demonstrated that each factor identified a different high-risk subgroup. Epidermal growth factor receptor (EGFR) positivity (> 10 fmol/mg protein) was found in 16.3% of patients, with 19.9% of patients positive for erbB-2 (> 250 units/mg protein) and 17.3% positive for cathepsin D (> 70 pmol/mg protein). Between 10% and 23.2% more node-negative patients currently seen in a regional cancer centre could be offered systemic adjuvant chemotherapy based on a single positive new factor. CONCLUSIONS: These tumour evaluations are straightforward using material already available in a regional steroid receptor laboratory or on tumour tissue available to pathologists. The economic impact is minimal; the 1995 cost of performing all 3 evaluations is Can$425-616 (US$304-440) per patient treated depending on the number of assays per run. Prospective clinical trials incorporating tumour EGFR, erbB-2 and cathepsin D are feasible and economically viable.
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Neoplasias de la Mama/química , Catepsina D/análisis , Receptores ErbB/análisis , Receptor ErbB-2/análisis , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/terapia , Quimioterapia Adyuvante , Distribución de Chi-Cuadrado , Estudios de Cohortes , Costos y Análisis de Costo , Femenino , Humanos , Técnicas para Inmunoenzimas , Persona de Mediana Edad , Posmenopausia , Guías de Práctica Clínica como Asunto , Premenopausia , Pronóstico , Receptores de Estrógenos/análisis , Receptores de Progesterona/análisis , Recurrencia , Estudios Retrospectivos , Factores de Riesgo , Factores de TiempoRESUMEN
In contrast to previous decades, the 1990s have witnessed an increase of new agents with significant activity in breast cancer, including chemotherapy, hormone therapy, and, more recently, biologic modifiers. All information appears to confirm that such a trend will persist and even accelerate in the coming decades. Unless clear strategies of development for new drugs are strictly followed, it will become difficult to adequately assess the many new agents with potentially important activity against breast cancer, and patient access may become a limiting key factor. The academic, global virtual concept is calling for the definition of a new relationship between the pharmaceutical industry and clinical researchers. The main aspect is related to the creation of partnerships with an academically controlled global strategy of development for promising new agents, in which the quality and independence of processes (adjuvant setting, for example) are critical. The means are based on the globalization of patient access (worldwide network) and the virtuality of the approach (modern means of communication as well as access to subgroups of patients). The Breast Cancer International Research Group is the first academic global virtual cooperative group in breast cancer and is making contributions in the development of new drugs, such as taxanes, new antiestrogens, and new cytokines.
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Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Industria Farmacéutica , Relaciones Interprofesionales , Investigación , Centros Médicos Académicos , Ensayos Clínicos como Asunto , Humanos , Oncología Médica/tendenciasRESUMEN
Given the single-agent activity of docetaxel and doxorubicin in metastatic breast cancer and their potential non-cross-resistance, several phase I/II pilot studies of either docetaxel/doxorubicin (TA) or TA plus cyclophosphamide (TAC) were conducted. The results of these studies show that the main toxicity is related to neutropenia and its consequences, although documented infections are rarely reported. Other toxicities are mild, while docetaxel-specific toxicities (fluid retention, nail changes, etc) are seldom seen. No significant cardiotoxicity, even when patients are exposed to a cumulative doxorubicin dose greater than 360 mg/m2, has been observed. In terms of efficacy, response rates in the range of 70% to 80% were noted in all studies, even for patients with visceral metastases. Preliminary data suggest that the combination of docetaxel with epirubicin is also feasible, with manageable toxicities and significant activity. Several phase III randomized trials using TA or TAC are presently being performed in first-line metastatic breast cancer and, most importantly, in the adjuvant setting to assess whether TA-based combinations will change the natural history of breast cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Taxoides , Neoplasias de la Mama/patología , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Ciclofosfamida/administración & dosificación , Docetaxel , Doxorrubicina/administración & dosificación , Humanos , Metástasis de la Neoplasia , Paclitaxel/administración & dosificación , Paclitaxel/análogos & derivados , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Considering the efficacy of docetaxel (Taxotere, Rhône-Poulenc Rorer, Antony, France) and doxorubicin in advanced breast cancer and their potential noncross-resistance, two pilot studies of docetaxel/doxorubicin (TA)-based combinations were conducted, one being a phase I dose-finding study of TA and the second a phase II study of docetaxel/doxorubicin/cyclophosphamide (TAC). The only significant toxicity, seen in both trials, was neutropenia and its consequences such as febrile neutropenia without significant documented infections. Extrahematologic and particularly docetaxel-specific side effects (fluid retention) were mild. Particularly noteworthy was the absence of significant cardiac toxicity; overall, there was only one case of congestive heart failure (1%). In terms of efficacy, response rates in excess of 70% and 80% were noted in both studies, even for patients with visceral metastases. Several phase III randomized trials using TA or TAC are presently being performed in first-line metastatic breast cancer and most importantly in the adjuvant setting to assess whether TA-based combinations will change the natural history of breast cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Paclitaxel/análogos & derivados , Taxoides , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Ensayos Clínicos como Asunto , Ciclofosfamida/administración & dosificación , Docetaxel , Doxorrubicina/administración & dosificación , Humanos , Metástasis de la Neoplasia , Paclitaxel/administración & dosificaciónRESUMEN
Considering the recommended dose of the docetaxel/doxorubicin combination (75 mg/m2 and 50 mg/m2, respectively), we decided to proceed with a pilot program in untreated metastatic breast cancer aimed at defining a multidrug regimen that could be later randomly compared with a standard doxorubicin-containing polychemotherapy regimen with equidoses of doxorubicin such as the FAC protocol (5-fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2) in first-line metastatic and adjuvant treatment of breast cancer patients. We proceeded with a pilot phase II study of the TAC combination, which consists of docetaxel 75 mg/m2 as a 1-hour infusion preceded by doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2, both given as an intravenous bolus. Three hundred seventy courses were delivered in 54 anthracycline-naive patients, among whom 62% had visceral metastases. Median relative dose intensity was above 98% for all drugs. Grade 4 neutropenia was the main toxicity (70% of cycles) and the incidence of febrile neutropenia and infection was acceptable (6% and 0.8% of cycles, respectively). Acute and chronic extrahematologic toxicities were mild, mostly grade 2, and the docetaxel-specific toxicities (fluid retention, nail changes, etc) were not major clinical problems; no patient was discontinued due to fluid retention. The major response rate was 73% overall and 79% in measurable disease. Time to progression and survival are still under evaluation. The TAC combination is an active and well-tolerated regimen that is the basis of two currently open, pivotal, randomized phase III trials comparing TAC with FAC in the metastatic and adjuvant treatment of breast cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Taxoides , Adulto , Anciano , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Ciclofosfamida/administración & dosificación , Docetaxel , Doxorrubicina/administración & dosificación , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Paclitaxel/administración & dosificación , Paclitaxel/análogos & derivados , Proyectos PilotoRESUMEN
The aim of this study was to examine the cellular distribution of osteopontin (OPN) protein [by immunohistochemical (IHC) analysis] and mRNA [by in situ hybridization (ISH)] in the primary tumors of lymph node negative (LNN) breast cancer patients and to determine whether the level of immunodetectable OPN may be associated with tumor aggressiveness. We examined OPN levels in tumors from 154 patients with LNN breast cancer who were followed for a median of 7 years (range 1.7-16.3 years). IHC staining for OPN was seen in tumor infiltrating macrophages and lymphocytes in 70% of these tumors, and in the carcinoma cells themselves in 26%. ISH was performed to determine cellular distribution of OPN mRNA expression in sections from selected tumors. OPN mRNA was detected in groups of tumor cells, individual tumor cells and tumor infiltrating macrophages and lymphocytes. Matched sections showed that some tumor cells with IHC staining for OPN protein were also positive for OPN mRNA by ISH, in contrast with previous studies which have shown OPN mRNA expression only in tumor infiltrating inflammatory cells. Our results thus indicate that OPN protein can be produced by breast cancer cells in vivo and suggest that it may also be taken up from the environment (i.e., secreted by inflammatory cells or other tumor cells). Tumor cell IHC staining intensity was then assessed using a semiquantitative scoring system. Univariate analysis showed tumor cell OPN positivity above an optimized cutpoint to be significantly associated with decreased disease-free survival (DFS) and overall survival (OS). The results of this pilot study thus suggest that the ability of breast cancer cells to either synthesize OPN or to bind and sequester OPN from the microenvironment may be associated with tumor aggressiveness and poor prognosis.
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Neoplasias de la Mama/química , Expresión Génica , Ganglios Linfáticos/patología , Sialoglicoproteínas/análisis , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Hibridación in Situ , Menopausia , Persona de Mediana Edad , Osteopontina , Pronóstico , ARN Mensajero/análisis , Sialoglicoproteínas/genéticaRESUMEN
OBJECTIVE: To determine the role of axillary node dissection by studying patient and tumour characteristics of invasive breast cancer through the Ontario Breast Screening Program (OBSP). DESIGN: A retrospective evaluation. SETTING: The London, Ont., branch of the OBSP. PATIENTS: Three groups of women seen were studied: 50 women with screen-detected breast cancers, which were palpable and detected by the nurse-examiner, 62 women with occult screen-detected breast cancers and 353 age matched women with invasive breast cancer from the LRCC prospective database, who served as controls. MAIN OUTCOME MEASURE: The proportion of involved axillary nodes within the 3 groups based on patient and tumour characteristics. RESULTS: Twenty-five (22.3%) of the 112 women had screen-detected tumours less than 1 cm in dimension, but only 1 had an involved axillary node. Twelve (19%) of the 62 women with occult screen-detected tumours had involved lymph nodes compared with 17 (34%) of the 50 women with palpable screen-detected cancers (NS). In the control group tumour dimension less than 1 cm versus 1 cm or larger had a marked effect on the probability of axillary node involvement (12.5% v. 40.7%, p = 0.001). In the palpable screen-detected group 3 times as many women with outer quadrant or central lesions had involved nodes as those with inner quadrant lesions (38% v. 12%) and for those with a family history of breast cancer almost twice as many had involved axillary nodes. In occult screen-detected patients there was more nodal involvement in patients aged 60 years or less than in those older than 60 years (35% v. 10%, p = 0.042); only 4 of 41 patients older than 60 years had involved nodes at surgery. A significant difference in nodal involvement was found with respect to high or intermediate grade versus low grade lesions in the occult group (44% v. 12%, p = 0.033). In the control group, tumour grade (intermediate and high [45.3%] v. low [20.0%]) and hormone replacement therapy (HRT) (current or recent use [56.5%] v. no use [34.5%]) were significant findings (p < 0.001 and p = 0.005 respectively). CONCLUSIONS: Women older than 60 years with tumours smaller than 1 cm had a low probability of nodal positivity (0% to 8.7%), but there is insufficient information in this group to give a 95% or better prediction of nodal status at the time of surgery. Studies of minimally invasive techniques such as sentinel node biopsy are needed in this group to minimize surgical morbidity in these women who, as a result of early diagnosis, have an excellent long-term outlook.
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Neoplasias de la Mama/patología , Escisión del Ganglio Linfático/métodos , Tamizaje Masivo/métodos , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Selección de Paciente , Distribución por Edad , Anciano , Anciano de 80 o más Años , Axila , Femenino , Necesidades y Demandas de Servicios de Salud , Humanos , Mamografía , Persona de Mediana Edad , Estadificación de Neoplasias , Ontario , Palpación , Estudios RetrospectivosRESUMEN
OBJECTIVE: To compare the histopathologic features and expression of p53 and c-erb B2 in the tumours detected by mammography only (clinically occult tumours) and the tumours detected by a nurse examiner (clinically palpable tumours). SETTING: London branch of the Ontario Breast Screening Program, which uses both clinical breast examination and mammography as screening methods. INTERVENTIONS: Pathologic review and immunohistochemical staining of all tumours detected between 1990 and 1993. OUTCOME MEASURES: Categorization of tumours by detection method and analysis of tumour size, grade, type, lymph node status and c-erb B2 and p53 expression in each group. RESULTS: From 1990 to 1993, 131 tumours were detected in patients ranging in age from 50 to 85 years (median 63 years). Sixty-seven occult tumours and 64 palpable lesions were detected. The occult tumours were significantly smaller (1.34 cm v. 2.29 cm, p < 0.0001) than the palpable ones and included a higher proportion of special-type lesions and ductal carcinoma in situ (43.3% v. 10.9%, p < 0.0001). Occult invasive carcinomas were of lower grade than palpable carcinomas (68.4% grade 1, 21.1% grade 2, 10.5% grade 3 v. 32.8% grade 1, 36.1% grade 2, 31.1% grade 3, p < 0.0001). Fewer occult lesions showed axillary nodal metastases (19.6% v. 40.6%, p = 0.02). No statistically significant differences were found for p53 or c-erb B2 positivity between the 2 groups. CONCLUSION: Tumours detected by different screening methods in a screening program have different pathologic characteristics.
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Neoplasias de la Mama/diagnóstico , Mamografía , Palpación , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/química , Neoplasias de la Mama/patología , Carcinoma/química , Carcinoma/diagnóstico , Carcinoma/patología , Carcinoma in Situ/química , Carcinoma in Situ/diagnóstico , Carcinoma in Situ/patología , Carcinoma Ductal de Mama/química , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Ductal de Mama/patología , Femenino , Humanos , Inmunohistoquímica , Metástasis Linfática , Persona de Mediana Edad , Proyectos Piloto , Receptor ErbB-2/análisis , Proteína p53 Supresora de Tumor/análisisRESUMEN
OBJECTIVE: To examine the association between expression of osteopontin (OPN), p53, other molecular markers (Ki-67, c-erb B2, and estrogen receptor protein) and tumor progression in a case of synchronous, bilateral, invasive mammary carcinomas of the same histology. DESIGN: Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissue sections. Plasma OPN level was determined by a quantitative antigen capture assay. SETTING: The patient was seen, treated, and followed up for a period of 5 years at the London Regional Cancer Centre, Ontario, Canada. PATIENT: A 60-year-old woman presented with bilateral infiltrating mammary carcinomas of the same histologic type and grade. Bilateral mastectomy and axillary node dissection showed involvement of 3 of 12 right axillary and 0 of 11 left axillary lymph nodes. She later developed a right chest wall recurrence, followed by widespread metastatic disease to the skull, liver, and left femur. RESULTS: The primary tumor of the right breast was OPN- and p53-positive, whereas the tumor of the left breast was negative for both markers. The development of right axillary lymph node metastases, chest wall recurrence, and distant metastases was associated in all instances with an immunohistochemical profile of high level expression of OPN and p53. Plasma assay for OPN at the time of last admission showed a markedly elevated OPN level. CONCLUSIONS: Increased p53 expression was found to be associated with increased tumor aggressiveness. The association of increased OPN expression with increased malignancy in breast cancer is a novel finding and raises the possibility of a role for OPN in tumor progression, as well as the potential for this marker in predicting clinical aggressiveness.
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Biomarcadores de Tumor/análisis , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Neoplasias Primarias Múltiples/patología , Fosfoproteínas/análisis , Sialoglicoproteínas/análisis , Proteína p53 Supresora de Tumor/análisis , Neoplasias de la Mama/química , Carcinoma in Situ/patología , Carcinoma Ductal de Mama/química , Carcinoma Ductal de Mama/secundario , Progresión de la Enfermedad , Resultado Fatal , Femenino , Humanos , Metástasis Linfática , Persona de Mediana Edad , Invasividad Neoplásica , Recurrencia Local de Neoplasia , OsteopontinaRESUMEN
Osteopontin (OPN) is a secreted, integrin-binding phosphoprotein that has been implicated in both normal and pathological processes; qualitative increases in OPN blood levels have been reported in a small number of patients with metastatic tumors of various kinds. We measured plasma OPN levels in 70 women with known metastatic breast carcinoma, 44 patient controls who were on follow-up after completion of adjuvant treatment for early breast cancer, and 35 normal volunteers. The median plasma OPN of patients with metastatic disease was 142 microgram/liter (range, 38-1312 microgram/liter) and was significantly different (P < 0.0001, Mann Whitney U test) from both control groups (medians, 60 and 47 microgram/liter; ranges, 15-117 and 22-122 microgram/liter). Furthermore, we found that increasing plasma OPN is associated with shorter survival (P < 0.001) when patients were grouped in terciles for plasma OPN. This was also demonstrated when using a Cox proportional hazards model. Median plasma OPN levels were significantly increased for three or more sites of involvement (median, 232 microgram/liter; n = 13) versus 1 or 2 metastatic sites (medians, 129 and 130 microgram/liter; n = 29 and 28, respectively). Plasma OPN levels were correlated with other biochemical markers related to the extent of disease, such as serum alkaline phosphatase, aspartate succinate aminotransaminase, and albumin (r = 0.81, 0.62, and -0.56, respectively; all P < 0.001). This study demonstrates a statistically significant elevation in plasma OPN in the majority ( approximately 70%) of a large series of patients with metastatic breast cancer when compared (95th percentile) to healthy women or patients who had completed adjuvant treatment for early-stage breast cancer. Furthermore, this is the first study to demonstrate that higher OPN levels in patients with metastatic breast cancer may be associated with an increased number of involved sites and decreased survival.
Asunto(s)
Biomarcadores de Tumor/sangre , Neoplasias de la Mama/sangre , Neoplasias de la Mama/patología , Sialoglicoproteínas/sangre , Adulto , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/terapia , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Menopausia , Persona de Mediana Edad , Metástasis de la Neoplasia , Osteopontina , Fosfoproteínas/sangre , Posmenopausia , Valores de Referencia , Análisis de Regresión , Factores de TiempoRESUMEN
PURPOSE: Previous phase I and II studies of intraperitoneal recombinant human tumor necrosis factor-alpha (rhTNF-alpha) suggested a high degree of efficacy in reducing or eliminating ascitic fluid. To more accurately determine the efficacy of this agent, the role of paracentesis versus paracentesis plus intraperitoneal rhTNF-alpha was studied in a randomized trial. PATIENTS AND METHODS: Thirty-nine patients with symptomatic ascites with a volume of > 1000 ml from recurrent epithelial ovarian carcinoma or primary peritoneal carcinoma, which was refractory to standard therapy, were randomized either to receive 0.06 mg/m2 rhTNF-alpha (Knoll, Canada) (the dose determined optimal from phase I and II studies) intraperitoneally after drainage of fluid or to receive drainage alone. A maximum of three treatments were given at weekly intervals. Eighteen patients were randomized to receive rhTNF-alpha. RESULTS: None of 18 evaluable rhTNF-alpha patients had either a complete response (CR) (no clinical evidence of ascites and < 400 ml of fluid on ultrasound) or a partial response (PR) (asymptomatic ascites and < or = 1000 ml of fluid ultrasound). There were no CRs or PRs in the 17 evaluable patients who received drainage alone. The intraperitoneal infusion of rhTNF-alpha was generally well tolerated. Moderate to severe toxicity consisted of pain/discomfort in 42.1%, fever/chills in 36.9%, nausea/vomiting in 10.5%, edema in 10.5%, and hypotension in 5.3% of patients receiving rhTNF-alpha. CONCLUSION: rhTNF-alpha, as given in this study, was not effective in preventing recurrence of ascites in this patient population.
Asunto(s)
Ascitis/terapia , Neoplasias Ováricas/complicaciones , Paracentesis , Factor de Necrosis Tumoral alfa/uso terapéutico , Ascitis/etiología , Protocolos Clínicos , Femenino , Humanos , Infusiones Parenterales , Persona de Mediana EdadRESUMEN
Anthracyclines are among the most effective and commonly-prescribed antitumor agents but have dose-limiting cumulative cardiotoxicity. We performed a pharmacoeconomic evaluation of the ability of dexrazoxane to prevent cardiac-related adverse events in patients with Stage IIIB or IV metastatic breast cancer who were treated with a median of 10 cycles of intravenous FAC (5-fluorouracil, doxorubicin and cyclophosphamide) at doses of 500/50/500 mg/m2 respectively. Dexrazoxane was given at 500 mg/m2 commencing at the seventh cycle of treatment. We determined the cost of each cardiac event prevented and the cost of each additional life-year saved by dexrazoxane use. The cost per cardiac event prevented was CDN $5745 and the cost per additional life-year saved was CDN $2856. With the increasing use of anthracyclines in Stages I and II breast cancer, these favorable clinical and economic results may broaden the range of therapeutic possibilities for anthracyclines in adjuvant and metastatic therapy of breast cancer.