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BACKGROUND: Neoadjuvant chemotherapy improves outcome in osteosarcoma. Determination of optimum regimens for survival, toxicity and prognostic factors requires randomised controlled trials to be conducted. PATIENTS AND METHODS: Between 1983 and 2002, the European Osteosarcoma Intergroup recruited 1067 patients with localised extremity osteosarcoma to three randomised controlled trials. Standard treatment in each was doxorubicin 75 mg/m(2) and cisplatin 100 mg/m(2). Comparators were addition of methotrexate (BO02/80831), a multidrug regimen (BO03/80861) and a dose-intense schedule (BO06/80931). Standard survival analysis methods were used to identify prognostic factors, temporal and other influences on outcome. RESULTS: Five- and 10-year survival were 56% (95% confidence interval 53% to 59%) and 52%, respectively (49% to 55%), with no difference between trials or treatment arms. Median follow-up was 9.4 years. Age range was 3-40 years (median 15). Limb salvage was achieved in 69%. Five hundred and thirty-three patients received the standard arm, 79% completing treatment. Good histological response to preoperative chemotherapy, distal tumour location (all sites other than proximal humerus/femur) and female gender were associated with improved survival. CONCLUSIONS: Localised osteosarcoma will be cured in 50% of patients with cisplatin and doxorubicin. Large randomised trials can be conducted in this rare cancer. Failure to improve survival over 20 years argues for concerted collaborative international efforts to identify and rapidly test new treatments.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Huesos del Brazo/patología , Neoplasias Óseas/tratamiento farmacológico , Huesos de la Pierna/patología , Osteosarcoma/tratamiento farmacológico , Sobrevida , Adolescente , Adulto , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Niño , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Análisis Multivariante , Clasificación del Tumor , Recurrencia Local de Neoplasia , Osteosarcoma/mortalidad , Osteosarcoma/patología , Modelos de Riesgos Proporcionales , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
AIM: The majority of clinicians, radiologists and pathologists have limited experience with soft tissue sarcomas. In 2004, national guidelines were established in The Netherlands to improve the quality of diagnosis and treatment of these rare tumours. This study evaluates the compliance with the guidelines over time. PATIENTS: Population-based series of 119 operated patients with a soft tissue sarcoma (STS) diagnosed in 1998-1999 (79 before implementation of new guidelines) and in 2006 (40 after implementation). METHODS: Coded information regarding patient and tumour characteristics as well as (the results of) pathology review was collected from the medical patient file by two experienced data-managers. RESULTS: Diagnostic imaging of the tumour was performed according to the guidelines in 75-100% depending on the site of the tumour (abdominal versus non-abdominal) as well as the time of diagnosis. Adherence to the guidelines with respect to invasive diagnostic procedures in patients with non-abdominal STS improved over time. A pre-operative histological diagnosis was obtained in 42% of the patients in 1998-1999 and in 72% of the patients in 2006 (p<0.001). The guidelines for reporting on pathology were increasingly adhered to. In 2006, (nearly) all pathology reports mentioned tumour size, morphology, tumour grade, resection margins and radicality. This represents a major improvement compared to the pathology reports in 1998-1999, where these aspects were not mentioned in 14-40% of the cases. The proportion of prospective pathology reviews by (a member of) the expert panel increased from 60% in 1998-1999 to 90% in 2006 (p=0.001). DISCUSSION: The compliance with the guidelines has been optimised by the increased attention to this group of patients. Most important factors have been the reporting of the results of the first evaluation and (discussions about) the centralisation of treatment. Further improvements could be reached by the prospective web based registry monitoring logistic aspects as well as parameters useful for the evaluation of the quality of care.
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Guías de Práctica Clínica como Asunto , Sarcoma/diagnóstico , Sarcoma/terapia , Neoplasias de los Tejidos Blandos/diagnóstico , Neoplasias de los Tejidos Blandos/terapia , Anciano , Anciano de 80 o más Años , Femenino , Adhesión a Directriz , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , Sarcoma/patología , Neoplasias de los Tejidos Blandos/patología , Resultado del TratamientoRESUMEN
Neutropenia following high-dose chemotherapy leads to a high incidence of infectious complications, of which central venous catheter-related infections predominate. Catheter-related infections and associated risk factors in 392 patients participating in a randomized adjuvant breast cancer trial and assigned to receive high-dose chemotherapy and peripheral stem-cell reinfusion were evaluated. Median catheter dwell time was 25 days (range 1-141). Catheter-related infections were seen in 28.3% of patients (11 infections per 1000 catheter-days). Coagulase-negative staphylococci were found in 104 of 186 positive blood cultures (56%). No systemic fungal infections occurred. Cox regression analysis showed that duration of neutropenia >10 days (P=0.04), using the catheter for both stem-cell apheresis and high-dose chemotherapy (P= <0.01), and use of total parenteral nutrition (TPN, P=0.04) were predictive for catheter-related infections. In conclusion, a high incidence of catheter-related infections after high-dose chemotherapy was seen related to duration of neutropenia, use of the catheter for both stem-cell apheresis and high-dose chemotherapy, and use of TPN. Selective use and choice of catheters could lead to a substantial reduction of catheter-related infectious complications.
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Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Cateterismo/efectos adversos , Catéteres de Permanencia/efectos adversos , Terapia Combinada/efectos adversos , Infecciones/etiología , Nutrición Parenteral Total/efectos adversos , Trasplante de Células Madre de Sangre Periférica/efectos adversos , Antineoplásicos/administración & dosificación , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/cirugía , Femenino , Humanos , Infecciones/epidemiología , Países Bajos , Neutropenia/etiología , Valor Predictivo de las Pruebas , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de TiempoRESUMEN
Benefit from chemotherapy treatment in breast cancer patients is determined by the molecular make-up of the tumour. In a retrospective analysis, we determined the molecular subtypes of breast cancer originally defined by expression microarrays by immunohistochemistry in tumours of patients who took part in a randomised study of adjuvant high-dose chemotherapy in breast cancer. In addition, the topoisomerase II alpha (TOP2A) amplification status was determined by fluorescence in situ hybridisation and chromogenic in situ hybridisation. 411 of the 753 tumours (55%) were classified as luminal-like, 137 (18%) as basal-like and 205 (27%) as human epithelial receptor type 2 (HER2) amplified. The basal-like tumours were defined as having no expression of ER and HER2; 98 of them did express epidermal growth factor receptor and/or cytokeratin 5/6. The luminal-like tumours had a significantly better recurrence free and overall survival than the other two groups. From the 194 HER2-positive tumours, 47 (24%) were shown to harbour an amplification of TOP2A. Patients with an HER2-amplified tumour randomised to the high-dose therapy arm did worse than those in the conventional treatment arm, possibly caused by the lower cumulative anthracycline dose in the high-dose arm. The tumours with a TOP2A amplification contributed hardly to this difference, suggesting that TOP2A amplification is not the cause of the steep dose-response curve for anthracyclines in breast cancer. Possibly, the difference of the cumulative dose of only 25% between the treatment arms was insufficient to yield a survival difference.
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Antígenos de Neoplasias/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/terapia , ADN-Topoisomerasas de Tipo II/genética , Proteínas de Unión al ADN/genética , Amplificación de Genes , Recurrencia Local de Neoplasia/enzimología , Recurrencia Local de Neoplasia/terapia , Adulto , Antraciclinas/administración & dosificación , Biomarcadores de Tumor/genética , Neoplasias de la Mama/clasificación , Neoplasias de la Mama/enzimología , Carboplatino/administración & dosificación , Quimioterapia Adyuvante , Ciclofosfamida/administración & dosificación , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Hibridación in Situ , Metástasis Linfática , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Países Bajos , Trasplante de Células Madre de Sangre Periférica , Proteínas de Unión a Poli-ADP-Ribosa , Pronóstico , Receptor ErbB-2/genética , Tiotepa/administración & dosificación , Resultado del TratamientoRESUMEN
BACKGROUND: Continuous ligand depletion of endocrine responsive tumours may enhance resistance to therapy. Intermittent treatment with tamoxifen (T) was considered to mimic (incomplete) ligand depletion and reintroduction. Furthermore it was postulated that alternating tamoxifen with a non-cross resistant endocrine modality could (further) postpone hormone resistance. PATIENTS AND METHODS: Postmenopausal patients with advanced breast cancer who did not progress after 4 months of first line T therapy were randomised to continue T (40 mg daily) or to 2 monthly intermittent T or intermittent/alternated T and medroxyprogesterone acetate (MPA, 300 mg daily). At progression during break or during MPA, T should be reintroduced. Endpoints of the study were progression free survival (PFS), time to resistance to tamoxifen and overall survival (OS). RESULTS: Of 593 registered patients, 276 were randomised. After 8 years follow-up the median PFS for continuous T, intermittent T and intermittent/alternated T and MPA was 11.0 (8.1-15.2), 8.0 (6.2-12.4) and 10.8 (7.1-16.7) months, respectively (NS). Resistance to tamoxifen was established only in 84%, 70% and 55% of patients in the three treatment arms, respectively. The median times from randomisation to resistance to tamoxifen were 12.5 (9.1-21.1), 13.2 (8.8-19.8) and 24.0 (16.9-60.9) months, respectively (p<0.001), without translation in differences in survival times. CONCLUSION: Intermittent T or intermittent/alternated T and MPA had no impact on PFS or OS as compared with classical continuous T in patients with advanced breast cancer. Intermittent/alternated T and MPA resulted in prolonged time to resistance to T, but this might partly be due to bias by omittance of the proof of tamoxifen resistance in a high proportion of the patients in this treatment arm.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos , Femenino , Humanos , Acetato de Medroxiprogesterona/administración & dosificación , Acetato de Medroxiprogesterona/efectos adversos , Persona de Mediana Edad , Tamoxifeno/administración & dosificación , Tamoxifeno/efectos adversosRESUMEN
A patient previously treated for bilateral breast cancer with mastectomy, radiation therapy and in remission on hormonal therapy for more than five years presented with abdominal symptoms from breast cancer relapse. She developed inappropriate polyuria and hypernatraemia, which responded to desmopressin. In combination with the absence of a high signal from the posterior lobe of the pituitary on MRI , these data indicated the presence of partial central diabetes insipidus. The anterior pituitary showed partial failure (low follicle-stimulating hormone, luteinising hormone and insulin-like growth factor-1 levels). Furthermore, primary adrenal insufficiency had developed, ascribed to bilateral tumour invasion of the adrenals. This rare combination of endocrinological failures in a patient with metastatic breast cancer is discussed.
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Neoplasias de las Glándulas Suprarrenales/complicaciones , Insuficiencia Suprarrenal/etiología , Neoplasias de la Mama/complicaciones , Carcinoma Ductal de Mama/complicaciones , Diabetes Insípida/etiología , Neoplasias de las Glándulas Suprarrenales/secundario , Glándulas Suprarrenales/diagnóstico por imagen , Glándulas Suprarrenales/patología , Insuficiencia Suprarrenal/diagnóstico , Biopsia , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/secundario , Diabetes Insípida/diagnóstico , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética , Persona de Mediana Edad , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: High-dose chemotherapy in the adjuvant treatment of breast cancer has been abandoned by many. PATIENTS AND METHODS: 885 patients with stage III primary breast cancer and four or more axillary lymph node metastases were randomised to receive either five courses of FEC (fluorouracil, epirubicin and cyclophosphamide) followed by radiation therapy and tamoxifen, or the same treatment but with high-dose alkylating chemotherapy (cyclophosphamide, thiotepa and carboplatin) replacing the fifth course of FEC. Of these patients, 621 had HER2/neu-negative disease, as determined by immunohistochemistry and chromogenic in situ hybridisation. RESULTS: At a median follow-up of 84 months, a trend for a better relapse-free survival was observed in the high-dose arm: (hazard ratio (HR) 0.84, P = 0.076, two-sided). The 621 patients with HER2/neu-negative disease benefited from high-dose therapy, while patients with HER2/neu-positive disease did not (test for interaction, P = 0.006). There was a marked relapse-free survival benefit for patients with HER2/neu-negative disease (71.5% versus 59.1%, 5 years after randomisation; HR 0.68, P = 0.002) and also a survival benefit (78.2% versus 71.0% at 5 years; HR 0.72, P = 0.02). CONCLUSIONS: The findings from this subgroup analysis provide additional evidence that HER2/neu-positive breast cancer is relatively resistant to alkylating agents. For HER2/neu-negative tumours, however, high-dose chemotherapy should remain the subject of clinical studies.
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Antineoplásicos Alquilantes/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Genes erbB-2 , Antineoplásicos Alquilantes/efectos adversos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inmunohistoquímica , Neoplasias Primarias Secundarias/inducido químicamente , Estudios Prospectivos , Análisis de SupervivenciaRESUMEN
PURPOSE: Hereditary non-polyposis colorectal cancer (HNPCC, Lynch syndrome) is characterized by the development of cancer of the colorectum, endometrium and other cancers. Cancer of the ovaries (OC) has frequently been reported in HNPCC. Colorectal cancer associated with HNPCC has a better survival chance compared to sporadic colorectal cancer. It is yet unknown whether patients with OC from HNPCC families (OC-HNPCC) also have a better survival. Therefore, the aim of the study was to compare the survival between patients with OC-HNPCC and a control group. METHODS: A total of 26 patients with OC were identified from the Dutch HNPCC Registry. A control group (52 cases) matched for age, stage and year of diagnosis was derived from the population-based Eindhoven Cancer Registry. Data on treatment were collected for all patients. Kaplan-Meier analysis was used to calculate the crude survival. RESULTS: The mean age at diagnosis of OC-HNPCC was significantly lower than the age of sporadic OC (49.5 vs 60.9 years). Compared to sporadic OC, OC-HNPCC was diagnosed at an earlier stage. The survival rate was not significantly different between patients with OC-HNPCC and the controls with sporadic OC. The cumulative 5-year-survival rates were 64.2 and 58.1% respectively. CONCLUSION: On the basis of our findings, we recommend to treat OC-HNPCC similar to sporadic OC.
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Neoplasias Colorrectales Hereditarias sin Poliposis/complicaciones , Neoplasias Colorrectales Hereditarias sin Poliposis/mortalidad , Neoplasias Ováricas/genética , Neoplasias Ováricas/mortalidad , Adulto , Anciano , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Proteína 2 Homóloga a MutS/genética , Mutación , Análisis de SupervivenciaRESUMEN
There are limited data that define the role of chemotherapy in the treatment of high-grade spindle cell sarcomas of bone, other than osteosarcoma or malignant fibrous histiocytoma (MFH-B). This prospective study evaluates the effect of doxorubicin and cisplatin on these tumours. Thirty-seven patients, age 65 years, with spindle cell sarcoma of bone, except osteosarcoma or MFH-B, were included. Chemotherapy consisted of doxorubicin and cisplatin every 3 weeks for six cycles. Resection was performed after three cycles. In 15 patients with metastases, response assessment showed three complete responses (CR), four stable disease (SD), five progression; three were not evaluable. Median time to progression was 30 months (95% Confidence Interval (CI), 8-51 months) for the operable non-metastatic patients; median survival 41 months (95% CI, 16-82 months). Median time to progression in the metastatic group was 10 months (95% CI, 0-18 months) and median survival was 14 months (95% CI, 4-45 months). This study suggests a limited role for doxorubicin and cisplatin in metastatic high-grade spindle cell sarcoma of bone, other than osteosarcoma or MFH-B cases.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Enfermedades Raras/tratamiento farmacológico , Sarcoma/tratamiento farmacológico , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Óseas/patología , Neoplasias Óseas/cirugía , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Terapia Combinada , Progresión de la Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Femenino , Humanos , Infusiones Intravenosas , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Enfermedades Raras/patología , Enfermedades Raras/cirugía , Sarcoma/patología , Sarcoma/cirugía , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
The aim of our study was to determine whether or not the tyrosine kinase receptor, HER2 (also known as ErbB2/Her2/neu), is overexpressed in human osteosarcomas (OS). We studied 15 biopsy and 18 resection specimens at the mRNA and protein levels. HER2 status in the OS specimens was assessed by immunohistochemistry (IHC) and quantitative Real-Time Polymerase chain reaction (PCR). In moderately immunopositive cases fluorescent in situ hybridisation (FISH) analysis was used in order to identify any possible gene amplification. 27 samples were evaluable for IHC and only 1 case showed a moderately positive membrane staining. The remaining samples showed no staining or focal cytoplasmic staining (2 samples). In the moderately positive case, FISH analysis showed no HER-2 gene amplification. There was also no overexpression of HER2 mRNA suggesting this sample was a false-positive immunostain. HER2 mRNA expression was present in all samples at a similar level to that in the breast cancer cell line, MCF7, which does not overexpress HER2 and was used as a negative control. In conclusion, this study shows that HER2 mRNA or membranous HER2 protein overexpression is absent in human OS. We noted various inconsistencies in previous published studies, with regard to methodology and the interpretation of the results based on poor methodology. We therefore conclude that the positive data with regard to HER2 overexpression reported in these previous studies is not reliable. Our results suggest that the monoclonal antibody trastuzumab (Herceptin(R)), directed against the HER2-receptor, is not likely to be an effective therapeutic agent in OS.
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Neoplasias Óseas/metabolismo , Genes erbB-2 , Osteosarcoma/metabolismo , Receptor ErbB-2/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Óseas/genética , Niño , Amplificación de Genes , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Osteosarcoma/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodosRESUMEN
BACKGROUND: The impact of aromatase inhibitors (AIs) on non-cancer-related outcomes, which are known to be affected by oestrogens, has become increasingly important in postmenopausal women with hormone-dependent breast cancer. So far, data related to the effect of AIs on lipid profile in postmenopausal women is scarce. This study, as a companion substudy of an EORTC phase II trial (10951), evaluated the impact of exemestane, a steroidal aromatase inactivator, on the lipid profile of postmenopausal metastatic breast cancer (MBC) patients. PATIENTS AND METHODS: The EORTC trial 10951 randomised 122 postmenopausal breast cancer patients to exemestane (E) 25 mg (n = 62) or tamoxifen (T) 20 mg (n = 60) once daily as a first-line treatment in the metastatic setting. Exemestane showed promising results in all the primary efficacy end points of the trial (response rate, clinical benefit rate and response duration), and it was well tolerated with low incidence of serious toxicity. As a secondary end point of this phase II trial, serum triglycerides (TRG), high-density lipoprotein cholesterol (HDL), total cholesterol (TC), lipoprotein a (Lip a), and apolipoproteins (Apo) B and A1 were measured at baseline and while on therapy (at 8, 24 and 48 weeks) to assess the impact of exemestane and tamoxifen on serum lipid profiles. Of the 122 randomised patients, those who had baseline and at least one other lipid assessment are included in the present analysis. The patients who received concomitant drugs that could affect lipid profile are included only if these drugs were administered throughout the study treatment. Increase or decrease in lipid parameters within 20% of baseline were considered as non-significant and thus unchanged. RESULTS: Seventy-two patients (36 in both arms) were included in the statistical analysis. The majority of patients had abnormal TC and normal TRG, HDL, Apo A1, Apo B and Lip a levels at baseline. Neither exemestane nor tamoxifen had adverse effects on TC, HDL, Apo A1, Apo B or Lip a levels at 8, 24 and 48 weeks of treatment. Exemestane and tamoxifen had opposite effects on TRG levels: exemestane lowered while tamoxifen increased TRG levels over time. There were too few patients with normal baseline TC and abnormal TRG, HDL, Apo A1, Apo B and Lip a levels to allow for assessment of E's impact on these subsets. The atherogenic risk determined by Apo A1:Apo B and TC:HDL ratios remained unchanged throughout the treatment period in both the E and T arms. CONCLUSIONS: Overall, exemestane has no detrimental effect on cholesterol levels and the atherogenic indices, which are well-known risk factors for coronary artery disease. In addition, it has a beneficial effect on TRG levels. These data, coupled with E's excellent efficacy and tolerability, support further exploration of its potential in the metastatic, adjuvant and chemopreventive setting.
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Androstadienos/farmacología , Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Colesterol/sangre , Inhibidores Enzimáticos/farmacología , Lípidos/sangre , Tamoxifeno/farmacología , Adulto , Anciano , Anciano de 80 o más Años , Androstadienos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Inhibidores de la Aromatasa , Arteriosclerosis/etiología , Arteriosclerosis/prevención & control , Neoplasias de la Mama/patología , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Posmenopausia , Factores de Riesgo , Tamoxifeno/uso terapéuticoRESUMEN
BACKGROUND: Women with hormone-responsive metastatic breast cancer (MBC) may respond to or have stable disease with a number of hormone therapies. We explored the efficacy and safety of the steroidal aromatase inactivator exemestane as first-line hormonal therapy in MBC in postmenopausal women. PATIENTS AND METHODS: Patients with measurable disease were eligible if they had received no prior hormone therapy for metastatic disease and had hormone receptor positive disease or hormone receptor unknown disease with a long disease-free interval from adjuvant therapy. They were randomized to tamoxifen 20 mg/day or exemestane 25 mg/day in this open-label study. RESULTS: Blinded independently reviewed response rates for exemestane and tamoxifen were 41% and 17%, respectively. Fifty-seven per cent of exemestane- and 42% of tamoxifen-treated patients experienced clinical benefit, defined as complete or partial response, or disease stabilization lasting at least 6 months. There was a low incidence of severe flushing, sweating, nausea and edema in women who received exemestane. One exemestane-treated patient had a pulmonary embolism with grade 4 dyspnea. CONCLUSIONS: Exemestane is well tolerated and active in the first-line treatment of hormone-responsive MBC. An ongoing EORTC phase III trial is comparing the efficacy, measuring time-to-disease progression, of exemestane and tamoxifen.
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Androstadienos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/secundario , Tamoxifeno/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Androstadienos/efectos adversos , Antineoplásicos Hormonales/efectos adversos , Femenino , Humanos , Persona de Mediana Edad , Posmenopausia , Tamoxifeno/efectos adversos , Resultado del TratamientoRESUMEN
The optimal duration of cytostatic treatment for metastatic breast cancer is still a matter of debate. Possible gain in the duration of remission has to be weighed against the side-effects of treatment. Our aim was to define the optimal duration of cyclophosphamide, methotrexate, 5-fluorouracil (CMF) treatment by studying the time to treatment failure, overall survival and using a Q-TWiST analysis. The treating physician's opinion was asked. The European Organization for Research and Treatment of Cancer (EORTC) Breast Cancer Group conducted a randomised trial in 204 non-progressing metastatic breast cancer patients after induction chemotherapy (CMF) to stop or continue treatment. Progression-free (PFS) and overall survival (OS) were studied. To gain more insight into the burden of treatment-related side-effects, Q-TWiST was analysed. In addition, we asked for oncologists' preferences as patients are likely to be influenced by their physicians' opinion. Continuation of CMF had a significantly longer time to treatment failure (TTF) 5.2 versus 3.5 months (P=0.011). There was no overall survival (OS) difference 14.0 versus 14.4 months (P=0.77). Mean quality-adjusted survival time was equal to 8.4 months for no further treatment and decreased to 7.9 months for continuation of CMF (95% Confidence Interval (CI) of difference equals 0.5+/-2.5 months). Almost half of the oncologists said they would favour continuous treatment for a 3-month gain in time to progression-a difference which was not found in this study. Based on these data, an interruption of chemotherapy (CMF), if this is the wish of the patient, is justified.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Ciclofosfamida/administración & dosificación , Toma de Decisiones , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Humanos , Metotrexato/administración & dosificación , Persona de Mediana Edad , Pautas de la Práctica en Medicina , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
BACKGROUND: Combination chemotherapy yields better response rates which do not always lead to a survival advantage. The aim of this study was to investigate whether the reported differences in the efficacy and toxicity of monotherapy with doxorubicin (DOX) versus combination therapy with cisplatin (CDDP) in endometrial adenocarcinoma lead to significant advantage in favour of the combination. PATIENTS AND METHODS: Eligible patients had histologically-proven advanced and/or recurrent endometrial adenocarcinoma and were chemo-naïve. Treatment consisted of either DOX 60 mg/m(2) alone or CDDP 50 mg/m2 added to DOX 60 mg/m2, every 4 weeks. RESULTS: A total of 177 patients were entered and median follow-up is 7.1 years. The combination DOX-CDDP was more toxic than DOX alone. Haematological toxicity consisted mainly of white blood cell toxicity grade 3 and 4 (55% versus 30%). Non-haematological toxicity consisted mainly of grade 3 and 4 alopecia (72% versus 65%) and nausea/vomiting (36 % versus 12%). The combination DOX-CDDP provided a significantly higher response rate than single agent DOX (P <0.001). Thirty-nine patients (43%) responded on DOX-CDDP [13 complete responses (CRs) and 26 partial responses (PRs)], versus 15 patients (17%) on DOX alone (8 CR and 7 PR). The median overall survival (OS) was 9 months in the DOX-CDDP arm versus 7 months in the DOX alone arm (Wilcoxon P = 0.0654). Regression analysis showed that WHO performance status was statistically significant as a prognostic factor for survival, and stratifying for this factor, treatment effect reaches significance (hazard ratio = 1.46, 95% confidence interval 1.05-2.03, P = 0.024). CONCLUSIONS: In comparison to single agent DOX, the combination of DOX-CDDP results in higher but acceptable toxicity. The response rate produced is significantly higher, and a modest survival benefit is achieved with this combination regimen, especially in patients with a good performance status.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antibióticos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Doxorrubicina/uso terapéutico , Neoplasias Endometriales/tratamiento farmacológico , Adenocarcinoma/patología , Adulto , Anciano , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/administración & dosificación , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Neoplasias Endometriales/patología , Femenino , Estado de Salud , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Pronóstico , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
The aim of this study was to investigate the efficacy and toxicity of carboplatin given as monotherapy in endometrial adenocarcinoma. Cisplatin is one of the most active drugs in gynaecological cancer types, but at the cost of an associated high toxicity. In this high-risk population of endometrial cancer patients, it is necessary to have chemotherapy regimens with a low toxicity. Patients eligible for this study were those with histologically-confirmed endometrial adenocarcinoma with evidence of recurrent and/or metastatic disease. Carboplatin was administered every 4 weeks as a first- (dose: 400 mg/m(2)) or second- (dose: 300 mg/m(2)) line chemotherapy. Of the 64 patients who entered the trial, 60 were eligible, 53 patients were evaluable for toxicity and 47 for efficacy. A total of 169 cycles of carboplatin was given with a median of 2 cycles per patient (range 1-11 cycles) to a median cumulative dose of 798 mg/m(2) (range 290-3879 mg/m(2)). No grade 4 toxicity or toxic deaths occurred. White Blood Cell (WBC) toxicity grade 3 was noted five times, mainly in the radiotherapy pre-treated patients. Grade 3 non-haematological toxicity consisted mainly of nausea and vomiting (21%). There was a total of eight responses (3 Complete Responses (CR) and 5 Partial Responses (PR) with an overall response rate (ORR) of 13% (95% Confidence Interval (CI) 6-25). No responses occurred in patients treated with prior chemotherapy. In evaluable patients, the ORR in all patients (n=47) and in those receiving first-line chemotherapy (n=33) were, 17% (95% CI 8-31) and 24% (95% CI 11-42), respectively. After a median follow-up of 379 days, the median duration of response was 488 days (range 141-5303 days) with two very long responses in patients with a CR. Carboplatin has a low toxicity and is active in chemotherapy-naive advanced endometrial carcinoma patients. These results lead us to propose its use in association in first-line chemotherapy in recurrent or advanced endometrial carcinoma patients. The choice of the initial dose can be determined according to whether the patients have received prior radiotherapy treatment.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Carboplatino/uso terapéutico , Neoplasias Endometriales/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Carboplatino/efectos adversos , Diarrea/inducido químicamente , Femenino , Humanos , Infusiones Intravenosas , Persona de Mediana Edad , Náusea/inducido químicamente , Trombocitopenia/inducido químicamente , Vómitos/inducido químicamenteRESUMEN
BACKGROUND: We performed a phase I study of polyethylene glycol (pegylated, Stealth) liposomal doxorubicin (Caelyx, Doxil) using a prolonged (6-week) dose interval to reduce the incidence of skin toxicity that was dose-limiting at more conventional dose intervals, and which appeared to be schedule dependent. PATIENTS AND METHODS: Eligible for the study were metastatic breast cancer patients who had received a maximum of one prior therapy for metastatic disease. The defined dose levels were 60, 70, 80 and 90 mg/m2. RESULTS: Twenty patients were assessed at starting doses of 60 mg/m2 (n = 9) or 70 mg/m2 (n = 11). The dose-limiting toxicity was mucositis. Severe skin toxicity was not observed at the 60 mg/m2 dose level, and occurred in only one patient treated at 70 mg/m2. Significant neutropenia, alopecia, and nausea and vomiting were rare events. No clinical cardiac events occurred, despite a median cumulative doxorubicin dose of 323 mg/m2 (range 5-630 mg/m2). Partial responses were documented in five patients. Pharmacokinetics were assessed in 15 patients, and confirmed the long terminal half-life of the agent (median 77 h) demonstrated in earlier studies. CONCLUSIONS: The recommended dose of Caelyx/Doxil using this schedule is 60 mg/m2 every 6 weeks. This is a safe and effective regimen that permits prolonged administration of anthracycline to patients with metastatic breast cancer.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacocinética , Adulto , Anciano , Biopsia con Aguja , Neoplasias de la Mama/mortalidad , Relación Dosis-Respuesta a Droga , Doxorrubicina/efectos adversos , Esquema de Medicación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Estudios de Seguimiento , Humanos , Liposomas , Dosis Máxima Tolerada , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Países Bajos , Medición de Riesgo , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
The aim of this study was to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and potential activity of combined gemcitabine and continuous infusion 5-fluorouracil (5-FU) in metastatic breast cancer (MBC) patients that are resistant to anthracyclines or have been pretreated with both anthracyclines and taxanes. 15 patients with MBC were studied at three European Organization for Research and Treatment of Cancer centres. 13 patients had received both anthracylines and taxanes. Gemcitabine was given intravenously (i.v.) on days 1 and 8, and 5-FU as a continuous i.v. infusion on days 1 through to 14, both drugs given in a 21-day schedule at four different dose levels. Both were given at doses commonly used for the single agents for the last dose level (dose level 4). One of 6 patients at level 4 (gemcitabine 1200 mg/m2 and 5-FU 250 mg/m2/day) had a DLT, a grade 3 stomatitis and skin toxicity. One DLT, a grade 3 transaminase rise and thrombosis, occurred in a patient at level 2 (gemcitabine 1000 mg/m2 and 5-FU 200 mg/m2/day). Thus, the MTD was not reached. One partial response and four disease stabilisations were observed. Only 1 patient withdrew from the treatment due to toxicity. The MTD was not reached in the phase I study. The combination of gemcitabine and 5-FU is well tolerated at doses up to 1200 mg/m2 given on days 1 and 8 and 250 mg/m2/day given on days 1 through to 14, respectively, every 21 days. The clinical benefit rate (responses plus no change of at least 6 months) was 33% with one partial response, suggesting that MBC patients with prior anthracycline and taxane therapy may derive significant benefit from this combination with minimal toxicity.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Taxoides , Adulto , Anciano , Antibióticos Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Hidrocarburos Aromáticos con Puentes/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Resistencia a Antineoplásicos , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Infusiones Intravenosas , Persona de Mediana Edad , Metástasis de la Neoplasia , GemcitabinaRESUMEN
OBJECTIVE: To investigate the clinical activity and toxicity of a combination chemotherapy consisting of cyclophosphamide (C), adriamycin (A) and cisplatin (P) for patients with primary adenocarcinoma of the Fallopian tube having FIGO stage III-IV disease. METHODS: The CAP-regimen consisted of cyclophosphamide 600 mg/m2, adriamycin 45 mg/m2, and cisplatin 50 mg/m2 administered intravenously on day one every 28 days. RESULTS: Twenty-four eligible patients with histologically-confirmed Fallopian tube adenocarcinoma were entered in the trial. Fourteen patients had FIGO stage III, and ten had stage IV disease. The median number of CAP cycles was six. Ten patients had a complete and six had a partial response (response rate: 67%, 95% confidence limits: 45-84%). WHO grade III-IV side-effects included haematological toxicity, nausea/vomiting and alopecia. Furthermore, mild signs of cisplatin-related peripheral neurotoxicity were observed. At a median follow-up of 40 months, nine patients were alive and 15 had died due to malignant disease. The median time to progression was 13 months for all patients. The median overall survival was 24 months and the 1-, 3- and 5-year survival and their 95% confidence limits were 73% (54-92%), 25% (4-46%) and 19% (0-38%), respectively. CONCLUSION: The present data confirm the therapeutic activity of the CAP-regimen in primary Fallopian tube adenocarcinoma. The response rate is moderate and the toxicity profile is acceptable.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de las Trompas Uterinas/tratamiento farmacológico , Adenocarcinoma/patología , Anciano , Antibióticos Antineoplásicos/administración & dosificación , Antineoplásicos Alquilantes/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/administración & dosificación , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Esquema de Medicación , Europa (Continente) , Neoplasias de las Trompas Uterinas/patología , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Studies have shown that utilities for a particular treatment, elicited by means of a hypothetical treatment scenario, may remain stable within the same patients when examined before, during, and after experiencing that treatment (within-group stability). However, other studies have found that utilities for a particular health state may differ between patient groups who are and who are not experiencing the particular health state (between-group differences). OBJECTIVE: The authors evaluated this apparent contradiction in the case of adjuvant chemotherapy for breast cancer. A related purpose was to examine whether a chemotherapy scenario adequately reflects the patients' own experiences with chemotherapy. METHOD: Forty-three patients with early-stage breast cancer evaluated their actually experienced health state and a chemotherapy scenario before, during, and after undergoing adjuvant chemotherapy (chemotherapy group). A control group of 51 patients for whom chemotherapy was not part of the treatment plan was interviewed at similar points in time. Utilities were elicited by means of a visual analog scale (VAS), a chained time trade-off (TTO), and a chained standard gamble (SG). RESULTS: The utilities for the chemotherapy scenario remained relatively stable over time in the 2 patient groups. Furthermore, the chemotherapy scenario was evaluated more positively by patients in the chemotherapy group than by control patients (e.g., utilities before chemotherapy: VAS 0.69 vs. 0.50, TTO 0.88 vs. 0.50, SG 0.92 vs. 0.58, all Ps < 0.01). Finally, patients in the chemotherapy group evaluated their actually experienced health states during chemotherapy higher than the chemotherapy scenario that was assessed at the same time (VAS 0.79 vs. 0.69, TTO 0.93 vs. 0.87, SG 0.97 vs. 0.96, all Ps < 0.05). CONCLUSIONS: Both within-group stability and between-group differences were found. A possible explanation for within-group stability may be that the chemotherapy scenario did not fully correspond to the patients' actual experiences with chemotherapy ("noncorresponding description"). Therefore, preferences did not change even when the patients' own clinical health status had changed. The between-group differences may be explained by "anticipated adaptation." Both explanations may work together to explain why utilities remain stable within the same patients but differ between different patient groups.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Quimioterapia Adyuvante/psicología , Satisfacción del Paciente/estadística & datos numéricos , Adulto , Neoplasias de la Mama/psicología , Toma de Decisiones , Femenino , Humanos , Persona de Mediana Edad , Países Bajos , Estudios Prospectivos , Años de Vida Ajustados por Calidad de Vida , Proyectos de Investigación , AutoeficaciaRESUMEN
When making decisions about adjuvant chemotherapy for early-stage breast cancer, costs and benefits of treatment should be carefully weighed. In this process, patients' preferences are of major importance. The objectives of the present study were: (1) to determine the minimum benefits that patients need to find chemotherapy acceptable, and (2) to explore potential preference determinants, namely: positive experience of the treatment, reconciliation with the treatment decision, and demographic variables. Preferences were elicited from patients scheduled for adjuvant chemotherapy (chemotherapy group: n = 38) before (T(1)), during (T(2)), and 1 month after chemotherapy (T(3)), and were compared to responses from patients not scheduled for chemotherapy (no-chemotherapy group: n = 38). The patients were asked, for a hypothetical situation, to indicate the minimum benefit (in terms of improved 5-year disease-free survival) to find adjuvant chemotherapy acceptable. In the chemotherapy group, the median benefit was 1% at all 3 measurement points. In the no-chemotherapy group the attitude towards chemotherapy became more negative over time, although not statistically significantly so (T(1): 12%, T(2): 15%, T(3): 15%; P = 0.10). At all measurement points, the patients in the chemotherapy group indicated that they would accept chemotherapy for significantly (P< 0.01) less benefit than the patients in the no-chemotherapy group. Of the demographic variables, age was related to preferences, but only at T(2)and only in the no-chemotherapy group. The more positive attitude towards chemotherapy and the stability of preferences in the chemotherapy group indicated that reconciliation with the treatment decision was a more important determinant of patients' preferences than positive experience of the treatment.