RESUMEN
AIM: To assess the activity and safety of non-pegylated liposomal doxorubicin (Myocet®) in combination with docetaxel and trastuzumab as first-line treatment of patients with HER-2/neu-positive metastatic breast cancer (MBC). PATIENTS AND METHODS: The maximum tolerated dose of the combination was defined in the phase I part of the study. In the phase II part, 45 HER-2/neu-positive MBC patients were enrolled to receive 6-8 cycles of Myocet® 50 mg/m2 (day 1), docetaxel 30 mg/m2 (days 2 and 9) plus trastuzumab (day 2, 4 mg/kg followed by 2 mg/kg/week) every 21 d until unacceptable toxicity or progression occurred. Objective response (primary end-point) and treatment tolerability were assessed according to World Health Organisation criteria. Cardiotoxicity was defined as signs and/or symptoms of congestive heart failure and/or a decrease in left ventricular ejection fraction (LVEF). RESULTS: The overall response rate was 55.6% (complete response 8.9%, partial response 46.7%), with a median time-to-progression of 10.9 months (C.I. 8.7-15.0). Median overall survival was not reached. The most frequent grade 3-4 adverse events were granulocytopaenia (60.0%), leukocytopenia (43.2%) and alopecia (35.6%). Grade 3-4 diarrhoea, pain, oral and skin toxicity (4.4%, each) and nausea/vomiting, thrombocytopenia and elevated alkaline phosphatase (2.2%, each) were also reported. In 2 patients LVEF fell to <50%, with a decrease from baseline>15%. LVEF median values remained stable from baseline to the end of the study (60%). CONCLUSIONS: The combination of Myocet®, docetaxel and trastuzumab is safe and shows promising activity as first-line treatment of HER-2-positive MBC.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Insuficiencia Cardíaca/inducido químicamente , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Docetaxel , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Doxorrubicina/análogos & derivados , Esquema de Medicación , Femenino , Insuficiencia Cardíaca/prevención & control , Humanos , Liposomas , Dosis Máxima Tolerada , Persona de Mediana Edad , Metástasis de la Neoplasia , Receptor ErbB-2/metabolismo , Taxoides/administración & dosificación , Taxoides/efectos adversos , Trastuzumab , Resultado del TratamientoAsunto(s)
Neoplasias Abdominales/tratamiento farmacológico , Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Resistencia a Antineoplásicos , Neoplasias Abdominales/diagnóstico por imagen , Neoplasias Abdominales/patología , Neoplasias Abdominales/cirugía , Adulto , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Bevacizumab , Carcinoma de Células Pequeñas/diagnóstico por imagen , Carcinoma de Células Pequeñas/patología , Carcinoma de Células Pequeñas/cirugía , Cetuximab , Exantema/inducido químicamente , Humanos , Masculino , Metástasis de la Neoplasia , Tomografía Computarizada por Rayos XRESUMEN
PURPOSE: Epidermal growth factor receptor (EGFR) is overexpressed in approximately 50% of invasive breast carcinomas and it is correlated with hormone resistance and poor prognosis. EGFR suppression by gefitinib, a quinazoline derivative that inhibits phosphorylation of the specific receptor, represents a novel therapeutic strategy. A dose-finding study was performed to evaluate the combination of gefitinib with weekly epirubicin in patients with pretreated metastatic breast cancer. METHODS: Fifteen patients were enrolled at four sequential dose levels. Gefitinib was administered orally, at the fixed daily dose of 250 mg. The starting dose of epirubicin was 20 mg/m2. Escalating dose levels of epirubicin were planned by increments of 5 mg/m2 per level, up to the maximum tolerated dose (MTD). Pharmacodynamic studies were performed by determining serum and tissue ERBB2 and EGFR. RESULTS: At the first three dose levels tested no patient experienced a dose-limiting toxicity (DLT). In cohort 4, two patients experienced DLTs (grade 4 dyspnea and asthenia, grade 3 diarrhea and thrombocytopenia) identifying the MTD of epirubicin as 35 mg/m2. Of the 14 cases assessable for response, partial response was documented in two patients, and stable disease in seven, giving an overall disease control rate of 64.2%. The comparison of pre- and post-therapy ERBB2 and EGFR values was not statistically significant between the subgroups of patients regarding responsiveness to treatment. CONCLUSIONS: The recommended dose of epirubicin for phase II studies is 30 mg/m2 in combination with gefitinib at the daily dose of 250 mg. Pharmacodynamic studies did not identify any biomarker predictive of response.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Anciano , Neoplasias de la Mama/sangre , Neoplasias de la Mama/secundario , Relación Dosis-Respuesta a Droga , Epirrubicina/administración & dosificación , Receptores ErbB/sangre , Femenino , Gefitinib , Humanos , Dosis Máxima Tolerada , Persona de Mediana Edad , Invasividad Neoplásica , Quinazolinas/administración & dosificación , Receptor ErbB-2/sangreRESUMEN
Physiological angiogenesis occurs during embryogenesis, wound healing and reproductive functions in adults. Abnormal angiogenesis takes place in certain chronic diseases (diabetes, psoriasis, rheumatoid arthritis, etc.) and tumours. Genetic changes and local stresses including hypoxia, glucose deprivation and oxidative stress play a pivotal role in angiogenesis switch, which is necessary for tumour development and is rate-limiting for tumour progression. Angiogenesis is tightly regulated by pro- and anti-angiogenic growth factors with a series of complex and interrelated steps. Activated endothelial cells (ECs) migrate as a solid cord and, subsequently, form lumina; the sprout tips then anastomose to form vessel loops or networks. One of the final events is the laying down of a basement membrane and the structural support of pericytes. The molecular alterations that sustain angiogenesis represent novel targets for rationally designed anti-cancer treatment strategies. Inhibition of angiogenesis presents certain advantages on conventional therapies, such as the direct accessibility from the circulation, and the potential low rate of drug resistance related to the genetic stability of ECs. Certain anti-angiogenic compounds were found to have potent anticancer property in in vivo experimental studies. Nevertheless, in contrast to preclinical studies, the first generation of anti-angiogenic drugs tested in clinical trials have shown a moderate activity in advanced disease partly due to suboptimal schedules of therapy or biases in study design.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Neovascularización Patológica/tratamiento farmacológico , Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Humanos , Hipoxia , Péptidos y Proteínas de Señalización Intercelular/fisiología , Neoplasias/irrigación sanguínea , Neovascularización Patológica/etiologíaRESUMEN
Thalidomide is a synthetic derivative of glutamic acid with sedative-hypnotic activity, which caused devastating teratogenic effects in the 1960s. This paper reviews the possible mechanisms of its teratogenic effect, its new therapeutic indications, the proposed mechanisms for its antitumor activity and, finally, reviews published studies of its application in oncology. Current data demonstrates that thalidomide is clinically promising in multiple myeloma, glioblastoma multiforme and renal cell cancer. Furthermore, a beneficial effect of the drug has been proposed in cancer-related cachexia, which merits further investigation. Well-designed, randomized studies are warranted to establish the possible indications of thalidomide as an antitumor compound.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Teratógenos/farmacología , Talidomida/uso terapéutico , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , Neoplasias Hematológicas/tratamiento farmacológico , Humanos , Teratógenos/toxicidad , Talidomida/efectos adversos , Talidomida/farmacocinética , Talidomida/farmacología , Talidomida/toxicidadRESUMEN
Apocrine carcinoma of the skin is a rare tumor. Wide surgical excision with complete removal of the neoplasm is the standard therapy and this appears to offer the best chance of cure. Radiotherapy may be used in case of local relapse or regional lymph node involvement. Systemic chemotherapy has not proved to be effective in the treatment of this tumor. We report on a 46-year-old woman with a recurrent apocrine carcinoma of the scalp that had previously been treated with surgery, radiotherapy and chemotherapy (Al-Saraff schedule). The patient was responsive to a second-line systemic chemotherapy regimen consisting of a weekly combination of methotrexate and bleomycin, and achieved long-term progression-free survival.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Glándulas Apocrinas , Carcinoma/terapia , Recurrencia Local de Neoplasia/terapia , Neoplasias de las Glándulas Sudoríparas/terapia , Glándulas Apocrinas/patología , Glándulas Apocrinas/cirugía , Carcinoma/tratamiento farmacológico , Carcinoma/patología , Carcinoma/cirugía , Cistoadenoma/terapia , Femenino , Humanos , Escisión del Ganglio Linfático , Persona de Mediana Edad , Disección del Cuello , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Neoplasias de las Glándulas Sudoríparas/patología , Neoplasias de las Glándulas Sudoríparas/cirugíaRESUMEN
Growth of solid tumors beyond a certain mass is dependent on the vascular bed from pre-existing host vasculature. The process of angiogenesis is essential not only for primary tumor growth but also for metastasis. The number of microvessels within the invasive component of a primary tumor reflects the degree of tumor angiogenesis. At present the most widely used method to assess neovascularization is the quantitation of intratumoral microvessel density (IMD) by immunohistochemical methods in which specific markers for endothelial cells are employed. In this paper we analyze the different methods used to assess IMD, as well as their advantages and potential methodological pitfalls. Several studies have shown a close correlation between IMD, tumor growth and the occurrence of metastasis, suggesting that IMD is a prognostic indicator of clinical relevance. Furthermore, preliminary studies suggest that determination of angiogenesis may predict responsiveness to some forms of conventional anticancer therapy. Although the histological microvessel density technique is the current gold standard to characterize tumor angiogenesis, it may not be the ideal tool for clinical purposes because it needs to be performed on biopsy material and does not assess the functional pathways involved in the angiogenic activity of tumors. Non-invasive assessment of tumor vascularity is possible in vivo by means of Doppler sonography, dynamic contrast-enhanced magnetic resonance imaging (MRI) and positron emission tomography (PET). These methods may be preferable to histological assay because they are non-invasive, survey the entire tumor, reflect both anatomic and physiologic characteristics, and may be useful to monitor the activity of antiangiogenic therapies.
Asunto(s)
Neoplasias/irrigación sanguínea , Neovascularización Patológica/diagnóstico , Animales , Endotelio/inmunología , Humanos , Inmunohistoquímica , Imagen por Resonancia Magnética , Microcirculación , Pronóstico , Tomografía Computarizada de EmisiónRESUMEN
BACKGROUND: Gemcitabine and docetaxel have been claimed to be active single agents in advanced pancreatic cancer. We determined the maximum tolerable dose of docetaxel combined with a weekly fixed dose of gemcitabine and assessed the activity of this combination in advanced pancreatic cancer. PATIENTS AND METHODS: Phase I. Patients were treated with gemcitabine on days 1 and 8, every three weeks, at a fixed dose of 1,000 mg/m2; docetaxel was given at escalating doses starting from 70 mg/m2 on day 8. Phase II. In accord with the optimal two-stage phase II study design, 18 patients were treated with gemcitabine (1000 mg/m2) and the maximum tolerable dose of docetaxel (70 mg/m2). RESULTS: Phase I. Dose-limiting toxicities occurred at the second dose level of docetaxel (80 mg/m2), with all three patients developing grades 3 or 4 neutropenia. Consequently, the dose tested in the phase II study was 70 mg/m2. Phase II. In the 18 patients enrolled in the study, we registered only one partial response. The time to progression was 3 months, and the median treatment survival was 5.4 months. Grade 3-4 toxicities consisted of neutropenia (three episodes) and thrombocytopenia (two episodes). Furthermore, 10 patients complained of grade 3 fatigue. CONCLUSIONS: The addition of docetaxel to gemcitabine does not appear to be useful in advanced pancreatic cancer, since gemcitabine alone achieves similar results.