Asunto(s)
Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/radioterapia , Traumatismos por Radiación/diagnóstico , Traumatismos por Radiación/etiología , Radioterapia Adyuvante/efectos adversos , Fraccionamiento de la Dosis de Radiación , Femenino , Humanos , Pronóstico , Enfermedades de la Piel/diagnóstico , Enfermedades de la Piel/etiologíaRESUMEN
The blood-brain barrier is a major obstacle for the chemotherapeutic drugs to effectively reach primary or secondary brain tumours. Stealth liposomal drugs are highly accumulated in tumoural tissues. In the present study we investigated the relative accumulation of(99m)Tc-DTPA radiolabelled stealth liposomal doxorubicin (Caelyx) in 10 patients with metastatic brain tumours and five patients with brain glioblastoma undergoing radiotherapy. Patients with metastatic brain lesions were treated with 10 consecutive fractions of radiotherapy (whole brain, 3 Gy/fraction, day 1-12) followed by a booster dose of 9 Gy (3 Gy/fraction, day 21-23). Caelyx, at a dose of 25 mg mg(-2)was given on day 1 and on day 21. Radiolabelled Caelyx accumulation was 13-19 times higher in the glioblastomas and 7-13 times higher in the metastatic lesions, as compared to the normal brain. The drug accumulation in the tumoural areas was 40-60% of the accumulation in the bone marrow of the skull bones. The normal brain radioactivity was <4% of the bone marrow, confirming an important shielding effect of the blood-brain barrier in the normal but not in the tumoural tissue. Four of 10 patients with metastatic lesions showed a complete response in CT-scan performed 2 months following therapy. There was no severe toxicity related to radiotherapy or to chemotherapy noted. It is concluded that stealth liposomal drugs selectively overcome the blood-brain barrier in the tumoural areas. The clinical importance of this observation is now under investigation.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Neoplasias Encefálicas/tratamiento farmacológico , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacocinética , Glioblastoma/tratamiento farmacológico , Adulto , Barrera Hematoencefálica , Médula Ósea/química , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/cirugía , Glioblastoma/metabolismo , Glioblastoma/cirugía , Humanos , Liposomas , Radiofármacos , Cráneo/química , Pentetato de Tecnecio Tc 99m , Distribución TisularRESUMEN
PURPOSE: Amifostine (WR-2721) is an important cytoprotective agent. Although intravenous administration is the standard route, pharmacokinetic studies have shown acceptable plasma levels of the active metabolite of amifostine (WR-1605) after subcutaneous administration. The subcutaneous route, due to its simplicity, presents multiple advantages over the intravenous route when amifostine is used during fractionated radiotherapy. PATIENTS AND METHODS: Sixty patients with thoracic, 40 with head and neck, and 40 with pelvic tumors who were undergoing radical radiotherapy were enrolled onto a randomized phase II trial to assess the feasibility, tolerance, and cytoprotective efficacy of amifostine administered subcutaneously. A flat dose of amifostine 500 mg, diluted in 2.5 mL of normal saline, was injected subcutaneously 20 minutes before each radiotherapy fraction. RESULTS: The subcutaneous amifostine regimen was well tolerated by 85% of patients. In approximately 5% of patients, amifostine therapy was interrupted due to cumulative asthenia, and in 10%, due to a fever/rash reaction. Hypotension was never noted, whereas nausea was frequent. A significant reduction of pharyngeal, esophageal, and rectal mucositis was noted in the amifostine arm (P <.04). The delays in radiotherapy because of grade 3 mucositis were significantly longer in the group of patients treated with radiotherapy alone (P <.04). Amifostine significantly reduced the incidence of acute perineal skin and bladder toxicity (P <.0006). CONCLUSION: Subcutaneous administration of amifostine is well tolerated, effectively reduces radiotherapy's early toxicity, and prevents delays in radiotherapy. The subcutaneous route is much simpler and saves time compared with the intravenous route of administration and can be safely and effectively applied in the daily, busy radiotherapy practice.
Asunto(s)
Neoplasias Abdominales/radioterapia , Amifostina/administración & dosificación , Neoplasias de Cabeza y Cuello/radioterapia , Protectores contra Radiación/administración & dosificación , Neoplasias Torácicas/radioterapia , Adulto , Anciano , Amifostina/efectos adversos , Distribución de Chi-Cuadrado , Fraccionamiento de la Dosis de Radiación , Estudios de Factibilidad , Femenino , Humanos , Inyecciones Subcutáneas , Persona de Mediana Edad , Traumatismos por Radiación/prevención & control , Protectores contra Radiación/efectos adversos , Resultado del TratamientoRESUMEN
Docetaxel has shown remarkable radiosensitizing in vitro properties. In a previous phase I/II dose escalation study in non-small-cell lung cancer (NSCLC) we observed a high response rate after concomitant boost radiotherapy and weekly docetaxel. The maximum tolerated dose was 30 mg m(-2) week(-1). In the present phase II study we evaluated whether weekly docetaxel and conventionally fractionated radiotherapy could be better tolerated and equally effective in the treatment of locally advanced NSCLC. Thirty-five patients with T3, T4/N2, T3/M0-staged disease were recruited. Docetaxel (30 mg m(-2)) was given as a 30 min infusion once a week. Asthenia and radiation-induced oesophagitis were the main side-effects of the regimen enforcing 2-week treatment delay in 6/35 (17%) patients and minor delay (3-7 days) in another 11/35 (31%) patients. Neutrophil, platelet and haemoglobin toxicity was minimal, but pronounced lymphocytopenia was observed. Complete response (CR) of the chest disease was observed in 12/35 (34%) patients and partial response in 16/35 (46%). Although not statistically significant (P=0.19), a higher CR rate (8/18; 44%) was observed in patients who accomplished their therapy within the scheduled treatment time (44-47 days) as compared to patients that interrupted their treatment for several days due to treatment-related toxicity (CR 4/17; 23%). The overall survival and the local progression-free survival at 1 year was 48% and 60% respectively. We conclude that docetaxel combination with radiotherapy is a promising approach for the management of locally advanced NSCLC that results in high CR rate. Further trials with docetaxel-based radiochemotherapy should integrate accelerated radiotherapy together with cytoprotection.