Pembrolizumab for advanced melanoma: experience from the Spanish Expanded Access Program.

BACKGROUND: The programmed death (PD-1) inhibitor pembrolizumab has been recently approved for the treatment of advanced melanoma. We evaluated the clinical activity of pembrolizumab in melanoma patients treated under the Spanish Expanded Access Program. METHODS: Advanced melanoma patients who failed to previous treatment lines were treated with pembrolizumab 2 mg/kg every three weeks. Patients with brain metastases were not excluded if they were asymptomatic. Data were retrospectively collected from 21 centers in the Spanish Melanoma Group. RESULTS: Sixty-seven advanced melanoma patients were analyzed. Most patients were stage M1c (73.1%), had high LDH levels (55.2%) and had ECOG PS 1 or higher (59.7%). For cutaneous melanoma patients, median overall survival was 14.0 months; the 18-month overall survival rate was 47.1%. Overall response rate was 27%, including three patients with complete responses (6.5%). Median response duration was not reached, with 83.3% of responses ongoing (3.5 m+ to 20.4 m+). From ten patients included with brain metastases, four (40%) had an objective response, two (20%) of them achieved a complete response. Significant prognostic factors for overall survival were LDH level, ECOG PS and objective response. There were no serious adverse events. CONCLUSION: Although this was a heavily pretreated cohort, pembrolizumab activity at the approved dose and schedule was confirmed in the clinical setting with long-term responders, also including patients with brain metastases.

Prognostic impact of bulky mediastinal lymph nodes (N2>2.5 cm) in patients with locally advanced non-small-cell lung cancer (LA-NSCLC) treated with platinum-based induction chemotherapy.

A group of 70 patients with locally advanced non-small-cell lung cancer (LA-NSCLC), treated in different phase II-III trials with platinum-based chemotherapy in two institutions, have been evaluated to identify potential baseline prognostic factors predicting their survival. The eligibility criteria were patients with stage IIIA (N2)-IIIB, Eastern Cooperative Oncology Group performance status 0.1 and less than 5% weight loss. All 37 patients with stage IIIA(N2) were treated with platinum-based induction chemotherapy followed by surgery plus radiotherapy if no progression was observed. The other 33 patients with stage IIIB were treated with platinum-based induction chemotherapy followed by conventional fractionation radiotherapy if no progression was observed. The overall response rate to induction chemotherapy was 40%. Median survival of the 70 patients was 13 months, with a 4-year survival of 15%. At univariate analysis, two prognostic factors correlated with survival: partial or complete response to induction chemotherapy (P<0.00001) and bulky mediastinal lymph nodes (N2>2.5 cm) (P=0.03). At multivariate analysis, only the response to induction chemotherapy retained statistical significance (P=0.00001). Randomized well-balanced prospective trials considering initially mediastinal N2 node size are needed to clearly establish the role of chemotherapy, surgery and radiotherapy in LA-NSCLC.

Brain metastases from colorectal carcinoma.

AIMS AND BACKGROUND: Brain metastases are an unusual finding in patients with colorectal carcinoma. We wished to determine the clinical presentation, the time interval between the diagnosis of colorectal carcinoma and the appearance of brain metastases, and the overall survival. PATIENT CHARACTERISTICS: The median age of our patients was 61 years. Brain metastases developed subsequently to the diagnosis of colorectal cancer in nine patients. All patients had neurologic symptoms. All patients had progressing systemic disease at the moment of intracranial presentation. Four patients received whole brain radiation therapy. The median survival was 11 weeks. DISCUSSION: The development of brain metastasis is a late event in the course of colorectal carcinoma and occurs most often in patients with extensive systemic disease that contraindicates surgical resection. Radiotherapy can improve the survival of this group of patients whereas the role of chemotherapy is still unclear due to the low frequency of such cases.

[Why evidence-based medicine? 20 years of meta-analysis]. / Por qué la medicina basada en la evidencia? 20 años de metaanálisis.

BACKGROUND: Meta-analysis, described within evidence-based medicine, has become a frequent issue in recent medical literature. An exhaustive search of reported meta-analysis from any medical specialty is described. MATERIAL AND METHODS: Search of papers included in Medline or Embase between 1973-1998. A study of intra and inter-reviewers liability about selection and classification have been performed. A descriptive analysis of the reported papers (frequency tables and graphics) is described, including differences of mean of reported meta-analysis papers by medical specialty and year. RESULTS: 1,518 papers were selected and classified. Most frequently found (45.91%) were: methodology (15.7%), psychiatry (11.79%), cardiology (10.01%) and oncology (8.36%). Inter personal agreement was 0.93 in selecting papers and 0.72 in classifying them. Between 1977-1987 overall mean of reported studies of meta-analysis (1.67 + 4.10) was significatively inferior to the 1988-1998 (49.54 + 56.55) (p < 0.001). Global number of meta-analysis was positively correlated (p < 0.05) with the number of studies about fundamentals and methodology during the study period. CONCLUSIONS: The method used to identify meta-analysis reports can be considered to be adequate; however, the agreement in classifying them in medical specialties was inferior. A progressive increase in the number of reported meta-analysis since 1977 can be demonstrated. Specialties with a greater number of meta-analysis published in the literature were: psychiatry, oncology and cardiology. Diffusion of knowledge about fundamentals and methodology of meta-analysis seems to have drawn and increase in performing and reporting this kind of analysis.

Pembrolizumab for advanced melanoma: experience from the Spanish Expanded Access Program

Background. The programmed death (PD-1) inhibitor pembrolizumab has been recently approved for the treatment of advanced melanoma. We evaluated the clinical activity of pembrolizumab in melanoma patients treated under the Spanish Expanded Access Program. Methods. Advanced melanoma patients who failed to previous treatment lines were treated with pembrolizumab 2 mg/kg every three weeks. Patients with brain metastases were not excluded if they were asymptomatic. Data were retrospectively collected from 21 centers in the Spanish Melanoma Group. Results. Sixty-seven advanced melanoma patients were analyzed. Most patients were stage M1c (73.1%), had high LDH levels (55.2%) and had ECOG PS 1 or higher (59.7%). For cutaneous melanoma patients, median overall survival was 14.0 months; the 18-month overall survival rate was 47.1%. Overall response rate was 27%, including three patients with complete responses (6.5%). Median response duration was not reached, with 83.3% of responses ongoing (3.5 m+ to 20.4 m+). From ten patients included with brain metastases, four (40%) had an objective response, two (20%) of them achieved a complete response. Significant prognostic factors for overall survival were LDH level, ECOG PS and objective response. There were no serious adverse events. Conclusion. Although this was a heavily pretreated cohort, pembrolizumab activity at the approved dose and schedule was confirmed in the clinical setting with long-term responders, also including patients with brain metastases (AU)

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Phase I trial of weekly gemcitabine at 3-h infusion in refractory, heavily pretreated advanced solid tumors.

Gemcitabine (2',2'-difluorodeoxycytidine) is a nucleoside analog with antitumor activity against a variety of malignancies. The critical enzyme cytidine kinase is saturated at plasma concentrations achieved after a 30-min infusion at conventional doses. Prolonged infusion time may yield higher intracellular dFdCTP concentrations. A phase I study was designed to determine the maximum tolerated dose (MTD) of gemcitabine, given by infusion for 3 h, in heavily pretreated patients. Twenty-seven patients (13 head and neck cancer, seven sarcoma, three esophageal cancer, three non-small-cell lung cancer and one ovarian cancer) were enrolled. Twenty patients were defined as refractory at first- or second-line chemotherapy. Four different entry dose levels (300, 400, 450 and 500 mg/m(2)) were evaluated for gemcitabine administered on days 1, 8 and 15 of a 28-day cycle. The MTD was defined as 450 mg/m(2), with granulocytopenia, thrombocytopenia and asthenia being dose limiting. The maximum grade III/IV patient toxicities for hemoglobin, leukocytes, neutrophils and platelets for all doses were 7, 19, 19 and 11%, respectively. Non-hematological toxicities included asthenia, nausea/vomiting and diarrhea. Thus, gemcitabine administered at a fixed 3-h infusion was well tolerated up to 450 mg/m(2) in heavily pretreated patients. Myelosupression and asthenia were dose-limiting toxicities.

¿Por qué la medicina basada en la evidencia? 20 años de metaanálisis / Why evidence based medicine? 20 years of experience

Fundamento: El metaanálisis, introducido a partir de la Medicina Basada en la Evidencia, se ha convertido en un tema habitual de la bibliografía en los últimos años. Se describe una búsqueda exhaustiva de publicaciones de metaanálisis de todas las especialidades médicas, su número y evolución temporal. Material y métodos: Búsqueda de artículos de metaanálisis en Medline y Embase entre 1973-1998. Estudio de fiabilidad interobservadores e intraobservador de la estrategia de selección y clasificación. Análisis descriptivo de las publicaciones (tablas de frecuencia y gráficos). Análisis de las diferencias de medias del número de publicaciones por especialidad y año. Resultados: Resultaron seleccionados y clasificados 1.518 artículos. Los más frecuentes (45,91 porciento) englobaban: metodología (15,7 porciento), psiquiatría (11,79 porciento), cardiología (10,01 porciento) y oncología (8,36 porciento). El acuerdo interobservadores en la selección fue de 0,93; en la clasificación fue 0,72. Entre 1977-1987 la media de estudios de metaanálisis de cualquier disciplina (1,67+4,10) es significativamente inferior a la 1988-1998 (49,54+56,55) (p<0,001). El total de metaanálisis se correlaciona positivamente (p<0,05) con el número de estudios sobre bases y metodología realizados durante el periodo estudiado. Conclusiones: Se puede considerar adecuado el método de identificación de estudios de metaanálisis, aunque ha existido un menor grado de acuerdo para clasificarlos según la especialidad correspondiente. Se constata una progresión en la publicación de metaanálisis desde 1977. Las disciplinas con más metaanálisis publicados en los últimos 20 años han sido psiquiatría, oncología y cardiología. La difusión del conocimiento de las bases y metodología del metaanálisis ha repercutido positivamente sobre la frecuencia de realización de estos análisis (AU)