Análisis de la carga anticolinérgica en el anciano frágil, pluripatológico y polimedicado / Analysis of the anticholinergic burden in the frail, multi-pathological and polymedicated elderly

PRESENTACIÓN DEL CASO: varón de 87 años sin alergias medicamentosas conocidas. Antecedentes personales: hipertensión arterial, cardiopatía isquémica tipo angor inestable, insuficiencia cardiaca, cervicalgia mecánica, osteoartritis, reflujo gastroesofágico, hiperplasia benigna de próstata, incontinencia urinaria y deterioro cognitivo leve. Medicación habitual: solifenacina/tamsulosina 6/0,4 mg (0-0-1), pantoprazol 20 mg (1-0-1), lorazepam 1 mg (0-0-1), ácido acetilsalicílico 100 mg (0-1-0), furosemida 40 mg (1-1-0), donepezilo 10 mg (0-0-1), valsartán 160 mg (1-0-0), bisoprolol 2,5 mg (1/2-0-0), tramadol/paracetamol 37,5/325 mg (1-0-1). Medidas no farmacológicas: absorbentes para la incontinencia urinaria (noche y súper-noche). El paciente acudió a la farmacia acompañado de su hijo refiriendo estreñimiento, sequedad de boca, desorientación, confusión y dos caídas en la última semana.EVALUACIÓN: la combinación de fármacos con acción anticolinérgica puede dar lugar a efectos adversos acumulativos, tanto centrales como periféricos. La exposición a una carga anticolinérgica (CA) alta se ha asociado con un incremento en el riesgo de caídas, deterioro de la función física y cognitiva e incremento de la mortalidad. Debido a la multimorbilidad del paciente, polifarmacia y sintomatología referida se calculó la CA y el riesgo anticolinérgico (RA) asociado al tratamiento farmacológico mediante la herramienta online Anticholinergic Burden Calculator, que emplea las siguientes 10 escalas: Anticholinergic Cognitive Burden Scale (ACB), Anticholinergic Risk Scale (ARS), Chew’s Scale (Chew), Anticholinergic Drug Scale (ADS), Anticholinergic Activity Scale (AAS), Anticholinergic Load Scale (ALS), Clinician-Rated Anticholinergic Scale (CrAS), Duran’s Scale (Duran), Anticholinergic Burden Classification (ABC) y Drug Burden Index (DBI).El paciente presentó una CA elevada y, por tanto, un RA alto según las escalas ADS, ABC y DBI. (AU)

Seguimiento farmacoterapéutico del paciente hepatópata / Pharmacotherapeutic monitoring of the hepatopathic patient

PRESENTACIÓN DEL CASO: paciente de 64 años con antecedentes de insuficiencia renal crónica, hepatopatía crónica Child-Pugh A5, hipertensión arterial y diabetes mellitus tipo 2 que recibe el alta hospitalaria tras superar una sepsis por Listeria monocytogenes. Al alta, se modifica su tratamiento antihipertensivo, suspendiendo losartán- hidroclorotiazida 100-12,5 mg e iniciando amlodipino 5 mg. Su medicación habitual consta de: amlodipino 5 mg (0- 0-1), furosemida 40 mg (1-0-0), omeprazol 20 mg (1-0-0), acenocumarol 4 mg (según hematología), insulina glargina (26-0-0), insulina asparta (según glucemia).Tras varias semanas, el paciente refiere cierta preocupación por la aparición de erupciones cutáneas pruriginosas en cara y cuello que empeoran con el paso de los días además de edemas periféricos.EVALUACIÓN E INTERVENCIÓN: derivamos al paciente a su médico de atención primaria (MAP) con un informe escrito por sospecha de reacción adversa (RA) a amlodipino. Tras revisión por su MAP, se mantiene amlodipino y se modifica la pauta de furosemida a 1-1/2-0 para tratar los edemas. Durante el posterior seguimiento, las afecciones cutáneas empeoran y el paciente presenta cansancio, temblor de manos y dificultad para hablar y concentrarse. Dada la sintomatología compatible con el ingreso previo por sepsis y sospecha de RA, volvemos a derivar a su MAP. A su vez, su MAP le deriva al hospital donde permanece en observación 24 horas. Se realiza bioquímica completa, hemocultivo, urocultivo, TAC craneal, placa de tórax y resonancia magnética.SEGUIMIENTO: el paciente presenta valores analíticos en rango y cultivos negativos. TAC y placa de tórax compatibles con la normalidad. En la resonancia magnética se aprecian depósitos de manganeso compatibles con encefalopatía hepática crónica. (AU)

Panhipopituitarismo secundario a metástasis hipofisaria en una paciente con cáncer de mama / Panhypopituitarism secondary to pituitary metastasis in a patient with breast cancer

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Long-term biomonitoring of breast cancer patients under adjuvant chemotherapy: the comet assay as a possible predictive factor.

Most chemotherapy treatments induce DNA damage in the exposed patients. Using the comet assay and peripheral blood mononuclear cells (PBMC), we have quantified this induced DNA damage and studied its relationship with GSTM1 and GSTT1 polymorphisms, and clinical parameters. For this purpose, 29 Caucasian women, breast cancer patients under CMF or CEF adjuvant chemotherapy were included in the study. The clinical parameters considered were (i) therapies side effects, like haematological and biochemical toxicities, (ii) prognostic and predictive factors, like hormonal receptor expression, tumour differentiation degree, sickness stage, and nodal status, and (iii) the effectiveness of the chemotherapy measured as five years relapse probability. The results were also related to the confounding factor age. Comet assay results indicate that 13 patients were characterised by absence of induced DNA strand breaks, and 16 patients presented induced DNA strand breaks along the treatment. Relationships between comet variables and clinical parameters, found with principal component analysis, correlations, one-way ANOVA and multivariate logistic regression analyses revealed that: (1) baseline levels of DNA damage are related to GSTM1 genotype and to hormonal receptor expression; (2) GSTM1 genotype also influences comet results after chemotherapy, as it does the AST level; (3) the tail moment values of the cycle 6.1 and the sickness stage might predict cancer relapse at five years: for the Stage, OR = 13.8 (IIB versus I+IIA), 95% CI 0.80-238.97, and for 6.1 cycle TM, OR = 1.3, 95%, CI 0.97-1.79, with a potential model (10* Stage (I-IIA = 0, IIB = 1) + 6.1 cycle), that has a good predictive capacity, with an area under ROC curve of 0.872 (CI 0.62-1.00). To our knowledge, this is the first time such a predictive value is found for the comet assay. Nevertheless, before the comet assay could be used as a tool for oncologists, this relationship should be confirmed in more patients, and problems of standardisation and data interpretation should be solved.

Impact of the incorporation of tyrosine kinase inhibitor agents on the treatment of patients with a diagnosis of advanced renal cell carcinoma: study based on experience at the Hospital Universitario Central de Asturias

INTRODUCTION: For nearly the past two decades, cytokines (CKs) have been the only systemic treatment option available for advanced renal cell carcinoma (RCC). In recent years, tyrosine kinase inhibitors (TKIs) have demonstrated clinical activity on this tumour. Our purpose is to describe one centre's experience with the use of CKs and TKIs in the treatment of patients with advanced RCC. MATERIALS AND METHODS: This study was designed as a retrospective chart review of RCC patients who were treated with CKs and/or TKIs in our department between July 1996 and June 2008. Efficacy and toxicity were assessed using World Health Organization (WHO) criteria. The Kaplan-Meier method was used to estimate progression-free (PFS) and overall (OS) survival. RESULTS: Ninety-four patients were classified into three groups depending on the modality of treatment administered: 46 were treated with CKs alone and/or chemotherapy (27 with immunotherapy, one with chemotherapy and 18 with both), 28 with TKIs alone (25 with sunitinib and 13 with sorafenib) and 20 with TKIs in second-line treatment following failure with CKs (17 with sunitinib, eight with sorafenib, four with bevacizumab and one with lapatinib). The median age was 60 years in the CK group and 65 and 62, respectively, in TKI in first and second-line treatment groups. Eighty-five percent of patients treated with CKs and 75% in the TKI group in first-line treatment and 80% in second-line treatment were men. Overall, 89% of patients had favourable risk, and 11% had intermediate risk. All patients were considered evaluable for toxicity. The main grade 3-4 (%) toxicity was asthenia for both groups, (ten in TKIs and 15 in CKs). Other grade 1-2 toxicities were mucositis (39), bleeding (8), hypertension (19), skin toxicity (33) and hypothyroidism (12.5) associated with TKIs; and anaemia (33), cough (29), asthenia (39) and emesis (14) associated with CKs. The objective response rate among 80 patients evaluable for activity was 10.6% with CKs and 46.5% and 35%, respectively, with TKIs in first- and second-line treatments. Disease stabilisation with CKs was recorded at 59% of patients and with TKIs 25% and 50% in first- and second-line treatment groups, respectively. The median progression-free survival (PFS) with CKs was 122 days [95% confidence interval (CI) 82-162] and with TKIs 201 days (65-337) in the first and 346 days (256-436) in second-line treatment groups. The median overall survival (OS) was 229 days (142-316) and 2,074 days (1,152-2,996) for patients treated with CKs and TKIs. CONCLUSIONS: Our results are in line with the activity and survival rates previously reported in the literature regarding the use of TKIs for patients with advanced RCC in first- and second-line treatment, which has demonstrated an acceptable toxicity level (AU)

Phase II study with the combination of gemcitabine and DTIC in patients with advanced soft tissue sarcomas.

PURPOSE: Based on the promising results of a Phase I study with a combination of gemcitabine and DTIC performed in advanced soft tissue sarcoma (ASTS) patients, and due to the limited efficacy of second or third line therapies in those patients, we designed a Phase II study to determine the activity of this new regimen. METHODS: Patients with ASTS, measurable disease, pretreated with chemotherapy, received gemcitabine 1,800 mg/m2 infused over 180 min followed by DTIC 500 mg/m2 (one cycle), every 2 weeks. The pharmacokinetics (PK) of gemcitabine and 2',2'-difluorodeoxyuridine (dFdU), and the accumulation of gemcitabine triphosphate (dFdCTP) by peripheral blood mononuclear cells were studied. The influence of the sequence of administration on those parameters was examined to exclude potential drug interactions. RESULTS: Twenty-six patients received a total of 158 cycles (mean four cycles, range 1-18). Grade 3-4 anemia (23% of patients), granulocytopenia (46%) or thrombocytopenia (12%), and grade 3 increase in AST (18%), ALT (21%), or gamma-glutamyl-transferase (9%) were noted. Response rate in 23 patients was 4% (95% CI: 0-24%), and in 8 of 11 patients stable disease lasted > 6 months. Progression-free rate (PFR) at 3 and 6 months was, respectively, 48 and 28%, and median overall survival 37 weeks. Pooled data from the Phase I and Phase II studies showed clinical benefit in patients with leiomyosarcomas (LMS) (57%) and malignant fibrous histiocytomas (MFH) (33%). The sequence of administration did not influence PK of gemcitabine or dFdU. There was a trend (P = 0.11) toward a lower accumulation of dFdCTP when DTIC preceded gemcitabine. CONCLUSIONS: Although the remission rate was low, PFR figures indicate that this regimen has activity in patients with ASTS. It should be compared with DTIC, or other gemcitabine-containing combinations, in patients with LMS or MFH, to determine whether this combination offers advantages in PFR or in overall activity.

Tratamiento adyuvante en pacientes diagnosticados de carcinoma no microcítico de pulmón: estado de la evidencia científica / Adjuvant treatment of non-small cell lung cancer patients: state of the scientific evidence

La cirugía representa el tratamiento curativo de elección para los pacientes que son diagnosticadosde carcinoma no microcítico de pulmón en estadio local. Sin embargo, gran parte de ellos experimentanuna recurrencia de su enfermedad lo que ha llevado al empleo de opciones terapéuticas tanto localescomo sistémicas con el ánimo de mejorar las posibilidades de curación. Durante las últimas décadasdiversos estudios comparativos heterogéneos y varios meta-análisis publicados en los años 95 y 97no demostraron de forma significativa una ventaja al asociar la quimioterapia y/o radioterapia adyuvantea la cirugía. Desde entonces y hasta nuestros días otros trabajos realizados con un número mayorde pacientes y empleando una quimioterapia más eficaz basada en combinaciones de platino, coincidenen describir un beneficio con su utilización aunque no de forma unánime. Más recientemente, unnuevo meta-análisis recopilando la mayoría de los estudios antes mencionados ha confirmado de formasignificativa una mejoría absoluta del 4% en la supervivencia global de los pacientes sometidos aquimioterapia adyuvante, especialmente en los estadios patológicos II-III tras cirugía y tratados conregímenes que incluyen cisplatino y vinorelbina. Queda por ser determinado el papel que desempeñanotros agentes como el uracilo/tegafur así como la radioterapia en el contexto adyuvante

Surgery is the current treatment of choice in patients with early-stage non-small cell lung cancer.Based on the high rates of recurrence, additional local and systemic treatments have been developed,aimed at improving the cure rates. The comparative studies about the benefits of post-operativeadjuvant chemotherapy and/or radiotherapy, and the meta-analysis studies made during the lastdecades, reviewed in some articles appeared in 95 and 97, did not confirm a significant improvementof the overall survival. Since then, new comparative trials carried out with a higher number of patientsand with more active and standard chemotherapy seem to show a benefit of the administration ofplatinum-based chemotherapy, although it has not gained general acceptance. More recently, a newmeta-analysis, that included the previous studies, has confirmed an overall increase of 4 % in survivalof patients treated by surgery and adjuvant chemotherapy, especially in stages II-III patients receivingschedules of cisplatin and vinorelbine. Further studies are needed to determine the real therapeuticvalue of other agents, as uracil-tegafur and radiotherapy

Phase I/II trial of doxorubicin and fixed dose-rate infusion gemcitabine in advanced soft tissue sarcomas: a GEIS study.

The aim of the study was to determine the dose-limiting toxicity and maximum tolerated dose of a first-line combination of doxorubicin and gemcitabine in adult patients with advanced soft tissue sarcomas and to explore its activity and toxicity, and the presence of possible interactions between these agents. Patients with measurable disease were initially treated with doxorubicin 60 mg m(-2) by i.v. bolus on day 1 followed by gemcitabine at 800 mg m(-2) over 80 min on days 1 and 8, every 21 days. Concentrations of gemcitabine and 2',2'-difluorodeoxyuridine in plasma, and gemcitabine triphosphate levels in peripheral blood mononuclear cells were determined during 8 h after the start of gemcitabine infusion. Myelosuppression and stomatitis were limiting toxicities, and the initial dose level was applied for the Phase II trial, where grade 3-4 granulocytopenia occurred in 70% of patients, grade 3 stomatitis in 46% and febrile neutropenia in 20%. Objective activity in 36 patients was 22% (95% CI: 9-35%), and a 50% remission rate was noted in leiomyosarcomas. Administration of doxorubicin preceding gemcitabine significantly reduced the synthesis of gemcitabine triphosphate. Clinical activity, similar to that of single-agent doxorubicin, and the toxicity encountered do not justify further studies with this schedule of administration.

Tratamiento de los sarcomas estromales del tracto gastrointestinal: papel del imatinib (Glivec) / No disponible

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Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study.

PURPOSE: To compare fotemustine and dacarbazine (DTIC) in terms of overall response rate (ORR) as primary end-point and overall survival, duration of responses, time to progression, time to occurrence of brain metastases (BM), and to assess safety and quality of life in patients with disseminated cutaneous melanoma. PATIENTS AND METHODS: Patients received either intravenous fotemustine 100 mg/m2 weekly for 3 weeks or DTIC 250 mg/m2/d for 5 consecutive days every 4 weeks (two cycles). Nonprogressive patients received a maintenance treatment every 4 weeks (fotemustine 100 mg/m2 or DTIC 250 mg/m2 for 5 days). RESULTS: Two hundred twenty-nine patients were randomly assigned to fotemustine or DTIC arms. The best ORR was higher in the fotemustine arm than in the DTIC arm in the intent-to-treat population (n=229; 15.2% v 6.8%; P=.043) and in full analysis set (n=221) (15.5% v 7.2%; P=.053). Similar median durations of responses (5.8 months with fotemustine v 6.9 months with DTIC) and time to progression (1.8 v 1.9 months, respectively) were observed. In patients without BM at inclusion, the median time to BM was 22.7 months with fotemustine versus 7.2 months with DTIC (P=.059). Median survival was 7.3 months with fotemustine versus 5.6 months with DTIC (P=.067). The main toxicity was grade 3 to 4 neutropenia (51% with fotemustine v 5% with DTIC) and thrombocytopenia (43% v 6%, respectively). No significant difference was noted for quality of life between arms. CONCLUSION: ORR was higher in the fotemustine arm compared to the DTIC arm in first-line treatment of disseminated melanoma. A trend in favor of fotemustine in terms of overall survival and time to BM was evidenced.

Prospective randomised phase II study of docetaxel versus paclitaxel administered weekly in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy.

BACKGROUND: Docetaxel and paclitaxel have activity in the second-line treatment of non-small-cell lung cancer (NSCLC), and can be administered as weekly schedules. This phase II randomised study was designed to test the efficacy and toxicity of both taxanes in patients with NSCLC previously treated with platinum-based chemotherapy. PATIENTS AND METHODS: Patients (n = 71) with documented NSCLC were randomised to receive docetaxel (n = 35 patients; 36 mg/m(2)) or paclitaxel (n = 36 patients; 80 mg/m(2)) as a 1 h weekly infusion for 6 weeks followed by a 2-week rest. The cycles were repeated until disease progression or non-acceptable toxicities occurred. RESULTS: Treatment achieved partial response of one versus five patients, median time-to-progression of 74 versus 68 days, and overall survival of 184 versus 105 days, with docetaxel and paclitaxel, respectively. The most common non-haematological toxicities were (docetaxel versus paclitaxel): grade 3/4 pulmonary toxicity in seven versus one patient; grade 2/3 diarrhoea in nine versus five; and grade 3/4 haematological toxicities occurred in two versus four patients. There were no treatment-related deaths. CONCLUSIONS: Docetaxel and paclitaxel administered weekly have discrete efficacy in patients with NSCLC previously treated with platinum-based chemotherapy. The higher non-haematological toxicity of docetaxel, particularly pulmonary toxicity and diarrhoea, is of concern and warrants further investigation.

Tratamiento domiciliario del cáncer avanzado de células renales basado en Interlukina-2 / Interleukin-2-based home therapy in advanced renal cell cancer

Propósito: Determinar la eficacia clínica y toxicidad de la interleukina 2 (rIL-2) administrada por vía subcutánea (s.c) y de forma ambulatoria en pacientes con carcinoma de células renales avanzado (ARCC). Material y métodos: Veintitrés pacientes consecutivos sin tratamiento previo con diagnóstico histológico de ARCC y enfermedad progresiva fueron incluidos en el estudio. La rlL-2 fue administrada por vías a una dosis de 18 millones 3 veces por semana o 9 millones 4 veces a la semana. Resultados: Veintitrés pacientes fueron evaluables pura toxicidad. Solo 2 pacientes toleraron la dosis de 18 millones 3 veces a la semana. Doce pacientes experimentaron fiebre con el tratamiento. Síntomas gripales severos fueron recogidos en 11 pacientes y chica de dolor/celulitis en la zona de la inyección fue referido por 6 pacientes. Dieciocho pacientes desarrollaron una leucocitosis reversible pero no se observó toxicidad hematológica o clínica de permeación vascular. Ningún paciente de 21 considerados evaluables para actividad respondió al tratamiento, 15 tuvieron una enfermedad estable y 6 una enfermedad progresiva. La mediana de tiempo a la progresión y supervivencia global fue de 12 semanas (intervalo de confianza al 95porciento; 2-38 semanas) y 42 semanas (10-75 semanas) respectivamente. Conclusiones: La dosis administrada a las dosis y esquema antes mencionadas no ha demostrado eficacia terapéutica en los pacientes con ARCC ocasionando una moderada a severa toxicidad no hematológica (AU)

A phase II trial of cyclophosphamide, epirubicin and vinorelbine in the treatment of advanced breast cancer.

BACKGROUND: Vinorelbine (Navelbin; N) has proven to be active in patients with advanced breast cancer (ABC) and cyclophosphamide (C) and epirubicin (Epiadriamycin: E) are still among the main cytostatic agents against this tumor. On this basis was carried out a study to determine the activity and toxicity of the combination of these three agents (CEN). PATIENTS AND METHOD: From April 1996 to March 1998, 59 patients with ABC were recruited of whom 56 were found eligible and evaluable for toxicity and 55 for activity. The treatment regimen was C: 400 mg/m2, E: 30 mg/m2 and N: 25 mg/m2 administered intravenously on days 1 and 8 of a 28-day cycle. RESULTS: The median number of cycles administered was 6 (range: 1-16). The most common hematological toxicity was grade (G) 3 and 4 neutropenia occurring in 36% of patients, associated with fever in 7% of them. Grade 3-4 thrombocytopenia and anemia occurred in 5% and 7%, respectively. Other G2-G3 non hematologic toxicities were: N/vomiting in 34%, alopecia in 73% and mucositis in 11% of patients. An objective response was achieved in 28 of 56 patients (50%) (95% confidence interval (CI): 37-63%): complete response (CR) in 9%, partial response (PR) in 41%. The median duration of response, time to progression and overall survival time was 54, 47 and 90 weeks, respectively. CONCLUSION: The CEN combination at these doses and treatment schedule appears to have acceptable tolerability but there is no apparent improvement in therapeutic efficacy when compared to other regimens used as first line treatment in ABC.

[The follow-up of the cancer patient: how and when?]. / Seguimiento del paciente oncológico: cómo y cuándo?

The medical resources devoted to cancer patient follow-up are growing. However, intensive follow-up is not translated to any significant improvement survival in a majority of patients. A few neoplasias have an effective salvage therapy, and are worth having strict follow-up to diagnose earlier the recurrence. In many tumours, as breast cancer, an early diagnosis of recurrence does not imply an improvement on survival. Tumoral markers are able to detect the presence of tumour cells even before being clinically apparent and are routinely used in the follow-up of tumours; however, they do not seem to improve survival. The cost-benefit relation of multiple revision in cancer patients apparently cured is debated. No general consensus is achieved to define the best tests to follow-up cancer patients. The trend is to minimize the diagnostic tests and to recommend a clinical follow-up with anamnesis and physical exploration.