Effects of lapatinib monotherapy: results of a randomised phase II study in therapy-naive patients with locally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: Lapatinib is a dual inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER-2) tyrosine kinases. This study investigated the pharmacodynamic and clinical effects of lapatinib in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). METHODS: In total, 107 therapy-naive patients with locally advanced SCCHN were randomised (2 : 1) to receive lapatinib or placebo for 2-6 weeks before chemoradiation therapy (CRT). Endpoints included apoptosis and proliferation rates, clinical response, and toxicity. RESULTS: Versus placebo, lapatinib monotherapy did not significantly increase apoptosis detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labelling or caspase-3 assays. A statistically significant decrease in proliferation using Ki67 assay was observed (P=0.030). In a subset of 40 patients that received 4 weeks of lapatinib or placebo, objective response rate (ORR) was 17% (n=4/24) vs 0% (n=0/16). In the lapatinib single-agent responders, all had EGFR overexpression, 50% had EGFR amplification, and 50% had HER2 expression by immunohistochemistry (including one patient with HER2 amplification). However, these patients showed variable modulation of apoptosis, proliferation, and phosphorylated EGFR on drug treatment. Following CRT, there was a statistically non-significant difference in ORR between lapatinib (70%) and placebo (53%). There was no clear correlation between changes in apoptosis or proliferation and response to chemoradiation. Mucosal inflammation, asthenia, odynophagia, and dysphagia were the most commonly reported adverse events with lapatinib. CONCLUSION: Short-term lapatinib monotherapy did not demonstrate apoptotic changes, but provided evidence of clinical activity in locally advanced SCCHN, and warrants further investigation in this disease.

Prevention of cisplatin-induced emesis by the oral neurokinin-1 antagonist, MK-869, in combination with granisetron and dexamethasone or with dexamethasone alone.

PURPOSE: The NK1-receptor antagonist MK-869 (L-754,030) has demonstrated antiemetic activity in humans receiving chemotherapy. Objectives of the present trial included the first assessment of oral MK-869 plus dexamethasone compared with a 5HT(3) antagonist plus dexamethasone for prevention of acute and delayed emesis after high-dose cisplatin. Furthermore, the study sought to confirm that addition of MK-869 to a 5HT(3) antagonist plus dexamethasone was more effective than just the 5HT(3) antagonist plus dexamethasone for prevention of acute and delayed emesis. METHODS: This multicenter, double-blind, parallel-group trial in 351 cisplatin-naïve patients evaluated prevention of acute (0 to 24 hours) and delayed emesis (primary efficacy parameter; days 2 to 5) after cisplatin (> or =70 mg/m(2)). Patients were randomized to four groups (I to IV) (n = number randomized; number evaluable): granisetron (10 microg/kg intravenously) pre-cisplatin followed by placebo on days 2 to 5 (group I) (n = 90; 90); granisetron and MK-869 (400 mg PO [by mouth]) pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group II) (n = 86; 84); MK-869 (400 mg PO) the evening before and pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group III) (n = 89; 88); or MK-869 (400 mg PO) pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group IV) (n = 86; 84). All patients also received dexamethasone (20 mg PO) before cisplatin. Additional medication was available to treat emesis or nausea at any time. RESULTS: In the acute period, 57%, 80%, 46%, and 43% of patients were without emesis in groups I, II, III, and IV, respectively (P <.01 for group II v group I). In the delayed period, the proportion of patients without emesis in groups I, II, III, and IV was 29%, 63%, 51%, and 57%, respectively (P <.01 for groups II, III, and IV v group I). The distribution of nausea scores in the delayed period was lower when comparing group II with group I (P <.05 for days 1 to 5 and days 2 to 5). One serious adverse event (dizziness) was rated as possibly related to MK-869. CONCLUSION: Once daily oral administration of MK-869 was effective in reducing delayed emesis and nausea after high-dose cisplatin. However, the combination of the 5HT3 antagonist plus dexamethasone was numerically superior to MK-869 plus dexamethasone in reducing acute emesis. Confirming and extending previous findings, the triple combination of a 5HT(3) antagonist, MK-869, and dexamethasone provided the best control of acute emesis.

Elderly patients with aggressive non-Hodgkin's lymphoma treated with CHOP chemotherapy plus granulocyte-macrophage colony-stimulating factor: identification of two age subgroups with differing hematologic toxicity.

PURPOSE: Standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy repeated at 3-week intervals is difficult to deliver in elderly patients with non-Hodgkin's lymphoma (NHL). The use of hemopoietic growth factors may decrease the hematologic toxicity of chemotherapy and allow the delivery of full-dose CHOP. PATIENTS AND METHODS: We conducted a phase II trial with the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) to CHOP chemotherapy in NHL patients older than 60 years of age. Twenty-six previously untreated patients were assessable; median age was 67 years (range, 61 to 84 years). CHOP included cyclophosphamide 750 mg/m2 intravenously day 1; doxorubicin 50 mg/m2 intravenously day 1; vincristine 1.4 mg/m2 (2 mg total dose) intravenously day 1; and prednisone 100 mg orally days 1 through 5. GM-CSF 5 microg/kg was administered subcutaneously on days 4 through 13. Cycles were repeated every 21 days for six cycles. Results were analyzed for the total group and for two age subgroups: 61 to 69 years (n = 15) and 70 years or older (n = 11). RESULTS: Sixteen patients (62%) achieved a complete response (CR), four patients (15%) achieved a partial response (PR), and six patients (23%) did not respond to therapy. After a median follow-up of 41 months, the median progression-free and overall survival were 19 and 30 months, respectively. Twenty patients completed six cycles. One hundred thirty-eight of the 156 planned cycles were delivered (88%). The relative dose-intensity was 95%. The chemotherapy-induced toxicity was important. Absolute neutrophil count was less than 500/mL in 43% of the cycles, platelet nadir was less than 20,000/mL in 19%, and febrile neutropenia occurred in 21%. There were no grades 3 to 4 mucositis. Treatment-related death occurred in two patients, and was associated with neutropenic septic shock. The toxicity related to GM-CSF was mild hypotension after the cytokine was administered in 7% of cycles. When the results of the study were analyzed by age subgroups, we observed that whereas response and median survival were similar in patients aged 61 to 69 years or 70 years or older, there were significant differences in dose delivery and toxicity. Chemotherapy was delivered in 86 of 90 planned cycles in patients aged 61 to 69 years, but in only 52 of 72 planned cycles in patients aged 70 to 84 years (P = .00008). Absolute neutrophil count was less than 500/mL in 24% of cycles in patients aged 61 to 69 years and 73% of cycles in patients aged 70 years or older (P = .00001). The platelet nadir of less than 20,000/mL occurred in 5% of patients aged 61 to 69 years and in 42% of patients aged 70 years or older (P < .0001). Fever and neutropenia occurred in 8% of patients aged 61 to 69 years and in 42% of patients aged 70 years or older (P < .0001). Mucositis (grades 1 to 2) occurred in 21% of patients aged 61 to 69 years and in 42% of patients aged 70 years or older (P = .006). CONCLUSION: CHOP chemotherapy plus GM-CSF is an active regimen in elderly patients with NHL. Despite cytokine support, the toxicity of the regimen is elevated. We have identified two age subgroups (61 to 69 and > or = 70 years) that do not differ in treatment efficacy but show large differences in treatment-related toxicity.

Risk factors for treatment-related death in elderly patients with aggressive non-Hodgkin's lymphoma: results of a multivariate analysis.

PURPOSE: It has been suggested that age is associated with chemotherapy-related death in patients with non-Hodgkin's lymphoma (NHL) treated with doxorubicin-containing chemotherapy. The purpose of this study was to evaluate the relative influence of increasing age and other clinical parameters on the occurrence of treatment-related death in elderly patients with intermediate- or high-grade NHL treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy. METHODS: A retrospective study of patients 60 years of age or older with intermediate- or high-grade NHL treated with CHOP chemotherapy in a single cancer center. The following variables were recorded: age (60 to 69, 70 to 79, and 80 to 94 years), histology (Working Formulation [WF] D, E, F, G, and H), Ann Arbor stage, B symptoms, extranodal involvement, bulky disease (> 7 cm), performance status (Eastern Cooperative Oncology Group [ECOG] scale), International Prognostic Index (IPI score), serum lactate dehydrogenase (LDH) level and doxorubicin relative dose-intensity (RDI). The relationship between these features and treatment-related death was assessed in univariate and multivariate logistic regression analysis. RESULTS: From 1982 to 1991, 267 consecutive patients were treated. Median age was 70 years (range, 60 to 94 years). There were 35 toxic deaths. Sixty-three percent of the deaths occurred after the first cycle. Infection accounted for 82% of the toxic deaths. In the univariate analysis, the features associated with an increased risk of toxic death were ECOG performance status 2 to 4 (relative risk [RR], 7.82), B symptoms (RR, 3.38), diffuse large-cell histology (RR, 3.06), bulky disease (RR, 2.58), serum levels of LDH (RR, 2.53), and IPI score (RR, 2.46). The age groups did not show significance. In the regression model, performance status 2 to 4 was the only independent predictor of treatment-related death (RR, 3.52; 95% confidence interval [CI], 2.98 to 4.06). CONCLUSION: Our results show that in elderly patients with NHL treated with doxorubicin-based chemotherapy the risk for treatment-related death is associated with poor performance status rather than with increasing chronologic age.

Factor V Leiden (R506Q) and risk of venous thromboembolism: a case-control study based on the Spanish population.

Resistance to activated protein C (APC) is a frequent cause of thrombophilia. Most patients showing APC-resistance have a G to A mutation at codon 506 of the factor V that converts arginine to glutamine. This mutation is present in populations worldwide with frequencies ranging from 0.01 to 0.05. Genotyping of 150 control individuals from the Spanish population showed that 3.33% of them carried the mutation. Several studies have measured resistance to APC (following a classical functional assay) and have determined the factor V genotype in a number of thrombophilic patients, in an attempt to compare the predictive value of both laboratory methods. To assess the incidence of the factor V mutation among Spanish thrombophilic patients, we genotyped 51 of these. The frequency of mutation carriers rose from 3.33% in the controls to 53% in the patients. We found significant differences for the thrombosis-free survival curves and for the age at the first thrombotic event between patients who carried or did not carry the mutation. Analysis of relatives of 16 patients who carried the factor V mutation suggests the existence of additional genes that modulate the effect of the factor V gene in the development of venous thrombosis among carriers of the G to A mutation.

Cefotaxima vs. cefalotina-gentamicina en el primer episodio febril de pacientes con tumores sólidos y neutropenia de corta duración / Cefotaxime vs Cephalotin-Gentamicin in the first febrile episode of patients having solid tumors and short-term neutropenia

Las infecciones no tratadas en un paciente neutropénico son rápidamente fatales y está plenamente justificado el uso de antibióticos en forma empírica. En el Instituto Nacional de Enfermedades Neoplásicas (INEN) el régimen de elección habitual para pacientes con el primer episodio febril con tumores sólidos y neutropenia de corta duración, es la asociación de gentamicina más cefalotina. Con el efecto de comparar la eficacia y toxicidad de un régimen de monoterapia con cefotaxima con este régimen combinado, llevamos a cabo un estudio prospectivo y randomizado comparando cefotaxima (1 g/8 h) versus la combinación de cefalotina (1 g/6 h) y gentamicina (4 mg/kg/día-dosis única-). Seleccionamos pacientes con tumores sólidos en el primer episodio febril que recibieron quimioterapia y desarrollaron neutropenia menor de 1000 neutrófilos/mm3. Con una duración esperada menor de 10 días. Se incluyeron 64 pacientes en el brazo de cefotaxima y 72 en el de cefalotina-gentamicina. El estudio se llevó a cabo entre mayo de 1993 hasta junio de 1994. La tasa de respuestas para el grupo de pacientes tratados con cefotaxima fue 75 por ciento y para el grupo tratado con cefalotina-gentamicina 69 por ciento. Las tasas de respuestas completas en los pacientes con infecciones microbiológicamente documentadas fueron 65.5 por ciento para el brazo de cefotaxima y 63.4 por ciento para el brazo de cefalotina-gentamicina. Los índices de falla fueron 23 por ciento para los pacientes incluidos en el brazo de cefotaxima y 30 por ciento para los pacientes tratados con cefalotina-gentamicina. No se demostró diferencias significativas en los índices de respuesta entre los dos brazos de tratamiento. No observamos efectos tóxicos secundarios que obligaran a suspender el tratamiento en ninguno de los dos esquemas. En conclusión: los índices de respueta obtenidos con los dos esquemas de tratamiento son adecuados en nuestro medio para la población de pacientes portadores de tumores sólidos que reciben quimioterapia y presenten un efecto infeccioso durante un período de neutropenia menor de 10 días. La combinación cefalotina-gentamicina requiere no sólo de un esquema posológico de mayor complejidad sino que también tiene una toxicidad potencialmente mayor y requiere de monitorización estrecha. La eficacia terapéutica fue mayor en el grupo que recibió cefotaxima, diferencia que no alcanzó significación estadística

Metopimazina en la prevención de la náusea y el vómito, inducido por quimioteapia a base de cisplatino en múltiples dosis / Metopimazine in prevention of nausea and vomiting chemoterapy induced (cisplatin)

Entre abril de 1993 y marzo 1994 llevamos a cabo el presente estudio con el fin de evaluar la eficacia de la metopimazina en la prevención de la emesis inducida por regímenes de platino administrados en cinco días. La metopimazina es un derivado fenotiacínico con moderada actividad antiemética. Este fue un estudio abierto, prospectivo y randomizado. Comparamos dos forma de administración de metopimazina: Régimen A: 25 mgr., 6 hr/días 1-5 EV, Régimen B: 50 mgr. antes y 4 horas después de la dosis de cisPlatino días 1-5 EV. Se utilizó además como parte de la antiemesis en ambos brazos de tratamiento: dexametasona 12 mgrs., clorfeniramina 8 mgr. y diazepán 10 mgrs. Todos los pacientes estuvieron hospitalizados. Ingresaron 70 pacientes de los cuales fueron evaluables 69. El promedio de edad fue 34.3 años (R: 16-63). La relación M/F 37/32. La distribución de neoplasias fue: testículo (40), cáncer de cérvix (21), tumores germinales del ovario (6), tumores germinales extragonadales (2). Ninguno tuvo metástasis hepática, ni al SNC; al ingreso 27 pacientes recibieron quimioterapia (Qt) por primera vez y el resto entre 2 a 5 cursos de Qt. Los esquema utilizados fueron: BEP (37 cursos), BIP (21 cursos), PEI (10 cursos). No encontramos diferencias en la distribución por edad, sexo, neoplasia, esquema de quimioterapia y número de cursos de quimioterapia recibidas entre los brazos de tratamiento. El 29 por ciento (95 por ciento CI 18.3-39.7) de los pacientes tuvieron control absoluto de las náuseas y el 24.6 por ciento tuvieron control absoluto de los vómitos durante los 5 días de tratamiento. Uno de nuestros pacientes incluido en el brazo B, fue retirado del estudio por haber presentado un evento de hipotensión y alteración de conciencia al iniciarse la administración de metopimazina. No se demostraron otros efectos adversos. Conclusión: metopimazina en la forma intravenosa puede ser una alternativa en la prevención de la náusea y el vómito inducidos por quimioterapia a base de cisPlatino. Se propone un estudio comparativo con otros regímenes considerados de uso estándar para comparar sus resultados

[Lymphomas of the gastrointestinal tract: a neoplastic disease of underdevelopment]. / Linfomas del tracto gastrointestinal: una enfermedad neoplásica del subdesarrollo.

458/3,495 malignant lymphomas seen at the Instituto de Enfermedades Neoplásicas between 1965-1992, had primary extranodal disease in the GI tract. This is one of the largest institutional series reported, which would suggest that this is a relatively frequent malignancy in Peruvian population. Fifty per cent of cases had a primary in the small bowel and 38.9 per cent in the stomach. The age at presentation, the clinical picture and the location at the intestine show similarities with the so called Mediterranean lymphoma. Cases were classified according to the TNM system, and patients in stages I-II were surgically resected; 80 per cent of them were alive and free of disease at 5 years. Gastric lymphomas with inoperable disease were treated with chemotherapy with a 5-year survival of 50 per cent.

Selection for pupation height in Drosophila melanogaster.

Divergent directional selection for high and low pupation height was practiced in D. melanogaster. A quick response was observed in the two directions of selection. This is the first time selection for low pupation sites was successful. Realized heritabilities were 18% and 13% for the high and low lines. Reciprocal crosses between divergent lines showed little or no dominance for low pupation sites. The need for a strict control of environmental factors when measuring pupation height is emphasized.