Dose and schedule-finding study of oral topotecan and weekly cisplatin in patients with recurrent ovarian cancer

Both weekly cisplatin chemotherapy and single agent topotecan have proven to be effective in recurrent ovarian cancer. Preclinical data show synergism between cisplatin and topotecan. Side effects for this combination are drug sequence dependent and predominantly haematologic. Since preclinical data suggest that Cremophor EL (CrEL), the formulation vehicle of paclitaxel, has a protective effect on haematological toxicity of cisplatin, CrEL was added to the combination cisplatin and topotecan. In this phase I study, escalating doses of oral topotecan administered on day 1, 2, 8, 9, 15, 16, 29, 30, 36, 37, 43, 44 were combined with weekly cisplatin 70 mg m−2d−1on day 1, 8, 15, 29, 36, 43 (scheme A) or with the presumably less myelotoxic sequence weekly cisplatin day 2, 9, 16, 30, 37, 44 (scheme B). In scheme C, CrEL 12 ml was administered prior to cisplatin in the sequence of Scheme A. 18 patients have received a total of 85 courses. In scheme A 4/10 patients, all treated with topotecan 0.45 mg m−2d−1, experienced DLT: 1 patient had vomiting grade 4, 1 patient had grade 4 neutropenia >5 days, 1 patient had >2 weeks delay due to thrombocytopenia and 1 patient due to neutropenia. Both patients in scheme B (topotecan 0.45 mg m−2d−1) had DLT due to a delay > 2 weeks because of prolonged haematological toxicity. No DLT was observed in the first 3 patients in scheme C (topotecan 0.45 mg m−2d−1). However, 2 out of 3 patients treated at dose level topotecan 0.60 mg m−2d−1in scheme C experienced DLT due to >2 weeks delay because of persistent thrombocytopenia or neutropenia. We conclude that there is a modest clinical effect of CrEL on haematological toxicity for this cisplatin-based combination regimen, which seems to reduce these side effects but does not really enable an increase of the oral topotecan dose. © 2001 Cancer Research Campaign  http://www.bjcancer.co

Derivation, internal validation, and recalibration of a cardiovascular risk score for Latin America and the Caribbean (Globorisk-LAC): A pooled analysis of cohort studies

Background Risk stratification is a cornerstone of cardiovascular disease (CVD) prevention and a main strategy proposed to achieve global goals of reducing premature CVD deaths. There are no cardiovascular risk scores based on data from Latin America and the Caribbean (LAC) and it is unknown how well risk scores based on European and North American cohorts represent true risk among LAC populations. Methods We developed a CVD (including coronary heart disease and stroke) risk score for fatal/non-fatal events using pooled data from 9 prospective cohorts with 21,378 participants and 1,202 events. We developed laboratory-based (systolic blood pressure, total cholesterol, diabetes, and smoking), and office-based (body mass index replaced total cholesterol and diabetes) models. We used Cox proportional hazards and held back a subset of participants to internally validate our models by estimating Harrell's C-statistic and calibration slopes. Findings The C-statistic for the laboratory-based model was 72% (70–74%), the calibration slope was 0.994 (0.934–1.055) among men and 0.852 (0.761–0.942) among women; for the office-based model the C-statistic was 71% (69–72%) and the calibration slope was 1.028 (0.980–1.076) among men and 0.811 (0.663–0.958) among women. In the pooled sample, using a 20% risk threshold, the laboratory-based model had sensitivity of 21.9% and specificity of 94.2%. Lowering the threshold to 10% increased sensitivity to 52.3% and reduced specificity to 78.7%. Interpretation The cardiovascular risk score herein developed had adequate discrimination and calibration. The Globorisk-LAC would be more appropriate for LAC than the current global or regional risk scores. This work provides a tool to strengthen risk-based cardiovascular prevention in LAC

Impact of common cardio-metabolic risk factors on fatal and non-fatal cardiovascular disease in Latin America and the Caribbean: An individual-level pooled analysis of 31 cohort studies

Background: Estimates of the burden of cardio-metabolic risk factors in Latin America and the Caribbean (LAC) rely on relative risks (RRs) from non-LAC countries. Whether these RRs apply to LAC remains unknown. Methods: We pooled LAC cohorts. We estimated RRs per unit of exposure to body mass index (BMI), systolic blood pressure (SBP), fasting plasma glucose (FPG), total cholesterol (TC) and non-HDL cholesterol on fatal (31 cohorts, n=168,287) and non-fatal (13 cohorts, n=27,554) cardiovascular diseases, adjusting for regression dilution bias. We used these RRs and national data on mean risk factor levels to estimate the number of cardiovascular deaths attributable to non-optimal levels of each risk factor. Results: Our RRs for SBP, FPG and TC were like those observed in cohorts conducted in high-income countries; however, for BMI, our RRs were consistently smaller in people below 75 years of age. Across risk factors, we observed smaller RRs among older ages. Non-optimal SBP was responsible for the largest number of attributable cardiovascular deaths ranging from 38 per 100,000 women and 54 men in Peru, to 261 (Dominica, women) and 282 (Guyana, men). For non-HDL cholesterol, the lowest attributable rate was for women in Peru (21) and men in Guatemala (25), and the largest in men (158) and women (142) from Guyana. Interpretation: RRs for BMI from studies conducted in high-income countries may overestimate disease burden metrics in LAC; conversely, RRs for SBP, FPG and TC from LAC cohorts are similar to those estimated from cohorts in high-income countries. Funding: Wellcome Trust (214185/Z/18/Z)Fil: Carrillo Larco, Rodrigo M.. Imperial College London; Reino UnidoFil: Stern, Dalia. Instituto Nacional de Salud Publica (insp);Fil: Hambleton, Ian R.. The University Of The West Indies; BarbadosFil: Hennis, Anselm. Pan American Health Organization; Estados UnidosFil: Cesare, Mariachiara Di. Middlesex University; Reino UnidoFil: Lotufo, Paulo. Universidade de Sao Paulo; BrasilFil: Ferreccio, Catterina. Pontificia Universidad Católica de Chile; ChileFil: Irazola, Vilma. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; Argentina. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Perel, Pablo. London School of Hygiene and Tropical Medicine; Reino UnidoFil: Gregg, Edward W. Imperial College London; Reino UnidoFil: Miranda, J. Jaime. Universidad Peruana Cayetano Heredia; PerúFil: Ezzati, Majid. Imperial College London; Reino UnidoFil: Danaei, Goodarz. Harvard Medical School; Estados UnidosFil: Aguilar Salinas, Carlos A.. Instituto Nacional de Ciencias Médicas y Nutrición; MéxicoFil: Alvarez Váz, Ramón. Universidad de la República; UruguayFil: Amadio, Marselle B.. Centro Universitario Senac Santo Amaro; BrasilFil: Baccino, Cecilia. Universidad de la República; UruguayFil: Bambs, Claudia. Pontificia Universidad Católica de Chile; ChileFil: Bastos, João Luiz. Universidade Federal de Santa Catarina; BrasilFil: Beckles, Gloria. Centers for Disease Control and Prevention; Estados UnidosFil: Bernabe Ortiz, Antonio. Universidad Peruana Cayetano Heredia; PerúFil: Bernardo, Carla DO. University of Adelaide; AustraliaFil: Bloch, Katia V.. Universidade Federal do Rio de Janeiro; BrasilFil: Blümel, Juan E.. Universidad de Chile; ChileFil: Boggia, Jose G.. Universidad de la República; UruguayFil: Borges, Pollyanna K.. Universidade Estadual do Ponta Grossa; BrasilFil: Bravo, Miguel. MELISA Institute; ChileFil: Brenes Camacho, Gilbert. Universidad de Costa Rica; Costa RicaFil: Carbajal, Horacio A.. Universidad Nacional de La Plata; ArgentinaFil: Castillo Rascón, María Susana. Universidad Nacional de Misiones; Argentin