Phase I clinical and pharmacokinetic study of pemetrexed and carboplatin in patients with malignant pleural mesothelioma.

PURPOSE: To determine the maximum tolerated dose (MTD) of pemetrexed and carboplatin given in combination, to derive a recommended dose for phase II studies, and to explore its efficacy. We assessed toxicities and explored the activity of the drug combination exclusively in patients with malignant pleural mesothelioma (MPM). The pharmacokinetics of both agents was investigated. PATIENTS AND METHODS: Twenty-seven patients (23 male, four female) with MPM were treated on five escalating dose levels. Doses ranged from pemetrexed 400 mg/m(2) (as a 10-minute intravenous infusion), followed by carboplatin area under the plasma concentration-time curve (AUC) 4 mg/mL.min (as a 30-minute intravenous infusion) to pemetrexed 500 mg/m(2), carboplatin AUC 6 mg/mL.min. All patients had a World Health Organization performance status of 1. A total of 163 courses of treatment were administered (median, six; range, one to 10). RESULTS: The main toxicity was hematologic, particularly neutropenia, although this was characteristically short-lived and caused few clinical problems. The MTD was pemetrexed 500 mg/m(2), carboplatin AUC 6, because three of the five patients treated at this dose level experienced a dose-limiting toxicity. Eight partial responses (in 25 assessable patients) were observed for a response rate of 32%. Seventy percent of patients noticed an improvement in symptoms, usually (84%) after only two courses. Median time to progression was 305 days, and median survival time was 451 days. CONCLUSION: The MTD was pemetrexed 500 mg/m(2) and carboplatin AUC 6 mg/mL.min. The recommended phase II dose of the combination is pemetrexed 500 mg/m(2) and carboplatin AUC 5 mg/mL.min. The combination is both active and well tolerated in MPM and deserves further exploration.

Missed opportunities for earlier HIV diagnosis within primary and secondary healthcare settings in the UK.

OBJECTIVE: To identify opportunities for earlier HIV diagnosis within primary and secondary care settings in the UK in Africans with newly diagnosed HIV infection. METHODS: A survey of newly diagnosed HIV-positive Africans attending 15 HIV treatment centres across London was conducted between April 2004 and February 2006. The survey consisted of a confidential self-completed questionnaire linked to clinician-completed clinical records. RESULTS: A total of 263 questionnaires were completed, representing an uptake rate of 79.5% of patients approached and 49.8% (131/263) of participants presented with advanced HIV disease (CD4 cell count < 200 cells/mul at diagnosis). In the year prior to HIV diagnosis 76.4% (181/237) had seen their GP, 38.3% (98/256) had attended outpatient services, and 15.2% (39/257) inpatient services, representing missed opportunities for earlier HIV diagnosis. Of those attending GP services the issue of HIV and/or HIV testing was raised for 17.6% (31/176) and 37.1% (78/210) had a previous negative HIV test, 32.5% of these within the UK. Medical attention was sought for wide ranging reasons, often not obviously connected to underlying HIV status. Despite the population predominantly coming from countries of high HIV prevalence personal appreciation of risk was comparatively low and knowledge of benefits of testing lacking. CONCLUSION: Africans are accessing health services but clinicians are failing to use these opportunities effectively for preventive and diagnostic purposes with regards to HIV infection. Comparatively low appreciation of personal risk and lack of perceived ill health within this community means clinicians need to be more proactive in addressing HIV.