How EU policies could reduce nutrient pollution in European inland and coastal waters.

Intensive agriculture and densely populated areas represent major sources of nutrient pollution for European inland and coastal waters, altering the aquatic ecosystems and affecting their capacity to provide ecosystem services and support economic activities. Ambitious water policies are in place in the European Union (EU) for protecting and restoring aquatic ecosystems under the Water Framework Directive and the Marine Strategy Framework Directive. This research quantified the current pressures of point and diffuse nitrogen and phosphorus emissions to European fresh and coastal waters (2005-2012), and analysed the effects of three policy scenarios of nutrient reduction: 1) the application of measures currently planned in the Rural Development Programmes and under the Urban Waste Water Treatment Directive (UWWTD); 2) the full implementation of the UWWTD and the absence of derogations in the Nitrates Directive; 3) high reduction of nutrient, using best technologies in wastewaters treatment and optimal fertilisation in agriculture. The results of the study show that for the period 2005-2012, the nitrogen load to European seas was 3.3-4.1 TgN/y and the phosphorus load was 0.26-0.30 TgP/y. Policy measures supporting technological improvements (third scenario) could decrease the nutrient export to the seas up to 14% for nitrogen and 20% for phosphorus, improving the ecological status of rivers and lakes, but widening the nutrient imbalance in coastal ecosystems (i.e. increasing nitrogen availability with respect to phosphorus), affecting eutrophication. Further nutrient reductions could be possible by a combination of measures especially in the agricultural sector. However, without tackling current agricultural production and consumption system, the reduction might not be sufficient for achieving the goals of EU water policy in some regions. The study analysed the expected changes and the source contribution in different European regional seas, and highlights the advantages of addressing the land-sea dynamics, checking the coherence of measures taken under different policies.

Cisplatin and escalating doses of paclitaxel and epirubicin in advanced ovarian cancer. A phase I study.

PURPOSE: The combination of paclitaxel and cisplatin is considered the standard regimen for advanced ovarian cancer (AOC). A meta-analysis has shown that the incorporation of anthracyclines into first-line chemotherapy might improve long-term survival by 7-10%. We designed a phase I-II study in patients with AOC using a combination of a fixed dose of cisplatin with paclitaxel and epirubicin both given at escalating doses every 3 weeks. The objectives of this study were to determine both the maximum tolerated dose (MTD) and the antitumor activity of this combination. METHODS: Six different dose levels were planned. The starting doses were cisplatin 75 mg/m2, paclitaxel 140 mg/m2, and epirubicin 50 mg/m2. The doses of paclitaxel were escalated in 20-mg/m2 increments, alternating with 20-mg/m2 increments of epirubicin. Ten patients with AOC entered the phase I study. Three patients each were enrolled at level I and level II and four patients at level III, and at each level, 15 courses were administered. Patients received a median of five courses. RESULTS: Nonhematological toxicity was generally mild, except for grade 3 mucositis in one course at levels II and III, and grade 3 vomiting in one course at levels I and III. Hematological toxicities were grade 3-4 neutropenia in 60%, 47% and 60% of courses at levels I, II and III, respectively, and grade 3 anemia in one course at level III. At level III two of four patients developed a dose-limiting toxicity which was grade 4 neutropenia lasting more than 1 week. CONCLUSIONS: The MTD was reached at level II with cisplatin 75 mg/m2, paclitaxel 160 mg/m2, and epirubicin 50 mg/m2. The phase II part of the study is currently ongoing.

High efficacy of paclitaxel and doxorubicin as first-line therapy in advanced breast cancer: a phase I-II study.

The aim of this study was to define the maximum tolerated dose (MTD) of paclitaxel (TAX) in combination with doxorubicin (ADM). To evaluate the efficacy and tolerability of this combination, TAX was administered in escalating doses of 30 mg/m2, starting from 120 mg/m2, by 1 hour continuous infusion, per group of three patients; ADM was administered at a fixed dose of 50 mg/m2, 24 hours before administering TAX (phase 1). The combination was recycled every 3 weeks. In phase II, TAX was administered at the MTD defined in phase I. Thirty-six women were enrolled. The MTD of TAX was 220 mg/m2. Objective responses were observed in 28/34 (82%) assessable patients. The median progression-free survival was 11.8 months and overall survival 27.8 months. The main clinical toxicity was neutropenia (grade III-IV) of short duration (94%). Two patients developed cardiac toxicity. The combination TAX+ADM is very effective in advanced breast cancer.

Ifosfamide and vinorelbine in advanced pretreated ovarian cancer: a phase II study.

PURPOSE: The response rate to salvage chemotherapy in advanced ovarian cancer (AOC) has been disappointing in patients who do not respond or relapse after platinum-containing regimens. Ifosfamide (IFO) showed an overall response rate of 20% and vinorelbine (VNR) 15.6%. Trials of the association of these two drugs for AOC have not yet been published. PATIENTS AND METHODS: Between April 1996 and August 1997, 17 patients with AOC were treated with intravenous IFO 2000 mg/m2 per day, days 1 to 3, with mesna uroprotection, and VNR 25 mg/m2 per day, days 1 and 8, every 3 weeks. All patients but one had been heavily pretreated. All patients had been treated with platinum compounds and 16/17 with taxanes. RESULTS: All 17 patients were evaluable for toxicity, and 16 for response (one lost to follow-up). One patient showed a partial response, 12 progressive disease and three stable disease. No complete responses were observed. The main toxicity was neutropenia (grade 3-4 in 82% of patients) with neutropenic fever in 17.6% of patients. In 70.5% of patients (19/59 of courses) VNR was not administered on day 8. In four patients (10/59 courses) the dose was reduced by 25% for persistent leukopenia grade 2-3. Other toxicities were not significant. CONCLUSIONS: This combination showed no activity in this set of patients. The poor outcome, as compared with the significant activity reported with the agents used singly, could be ascribed to the patients' characteristics, the low dose intensity of VNR administered and possible cross-resistance between the study drugs and previously used agents.

Paclitaxel as salvage therapy in advanced pretreated ovarian cancer: a phase II study.

The response rate to salvage chemotherapy in advanced ovarian cancer has been disappointing in patients who do not respond or who relapse after platinum-containing regimens. In these cases, the identification of new drugs is a substantial challenge. The efficacy of one of these, paclitaxel, has already been assessed in many phase II trials. From July 1993 to October 1995, 33 patients with advanced ovarian cancer, recurrent or refractory after platinum-based regimens, entered our study. Paclitaxel was given by 3-hour intravenous infusion every 3 weeks. All the patients were evaluable for toxicity and 27 for response. Nine patients (33.3%) responded: 6 complete (22.2%) and 3 partial responses (11.1%). Six responses (35.3%) were observed in the 17 platinum-resistant patients and 3 (30%) in the 10 platinum-responders. World Health Organization (WHO) grade 3-4 neutropenia was common (13/33 patients, 39.4%) and peripheral neurotoxicity was observed in 29 patients (87.8%), but was WHO grade 3 in four cases (12.1%). Alopecia was ubiquitous, whereas other toxic effects were not significant. The overall response rate to paclitaxel in this study is similar to that reported in others and the high complete response (CR) rate should be emphasized. These data confirm the significant activity and safety of this drug in patients with advanced ovarian cancer, even in platinum-resistant cases.

Paclitaxel neurotoxicity: clinical and neurophysiological study of 23 patients.

Paclitaxel is the prototype of a new class of chemotherapeutic agents with an antimitotic effect that is related to its ability to interfere with the microtubule system. It causes peripheral neurological toxicity by means of its activity on the axonal microtubules. To define the clinical and neurophysiological characteristics of paclitaxel neuropathy 23 patients undergoing paclitaxel therapy at a dose of 175 mg/m2 were studied. The patients were divided into two groups, with only one group receiving pretreatment with potentially neurotoxic drugs such as cisplatin and carboplatin. The results showed a high incidence of mild neurotoxicity in both groups. Treatment was discontinued due to severe neurotoxicity in only one patient pretreated with platinum-compounds. The clinical and neurophysiological data make it possible to define paclitaxel neurotoxicity as a distal axonal neuropathy with a summatory effect in patients pretreated with cisplatin; the possible reversibility of paclitaxel neurotoxicity requires further confirmation.