Defining and analysing symptom palliation in cancer clinical trials: a deceptively difficult exercise

The assessment of symptom palliation is an essential component of many treatment comparisons in clinical trials, yet an extensive literature search revealed no consensus as to its precise definition, which could embrace relief of symptoms, time to their onset, duration, degree, as well as symptom control and prevention. In an attempt to assess the importance of these aspects and to compare different methods of analysis, we used one symptom (cough) from a patient self-assessment questionnaire (the Rotterdam Symptom Checklist) in a large (>300 patient) multicentre randomized clinical trial (conducted by the Medical Research Council Lung Cancer Working Party) of palliative chemotherapy in small-cell lung cancer. The regimens compared were a two-drug regimen (2D) and a four-drug regimen (4D). No differences were seen between the regimens in time of onset of palliation or its duration. The degree of palliation was strongly related to the initial severity: 90% of the patients with moderate or severe cough at baseline reported improvement, compared with only 53% of those with mild cough. Analyses using different landmark time points gave conflicting results: the 4D regimen was superior at 1 month and at 3 months, whereas at 2 months the 2D regimen appeared superior. When improvement at any time up to 3 months was considered, the 4D regimen showed a significant benefit (4D 79%, 2D 60%, P = 0.02). These findings emphasize the need for caution in interpreting results, and the importance of working towards a standard definition of symptom palliation. The current lack of specified criteria makes analysis and interpretation of trial results difficult, and comparison across trials impossible. A standard definition of palliation for use in the analysis of clinical trials data is proposed, which takes into account aspects of onset, duration and degree of palliation, and symptom improvement, control and prevention. © 1999 Cancer Research Campaig

Derivation of predicted no-effect concentrations for lindane, 3,4-dichloroaniline, atrazine, and copper

Environmental risk assessment is a key feature of regulations controlling the placing of new, and the maintenance of existing, chemicals products in the market place. For example, European Commission Directive 93/67/EC on Risk Assessment for New Notified Substances and Commission Regulation (EC) No. 1488/94 on Risk Assessment for Existing Substances requires that risk assessments be carried out for new and existing substances in the European Community. The process of environmental risk assessment seeks to determine the balance of probability of species and communities being damaged by chemical releases. The process relies upon a valid estimation of a predicted environmental concentration (PEC) in relevant environmental compartments and a predicted no effect concentration (PNEC) below which the organisms present in that compartment are unlikely to be significantly affected. If the PEC exceeds the PNEC there is a potential for damaging effects to occur. This article focuses on the determination of PNECs for risk assessment. Methods for determining a PNEC described in OECD Monograph 26 (1989, Report of the OECD Workshop on Ecological Effect Assessment, Paris, France, have been applied to data derived for the four chemicals lindane, 3,4-dichloroaniline, atrazine, and copper in a series of collaborative research projects funded by the European Commission

Development of methods for evaluating toxicity to freshwater ecosystems

This article presents a summary of a collaborative research program involving five European research groups, that was partly funded by the European Commission under its Environmental Research Program. The objective of the program was to develop aquatic toxicity tests that could be used to obtain data for inclusion at Level 2 of the Risk Evaluation Scheme for the Notification of Substances as required by the 7th Amendment to EC Directive 79/831/EEC. Currently only a very limited number of test methods have been described that can be used for this purpose and these are based on an even smaller number of test species. Tests based upon algae (Chlamydomonas reinhardi, Scenedesmus subspicatus, and Euglena gracilis), protozoa (Tetrahymena pyriformis), rotifera (Brachionus calyciflorus), crustacea (Gammarus pulex), and diptera (Chironomus riparius) were developed. The tests encompassed a range of end points and were evaluated against four reference chemicals: lindane, 3, 4-dichloroaniline (DCA), atrazine, and copper. The capacity of the tests to identify concentrations that are chronically toxic in the field was addressed by comparing the effects threshold concentrations determined in the laboratory tests with those determined for similar and/or related species and end points in stream and pond mesocosm studies. The lowest no-observed-effect concentrations (NOEC), EC(x), or LC(x) values obtained for lindane, atrazine, and copper were comparable with the lowest values obtained in the mesocosms. The lowest chronic NOEC determined for DCA using the laboratory tests was approximately 200 times higher than the lowest NOEC in the mesocosms

The development of toxicity tests for freshwater pollutants and their validation in stream and pond mesocosms

The number and variety of freshwater species and bioassay procedures currently recommended in European Directives for assessing the risk posed by pollutants to freshwater ecosystems is rather limited. The aim of the three consecutive European Commission-sponsored programmes described here was to modify or develop new laboratory methods that could be used for evaluating toxicity to freshwater species and which would be suitable for incorporation into the current "notification scheme" for new substances. An essential phase of each project was a validation process in which results of laboratory tests were compared with values obtained in the field using structural and functional responses of communities. The laboratory tests were developed by Fraunhofer-Institut für Umweltchemie und Ökotoxikologie (FhG) Potsdam-Rehbrücke with algae, protozoa and a variety of in vitro cellular/subcellular preparations; by the State University of Ghent with water column invertebrates, and by Cardiff University with benthic invertebrates. The laboratory tests included in vitro procedures, conventional whole organism single species tests, simple multi-species systems and microcosms. The field validation was carried out by Shell Research Sittingbourne employing artificial streams and by FhG Schmallenberg and GSF-Forschungszentrum für Umwelt und Gesundheit, Munich with artificial ponds and included single species responses but also structural and functional community responses. The same reference chemicals: lindane, copper, 3,4-dichloroaniline and atrazine were used by all laboratories. A comparison of the most sensitive toxicity response determined for each reference chemical using the laboratory toxicity tests, with that determined by the field simulation procedures revealed that for the reference chemicals lindane, copper and atrazine, adverse effects were not detected either for single organisms or for structural and functional characteristics of the community or ecosystem, at concentrations below those identified in the laboratory toxicity tests. In the case of dichloroaniline, however, effects on the population dynamics of one species in the pond mesocosm were recorded at a concentration ×16 below that reported in the laboratory. We conclude that appropriately designed, relatively simple and inexpensive laboratory toxicity tests with a selection of test species are generally adequate, with small application factors, for predicting the environmental risk of polluting chemicals to freshwater ecosystems

Differential susceptibility of pine weevil, Hylobius abietis (Coleoptera: Curculionidae), larvae and pupae to entomopathogenic nematodes and death of adults infected as pupae

The large pine weevil Hylobius abietis is a serious pest of reforestation in northern Europe. Development takes place in the stumps of felled conifer trees and emerging adults feed on and kill newly planted trees. Application of entomopathogenic nematodes around tree stumps has been shown to reduce the emergence of adult weevils. In order to target application at the most susceptible stage, the susceptibility of larvae and pupae to Heterorhabditis downesi and Steinernema carpocapsae was compared in a close-contact assay on filter paper. An average of 95.8 % of larvae were killed by H. downesi and 82.1 % by S. carpocapsae while only 16.3 and 15.0 % of pupae were killed by these two species, respectively. However, many of the H. abietis that were exposed as pupae died after metamorphosis to callow adult, with mortality of pupae and callow adults combined reaching 62.5 % for H. downesi and 69.9 % for S. carpocapsae. For both nematode species significantly more insects died as larvae than as either pupae or pupae/callow adults. When pupae were exposed to infective juveniles (IJs) for 2 days and were then washed while still pupae to remove surface IJs, adults were later found to be infected indicating that IJs can infect pupae, survive metamorphosis and subsequently kill adults