New treatments for advanced cancer: an approach to prioritization

The allocation of funding for new anticancer treatments within the UK has not kept pace with demand. Clinicians find themselves restricted in the use of licensed drugs which they feel are in the best interests of individual patients. Against this, health authorities have a duty to ensure that scarce resources are used equitably to meet the needs of the local population as a whole. Differential levels of funding for new treatments across the country have led to concerns about rationing by postcode. This paper outlines an approach to the prioritization of new treatment for advanced cancer developed jointly by clinicians and health authorities in South London. The approach involves evidence reviews and consensus meetings. Existing and new treatments are rated on a four-point ‘relative effectiveness scale’, which takes account of the impact of the treatment on quality of life and on survival. The strength of evidence supporting each effectiveness rating is also classified. Health Authorities have used these ratings to determine overall funding levels, while leaving decisions on individual patients to the relevant Trusts. © 2000 Cancer Research Campaig

Colon and rectal cancer incidence and water trihalomethane concentrations in New South Wales, Australia

BACKGROUND There is evidence, although inconsistent, that long term exposure to disinfection by products (DBPs) increases the risk of bowel cancer. No study has been conducted in Australia to examine this association and due to difference in the methods of disinfection the risk can vary across geographical regions and. This study was conducted to analyse the association of trihalomethanes (THMs) in water with colon and rectal cancer in NSW Australia. METHODS Average yearly concentrations of total and individual species of THMs were obtained for 50 local government areas (LGAs). Indirectly-standardized incidence rates of colon and rectal cancers in LGAs for the period 1995 to 2001 were regressed against mean THM concentrations lagged five years, adjusting for socioeconomic status, high risk drinking, smoking status, usual source of water and year of diagnosis, including local and global random effects within a Bayesian framework. The incidence rate ratios (IRRs) for an interquartile range (IQR) increase in THMs were estimated. RESULTS Using five year lag of exposure there was a positive association between bromoform concentration and CRC in men (IRR = 1.025, 95% CI 1.010, 1.040) but not in women (IRR = 1.003, 95% CI 0.987, 1.018). The association in men was mainly found in colon cancer with bromoform (IRR = 1.035, 95% CI 1.017, 1.053). There was no appreciable association of colorectal cancer with other species of THMs. Sensitivity analyses did not materially change the associations observed. CONCLUSION A positive association was observed between colon cancer and water bromoform concentrations in men. Given the potential population impact of such an association, further research into the relationship between THMs, particularly brominated species, and colorectal cancer is warranted.This study was conducted as part of a PhD thesis. The PhD was funded by the Endeavor International Postgraduate Research Scholarship program of the Australian Government and the University of Sydney’s international postgraduate award program and Sydney School of Public Health. The expenditure for data collection was borne by the Sydney School of Public Health, the University of Sydney. The case data were provided by the NSW central cancer registry. The exposure data were provided by the Sydney Water Corporation and the Hunter Water Corporation in NSW, Australia

Iododoxorubicin in advanced breast cancer: a phase II evaluation of clinical activity, pharmacology and quality of life.

Iododoxorubicin 80 mg m-2 i.v. was given 3 weekly for a maximum of six cycles as first-line chemotherapy to 14 evaluable women with metastatic breast cancer. The response rate was 14% (95% confidence intervals 4-40%); median time to progression was 3.5 months (range 0.7 to > 9.3) and median survival was 10.2 months (range 2.3 to > 20.4). Neutropenia was the main toxicity but was not associated with severe sepsis. Two patients had a significant (> 10%) but asymptomatic fall in cardiac ejection fraction; other toxicities were mild. Plasma pharmacokinetics was studied during the first cycle of treatment. Iododoxorubicin was extensively metabolised to iododoxorubicinol. Neutropenia and thrombocytopenia were both significantly correlated with the area under the concentration-time curve (AUC) for iododoxorubicin and the total AUC for iododoxorubicin and iododoxorubicinol. Quality of life (QOL), evaluated by self-report questionnaire and interview, showed little evidence of benefit in terms of physical symptom relief, level of activity, psychological symptoms or global evaluation of QOL during treatment. Iododoxorubicin is subjectively less toxic than standard anthracyclines, but at the dose and schedule used has limited activity in metastatic breast cancer, possibly because iododoxorubicinol is not clinically active

Costs and consequences of different chemotherapy regimens in metastatic colorectal cancer

An economic sub-study was run alongside a large multi-centre randomised trial (MRC-CR06) comparing three chemotherapy regimens; de Gramont, Lokich and raltitrexed in patients with metastatic colorectal cancer. Patients in six of 45 centres in the main trial were approached to take part in the sub-study. Chemotherapy delivery costs were assessed in each sub-study centre with external validity verified by questionnaire to all other centres. Patient representativeness was assessed. Stochastic resource use data, including patient borne costs and non-hospital health service resource use were monitored prospectively. Mean total societal costs were de Gramont=£5051 (s.d. £1910), raltitrexed=£2616 (s.d. £991) and Lokich=£2576 (s.d. £1711). In pairwise comparisons, statistically significant mean total cost differences were shown for de Gramont vs Lokich (mean difference=£2475, 95%CI £914–£4037, P<0.01) and for de Gramont vs raltitrexed (mean difference=£2435, 95%CI £922–£2948, P<0.01). Sensitivity analyses showed little effect on overall costs. The main trial showed de Gramont and Lokich to be equally effective in terms of survival, quality of life and response rates but Lokich had higher toxicity and hand-foot syndrome. Raltitrexed showed similar response rates and overall survival but increased toxicity and inferior quality of life making it a clinically inferior regimen despite its ease of administration and costs. For a comparable clinical outcome, Lokich can be administered for approximately half the cost of de Gramont

Antarctic Climate Change and the Environment

The Antarctic climate system varies on timescales from orbital, through millennial to sub-annual, and is closely coupled to other parts of the global climate system. We review these variations from the perspective of the geological and glaciological records and the recent historical period from which we have instrumental data (the last 50 years). We consider their consequences for the biosphere, and show how the latest numerical models project changes into the future, taking into account human actions in the form of the release of greenhouse gases and chlorofluorocarbons into the atmosphere. In doing so, we provide an essential Southern Hemisphere companion to the Arctic Climate Impact Assessment

Can nuclear weapons fallout mark the beginning of the Anthropocene Epoch?

Many scientists are making the case that humanity is living in a new geological epoch, the Anthropocene, but there is no agreement yet as to when this epoch began. The start might be defined by a historical event, such as the beginning of the fossil-fueled Industrial Revolution or the first nuclear explosion in 1945. Standard stratigraphic practice, however, requires a more significant, globally widespread, and abrupt signature, and the fallout from nuclear weapons testing appears most suitable. The appearance of plutonium 239 (used in post- 1945 above-ground nuclear weapons tests) makes a good marker: This isotope is rare in nature but a significant component of fallout. It has other features to recommend it as a stable marker in layers of sedimentary rock and soil, including: long half-life, low solubility, and high particle reactivity. It may be used in conjunction with other radioactive isotopes, such as americium 241 and carbon 14, to categorize distinct fallout signatures in sediments and ice caps. On a global scale, the first appearance of plutonium 239 in sedimentary sequences corresponds to the early 1950s. While plutonium is easily detectable over the entire Earth using modern measurement techniques, a site to define the Anthropocene (known as a Ògolden spikeÓ) would ideally be located between 30 and 60 degrees north of the equator, where fallout is maximal, within undisturbed marine or lake environments

Pliocene Te Aute limestones, New Zealand: Expanding concepts for cool-water shelf carbonates

Acceptance of a spectrum of warm- through cold-water shallow-marine carbonate facies has become of fundamental importance for correctly interpreting the origin and significance of all ancient platform limestones. Among other attributes, properties that have become a hallmark for characterising many Cenozoic non-tropical occurrences include: (1) the presence of common bryozoan and epifaunal bivalve skeletons; (2) a calcite-dominated mineralogy; (3) relatively thin deposits exhibiting low rates of sediment accumulation; (4) an overall destructive early diagenetic regime; and (5) that major porosity destruction and lithification occur mainly in response to chemical compaction of calcitic skeletons during moderate to deep burial. The Pliocene Te Aute limestones are non-tropical skeletal carbonates formed at paleolatitudes near 40-42°S under the influence of commonly strong tidal flows along the margins of an actively deforming and differentially uplifting forearc basin seaway, immediately inboard of the convergent Pacific-Australian plate boundary off eastern North Island, New Zealand. This dynamic depositional and tectonic setting strongly influenced both the style and subsequent diagenetic evolution of the limestones. Some of the Te Aute limestones exhibit the above kinds of "normal" non-tropical characteristics, but others do not. For example, many are barnacle and/or bivalve dominated, and several include attributes that at least superficially resemble properties of certain tropical carbonates. In this regard, a number of the limestones are infaunal bivalve rich and dominated by an aragonite over a calcite primary mineralogy, with consequently relatively high diagenetic potential. Individual limestone units are also often rather thick (e.g., up to 50-300 m), with accumulation rates from 0.2 to 0.5 m/ka, and locally as high as 1 m/ka. Moreover, there can be a remarkable array of diagenetic features in the limestones, involving grain alteration and/or cementation to widely varying extents within any, or some combination of, the marine phreatic, burial, and meteoric diagenetic environments, including locally widespread development of meteoric cement sourced from aragonite dissolution. The message is that non-tropical shelf carbonates include a more diverse array of geological settings, of skeletal and mineralogical facies, and of diagenetic features than current sedimentary models mainly advocate. While several attributes positively distinguish tropical from non-tropical limestones, continued detailed documentation of the wide spectrum of shallow-marine carbonate deposits formed outside tropical regions remains an important challenge in carbonate sedimentology

Extraordinary human energy consumption and resultant geological impacts beginning around 1950 CE initiated the proposed Anthropocene Epoch

Growth in fundamental drivers—energy use, economic productivity and population—can provide quantitative indications of the proposed boundary between the Holocene Epoch and the Anthropocene. Human energy expenditure in the Anthropocene, ~22 zetajoules (ZJ), exceeds that across the prior 11,700 years of the Holocene (~14.6 ZJ), largely through combustion of fossil fuels. The global warming effect during the Anthropocene is more than an order of magnitude greater still. Global human population, their productivity and energy consumption, and most changes impacting the global environment, are highly correlated. This extraordinary outburst of consumption and productivity demonstrates how the Earth System has departed from its Holocene state since ~1950 CE, forcing abrupt physical, chemical and biological changes to the Earth’s stratigraphic record that can be used to justify the proposal for naming a new epoch—the Anthropocene