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system. Therefore, leucocyte hypomethylation might represent a kind of paraneoplastic symptom, caused by the demands of the growing tumour for nutrients involved in methyl-group metabolism or by some interference with haematopoiesis. One might therefore expect that hypomethylation is increased with the extension and growth of the tumour. Unfortunately, the researchers did not assess this relation between hypomethylation and tumour growth. Likewise, how the amount of methylation in the leucocytes relates to those seen in the cancer tissue is uncertain. Clearly, the Moore study findings suggest interesting new avenues for research. Moore and colleagues rightly emphasise the need for assays to screen people at risk of bladder cancer and especially for those at risk of recurrence. Detection of bladder-cancer cells with hypomethylated DNA in urine might become practical in the future,10 but whether 5-methylcytosine content in leucocytes will provide a good biomarker for this purpose remains uncertain, because the amounts of methylation in controls and patients overlapped considerably. Additionally, the study9 did not record a linear relation between (decreased) amounts of methylation and cancer risk. Nonetheless, the findings by Moore and co-workers might lead to improved prevention and diagnostics of bladder cancer if the mechanism by which cancers cause altered DNA methylation in leucocytes is
clarified. The researchers’ recommendation for similar studies in other cancer types should be followed. The study illuminates once more how cancers might have systemic effects long before their metastatic spread becomes apparent. Wolfgang A Schulz Urologische Klinik, Heinrich Heine University, Düsseldorf, Germany
[email protected] The author declared no conflicts of interest. 1 2 3 4 5 6
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Wilson AS, Power BE, Molloy PL. DNA hypomethylation and human diseases. Biochim Biophys Acta 2007; 1775: 138–62. Hoffmann MJ, Schulz WA. Causes and consequences of DNA hypomethylation in human cancer. Biochem Cell Biol 2005; 83: 296–21. Yates DR, Rehman I, Abbod MF, et al. Promoter hypermethylation identifies progression risk in bladder cancer. Clin Cancer Res 2007; 13: 2046–53. Jones PA, Baylin SB. The epigenomics of cancer. Cell 2007; 128: 683–92. Barreto G, Schäfer A, Marhold J, et al. Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature 2007; 445: 671–75. Yi P, Melnyk S, Pogribna M, Pogrybny LP, Hine RJ, James SJ. Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNA hypomethylation. J Biol Chem 2000; 275: 29318–23. Ma Y, Stampfer MJ, Christensen B, et al. A polymorphism of the methionine synthase gene—association with plasma folate, vitamin B12, homocyst(e)ine, and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 1999; 8: 825–29. Kim YI. Methylenetetrahydrofolate reductase polymorphisms, folate, and cancer risk: a paradigm of gene-nutrient interactions in carcinogenesis. Nutr Rev 2000; 58: 205–09. Moore LE, Pfeiffer RM, Poscablo C, et al. Genomic DNA hypomethylation as a biomarker for bladder cancer susceptibility in the Spanish Bladder Cancer Study: a case–control study. Lancet Oncol 2008; 9: 359–66. Seifert HH, Schmiemann V, Mueller M, et al. In situ detection of global DNA hypomethylation in exfoliative urine cytology of patients with suspected bladder cancer. Exp Mol Pathol 2007; 82: 292–97.
NICE and The Lancet Oncology join forces In this issue of The Lancet Oncology, we publish a Special Report by the UK National Institute for Health and Clinical Excellence (NICE).1 This report is the first in a new initiative between NICE and The Lancet Oncology to increase the dissemination of NICE’s technology appraisals for oncology drugs. NICE is an independent organisation within the UK National Health Service (NHS) that provides guidance for the prevention and treatment of disease for patients in England and Wales. One of NICE’s responsibilities is to provide guidance to the NHS on the use of new and established health technologies (ie, drugs and other treatments or procedures) on the basis of an assessment of their clinical and cost effectiveness. The Special Report in this month’s issue details recommendations for rituximab for relapsed or refractory stage III or IV http://oncology.thelancet.com Vol 9 April 2008
follicular non-Hodgkin lymphoma (in combination with chemotherapy for induction treatment; as monotherapy for maintenance treatment; and as monotherapy for induction treatment when all alternative treatment options have been exhausted). Medical journals can play an important part in communicating to a wider audience the workings behind decisions and announcements (such as recommendations, appraisals, or policies) made by publicly funded organisations, thus giving an insight into how such decisions are made and helping to increase accountability. Since 2004, The Lancet Oncology has been publishing short reports by the WHO International Agency for Research on Cancer (IARC) that have provided IARC an opportunity to summarise key findings from their Monograph
Published Online February 27, 2008 DOI:10.1016/S14702045(08)70037-8 See News page 320
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programme at least 12 months before the full report appears in print. The articles by NICE will complement NICE’s other publications (ie, full appraisal, quick reference guide, and information for the public) that are issued when a final appraisal is announced, and will provide oncologists with an overview of the decision-making processes that have gone into issuing the appraisal as well as a discussion of the pertinent clinical evidence and economic considerations that influenced the decision. Since its establishment in 1999, NICE has published 35 appraisals of drugs for treating cancer, 33 of which are discussed in a recent Keynote Comment by Michael Rawlins, Chairman of NICE.2 NICE’s decisions can sometimes be controversial, taking up many column inches in the popular media, both in the UK and internationally, so further detail of the thought processes underlying the decisions could help doctors explain NICE’s final recommendations to their patients. Furthermore, NICE’s recommendations are not just relevant to the UK (the issue of paying for modern cancer care is of global concern),3 thus NICE’s decisions and reasoning are of interest to health-care authorities and drug-funding organisations across the world. NICE currently works with other medical journals to provide summaries to doctors of new clinical guidelines.4 As yet, however, no formal collaboration exists between NICE and a journal to highlight when a decision on a technology is made—a decision that is fundamental to subsequent guidelines. Thus, this new collaboration will provide a record of NICE’s oncology-related appraisals (and reappraisals where a change to existing recommendations
is made) in the medical literature, and will make knowledge of and details of their recommendations more accessible to worldwide audiences. Commenting on this collaboration, Carole Longson, Director of the Centre for Health Technology Evaluation at NICE, said: “This is an exciting opportunity for NICE to work with a prominent medical journal and highlight our recommendations to their readers. Developments in cancer therapy are ever increasing and it is important these new technologies are assessed by an independent organisation to assess their value to the NHS. We hope the readers of The Lancet Oncology find this Special Report a useful aid to understanding how we make our assessments and decisions”. The oncology drug pipeline is a busy one, and NICE has many technology appraisals in development for drugs against cancer. We hope our collaboration with NICE will provide a useful aid for understanding the complex processes involved in deciding which oncology drugs are approved for use in the NHS. Lidia Siemaszkiewicz The Lancet Oncology, London, UK 1
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Gajraj E, Chung H, Longson C, Stevens A. Rituximab for follicular nonHodgkin lymphoma. Lancet Oncol 2008; published online Feb 27. DOI:10.1016/S1470-2045(08)70036-6. Rawlings M. Paying for modern cancer care—a global perspective. Lancet Oncol 2007; 8: 749–51. Schwartsmann G, Picon PD. When drugs are worth more than gold! Lancet Oncol 2007; 8: 1049–50. Norton C, Thomas L, Hill J. Management of faecal incontinence in adults: summary of NICE guidance. BMJ 2007; 334: 1370–71.
Inappropriate ATAC on tamoxifen The 100-month findings in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) update trial,1 confirm that postmenopausal patients with early-stage breast cancer treated with tamoxifen or anastrazole have the same overall survival (OS) even after prolonged follow-up. This finding is explained by competing causes of death that might have occurred in this group of patients and by a non-significant, otherwise unexplained higher number of deaths due to non-breast cancer in the anastrazole group. An alternative explanation might be that the advantage of anastrazole is restricted to a small subgroup of patients who cannot be distinguished in the 314
present conditions, while most patients still benefit from treatment with tamoxifen. The effect of genetic polymorphism of the cytochrome P450 CYP2D6 on tamoxifen metabolism might support this view.2 Patients homozygous for the wild-type gene (almost 80%) metabolise tamoxifen to the active form endoxifen more efficiently, and therefore, have the greatest advantage compared with those who are heterozygous or homozygous for the mutated gene (intermediate or poor metabolisers). Punglia and co-workers3 used a mathematical model to extrapolate this hypothesis to the findings of the Breast International Group (BIG) 1-98 trial http://oncology.thelancet.com Vol 9 April 2008