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Journal of Clinical Oncology, Vol 22, No 16 (August 15), 2004: pp. 3430 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.99.131
In Reply:
Gastrointestinal Unit, Royal Marsden Hospital, London, United Kingdom We are grateful for the letter from Beguin and Weber. They suggest several additional explanations of our findings that the higher the presentation serum selenium in aggressive non-Hodgkin's lymphoma (NHL) patients, the better the dose delivery, response to first treatment, and overall survival.1 Beguin and Weber propose that the serum selenium varies with the extent of disease and disease activity, and speculate that because tumors are selenium sequesters, the disease would be helped (not hindered) by selenium supplementation as an adjunct to conventional treatment. Taking their arguments in turn, their suggestion that serum selenium varies according to the extent of disease is based on their own observations in relation to chronic lymphocytic leukemia and these did not reach significance.2,3 Confounding of their observation of an inverse association between stage and serum selenium level by performance status (PS) cannot be excluded, given that PS was not measured. Extrapolation of their findings to aggressive NHL may not be warranted. Turning to their second statement, that tumor activity determines serum selenium levels, their evidence from a series of 70 acute myelogenous leukemia patients is more compelling. Their study revealed reduced serum selenium levels pretreatment, compared with controls, and the return to normal levels on successful treatment or further decline on treatment failure—findings also noted by Sundstrom et al in a study of 40 ovarian cancer patients and Broghamer et al in lymphomas.4–6 These data add to our contention that the associations we described in aggressive NHL are due to causal relationships. The paramount question raised by this hypothesis is whether host selenium deprivation provides the host's tumor with a survival advantage that could be overcome through supplementation. Beguin and Weber touch on this issue in there next suggestion of an alternative explanation of our findings—that tumors could sequester selenium, a concern that is to us, in fact, encouraging. The preferential uptake of selenomethionine-75 by lymphomas was the basis of nuclear medicine studies in the 1970s.7 Although such a process may provide a survival advantage to tumor cells in an increasingly selenium-deficient host, such a process may answer one of the most difficult conundrums of selenium chemopreventive research: why are metaplastic and neoplastic cells, be they of breast or prostate origin, so much more susceptible to cell death compared with their normal equivalents? Asked a different way, why does a therapeutic index exist for selenium compounds in relation to malignant and normal tissues? If tumor cells sequester selenium relative to nonmalignant cells, it seems reasonable to assume that the threshold between antioxidant activity and reactive species generation will be crossed sooner in neoplastic cells, resulting in malignant cell death before that of normal cells. Beguin and Weber's assertion that selenium supplementation could have unforeseen deleterious effects on outcome was not seen in the selenium supplementation trials in ovarian and gynecologic cancer patients undergoing chemotherapy conducted by Sieja and Sundstrom et al8–10 Thus, we remain of the mind that investigation of selenium supplementation as an adjunct to conventional chemotherapy in aggressive lymphoma would be ethical and worthwhile. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Last KW, Cornelius V, Delves T, et al: Presentation serum selenium predicts for overall survival, dose delivery, and first treatment response in aggressive non-Hodgkin's lymphoma. J Clin Oncol 21:2335–2341, 2003 2. Beguin Y, Delbrouck JM, Robaye G, et al: Correlation of serum trace elements with other biological parameters in hemoproliferative disorders, in Bratter P, Schramel P (eds): Trace Element Analytical Chemistry in Medicine and Biology. Berlin, Germany, Walter de Gruyer, 1987, pp 537–545 3. Beguin Y, Brasseur F, Weber G, et al: Observations of serum trace elements in chronic lymphocytic leukemia. Cancer 60:1842–1846, 1987[CrossRef][Medline]
4. Beguin Y, Bours V, Delbrouck JM, et al: Relationship of serum selenium levels to tumor activity in acute non-lymphocytic leukemia. Carcinogenesis 10:2089–2091, 1989 5. Broghamer WL Jr, McConnell KP, Grimaldi M, et al: Serum selenium and reticuloendothelial tumors. Cancer 41:1462–1466, 1978[CrossRef][Medline]
6. Sundstrom H, Yrjanheikki E, Kauppila A: Serum selenium in patients with ovarian cancer during and after therapy. Carcinogenesis 5:731–734, 1984 7. Masaoka A, Kyo S: 75Se-selenomethionine scintigraphy in mediastinal diseases. J Thorac Cardiovasc Surg 75:419–424, 1978[Abstract] 8. Sieja K: Selenium (Se) deficiency in women with ovarian cancer undergoing chemotherapy and the influence of supplementation with this micro-element on biochemical parameters. Pharmazie 53:473–476, 1998[Medline] 9. Sieja K: Protective role of selenium against the toxicity of multi-drug chemotherapy in patients with ovarian cancer. Pharmazie 55:958–959, 2000[Medline]
10. Sundstrom H, Korpela H, Sajanti E, et al: Supplementation with selenium, vitamin E and their combination in gynaecological cancer during cytotoxic chemotherapy. Carcinogenesis 10:273–278, 1989
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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