Selenium during cancer treatment

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1 Concerted Action for Complementary and Alternative Medicine Assessment in the Cancer Field (CAM-Cancer) Project initiated under the European Commission 5th Framework Program "Quality of Life", now hosted by the National Information Center for Complementary and Alternative Medicine in Tromsø, Norway. Scientific Co-ordinator Barbara Wider Selenium during cancer treatment Written by Gabriele Dennert and the CAM-Cancer Consortium. Updated October 20, 2013 Abstract and key points This summary is currently (April 2016) being updated, the version published here was last updated in October The trace element selenium is a nutrient essential to human health and occurs naturally in various food types. Inorganic forms (e.g. sodium selenite or selenite) and organic forms (e.g., selenomethionine) are both used in large numbers of selenium-containing medications, nutritional supplements or dietary aids that are promoted for medical or health purposes. These may contain either selenium alone (mono-supplements) or selenium in combination with other trace minerals as well as vitamins. The trace element selenium is nutritionally essential for human health. Supplemental selenium has been promoted for the treatment of cancer as well as the prevention or treatment of cancer-related symptoms and adverse effects of cancer therapy. There is no evidence that selenium yeast supplements can prolong progression-free survival in people with non-small-cell lung cancer. The role of selenium supplements during radio- or chemotherapy for cancer treatment, or the prevention of therapy-associated adverse effects, is unclear. There is no evidence that selenium alleviates lymphoedema after surgery. Selenium is toxic in high doses and might have adverse effects when taken at supranutritional doses for longer periods of time. Supplemental selenium has been promoted for the treatment of cancer as well as the prevention or treatment of cancer-related symptoms and adverse effects of cancer therapy. The role of selenium in the treatment of cancer, as well as the treatment or prevention of therapy-associated adverse effects, is unclear. One trial found an increased rate of remission in patients with non-hodgkin lymphoma receiving CHOP-28 therapy plus selenium but the generalisability of these findings is uncertain. Another randomised clinical trial found no benefit of selenium yeast on five-year progression-free survival in people with resected stage I non-small-cell lung cancer. 1 / 10

2 Although a number of health problems have been linked to selenium deficiency, selenium is toxic in large doses and might have adverse effects when taken at supranutritional doses for longer periods of time. Long-term supplementation has caused symptoms of chronic overexposure and has also been linked to increased risks of developing type 2 diabetes mellitus. What is it? Description The trace element selenium (Se) is nutritionally essential for human health and is naturally present in various food groups including grains, pulses, meat and fish. Although a number of health problems have been linked to selenium deficiency, selenium is also toxic in large doses. Selenium occurs naturally in a number of inorganic forms (e.g. selenite, selenate, selenide) and is also found in organic compounds (e.g. selenomethionine, selenocysteine). 1 For details on selenium in human nutrition, please refer to the summary: Selenium prevention. History The element selenium was discovered in 1817 by the Swedish chemist Jöns Jakob Berzelius. In the 1930s, toxic properties of selenium were discovered in cattle, and in 1957, selenium was identified as an essential nutrient for mammals. Ingredients Licensed preparations for the treatment of selenium deficiency contain sodium selenite and can be obtained as liquid solutions for oral intake or intravenous administration. In addition, a large number of selenium-containing nutritional supplements or dietary aids are marketed for medical or health purposes. These contain either selenium alone (in inorganic or organic forms) or selenium in combination with other trace minerals as well as vitamins. Fermentation of yeast in a medium that is rich in inorganic selenium yields selenised yeast which contains 80 90% organic forms such as selenomethione, Se-methylselenocysteine and -glutamyl-se-methylselenocysteine. 2 Application and dosage Selenium supplements are marketed as tablets, capsules, pellets and liquid solutions for oral intake. Mono-selenium preparations usually contain µg selenium per single dose, while multi-component supplements usually contain between 30 50µg selenium. Licensed preparations for the treatment of selenium deficiency contain sodium selenite and are available as liquid solutions for oral intake or intravenous administration. Supplemental selenium is often taken in doses ranging from µg/day. The recommended daily 2 / 10

3 allowance for adults is 55µg/day, which is sufficient to raise plasma selenium to 1 1.2µM and to maximise glutathione peroxidase; the upper limit is 400µg/day. 3 For the prevention and treatment of adverse effects of chemo- or radiotherapy, even higher doses have been recommended. 4 Fakih (2008) investigated whether selenium supplementation allowed the escalation of the dose of irinotecan above the maximum tolerated dose (125 mg/qm in weekly application). 5 The primary dose-limiting adverse effect of irinotecan is diarrhoea. This phase-1-dose escalation trial found that selenomethionine (2.200 µg/day) did not allow a safe dose-escalation of irinotecan; 3 of 4 evaluable participants who received the escalated dose suffered from dose-limiting diarrhoea. Claims of efficacy/alleged indication(s) Selenium supplementation in people with cancer has been promoted for several distinct purposes: Increasing the efficacy of conventional radio- and chemotherapy during cancer treatment. Prevention of relapse or metastases in people with a complete remission of cancer. Prevention and treatment of the adverse effects of conventional cancer therapy. Mechanism(s) of action Selenium is bound to selenoproteins in the human body after intestinal absorption and incorporated into proteins either specifically, in catalytically active selenoenzymes, or unspecifically in tissue proteins. 6 More than 25 selenium-containing enzymes have been identified to date. There are at least two functional groups of selenoproteins. The first is involved in redox processes in the tissue (glutathione peroxidases, thioredoxin reductase), the second in thyroid hormone metabolism (iodothyronine deiodinases). Furthermore, several selenoproteins have been linked to a variety of health conditions. 7 Selenium is claimed to be an antioxidant. An antioxidant is an agent that is able to lower the level of unstable and reactive molecules (free radicals, or reactive oxygen species; ROS) in the tissues, and in turn protect tissues against ROS-induced damage, which putatively contributes to cancer development and induces or aggravates the adverse effects of cancer therapy. 8 The bioavailability of ingested organic and inorganic selenium as a function of absorption, metabolism and excretion is reported to be between 50% and 90%, depending on the form of selenium and type of preparation. 6 Prevalence of use Representative figures for the use of selenium supplements among people living with cancer are unavailable. Surveys from Germany suggest that between 4% and 10% of people with cancer use selenium supplements A systematic review of international studies on the use of complementary and alternative medicine in prostate cancer patients identified 11 studies, which reported 4 27% used selenium supplements / 10

4 Legal issues Most, but not all, forms of selenium are freely marketable for human use within the EU (selenised yeast, for example, is not), but may be available to customers through Internet resellers. Licensed drugs for the treatment of selenium deficiency are available over the counter in most EU and other European countries; a prescription is required in Denmark and Germany (although in Germany only for preparations containing more than 50µg selenium). 13 Cost(s) and expenditures The cost of 100 µg of inorganic selenium is around 0.50 ( ) via Internet pharmacies; this amounts approximately 15 a month. Expenditures are higher for prescription drugs than for over-the-counter nutritional supplements, but may be reimbursable in some countries when the patient has a diagnosis of selenium deficiency. Does it work? This summary is currently (April 2016) being updated, the version published here was last updated in October Treating cancer and preventing recurrence Asfour et al. (2007) investigated the use of high doses of sodium selenite in the treatment of non-hodgkin lymphoma. 14 Fifty participants with aggressive lymphoma were randomised into the intervention group r eceiving CHOP-28 plus selenium and a control group, which received CHOP-28 alone (CHOP: cyclophosphamide, vincristine, adriamycin; cycle length: 28 days). Sodium selenite (200µg/kg/day = about 14 mg/day for a 70 kg adult) was administered orally on each day of the first course of chemotherapy. More participants in the selenium group reached complete remission compared to the control group (60% vs. 40%). The overall survival rate after two years was 72% in the control group and 80% in the selenium group (no statistically significant difference). Generalisability of these results to other patients is limited as the report lacks information about the histological type of the lymphomas and the distribution of risk factors (for example, the International Prognostic Index) between both groups. Both parameters strongly predict the response to CHOP chemotherapy. Also it should be mentioned that CHOP-28 is not the standard therapy for aggressive lymphoma in high-income countries. Karp et al. (2013) conducted a double-blind, placebo-controlled randomised trial for the prevention of second primary tumours (SPT) in persons with resected stage I non-small-cell lung cancer. 15 The verum group took 200µg of selenium yeast daily. The trial was terminated early after an interim analysis of 1522 patients showed no benefit of selenium over placebo with regard to the incidence of SPT and five-year progression-free survival. At the five-year mark, 28% in the selenium group and 22% in the placebo group had experienced cancer progression. 4 / 10

5 To summarise, there is insufficient evidence to support the use of selenium for treating cancer or preventing recurrence. Alleviating the adverse effects of conventional therapy Systematic review A Cochrane review has assessed the use of selenium mono-supplements for the prevention or alleviation of adverse effects of conventional cancer therapy. 16 Two randomised clinical trials were identified, which used sodium selenite for the treatment of lymphedema and the prevention of erysipelas in affected limbs after cancer surgery. 17,18 Both trials were considered to be at high risk of bias, and the authors of the review concluded that it was unclear whether the reported results in these trials reflected a clinically relevant reduction in postoperative lymphedema or erysipelas infection in the selenium group. Generalisation to other cancer patients was also considered questionable. Clinical trials Two randomised trials have investigated the efficacy of sodium selenite for the treatment of selenium deficiency in cancer patients receiving radiotherapy. All study participants had subclinical selenium deficiency (i.e., whole-blood concentration below 85µg/l) and received radiotherapy for gynaecological cancers (n=81) 19 or head and neck cancers (n=39) with or without concomitant selenium supplementation. 20,21 Both trials also reported on radiotherapy-associated side effects as secondary outcomes. A pooled analysis of both trials found that blood selenium levels were normalised by selenium supplementation. 22 For secondary outcomes, the gynaecological trial found an overall decreased risk of diarrhoea (grade 2 or higher according to the National Cancer Institute Common Toxicity Criteria version 2) in the selenium group. No differences in survival rates were seen. While the rate of stomatitis was higher in the selenium group (intervention vs. no intervention group: 36.4% vs. 23.5%.), participants that received selenium complained less about loss of taste (22.7% vs. 47.1%), and dysphagia (22.7% vs. 35.3%) and with an almost identical frequency about dry mouth (22.7% vs. 23.5%); none of these differences were statistically significant. Hu et al. (1997) measured biomarkers of cisplatin toxicity using a randomised crossover design with 41 participants. 23 A dose of 4000µg/day seleno-kappacarrageenan was administered orally over eight days in the intervention groups (organic selenium compound: carrageenan is a polysaccharide). Investigators reported a higher white blood count (WBC) at day 14 after chemotherapy and lower levels of cisplatin toxicity biomarkers in urine with selenium, suggesting reduced cisplatin-associated bone marrow suppression and nephrotoxicity. Red blood and platelet count did not differ, but fewer blood transfusions and doses of G-CSF (growth factor for leucocytes) were administered during chemotherapy cycles with selenium. Although the results of this study are interesting, the clinical relevance of the results is disputable. For WBC, means were compared in the presence of concomitant G-CSF application. G-CSF can lead to an excessively high WBC and the comparison of means is sensitive towards extreme values. Differences in 5 / 10

6 urine biomarkers were found 24 hours and 48 hours after cisplatin application, but not 72 hours after application, and blood biomarkers and the laboratory reference limits were not reported. Cisplatin nephrotoxicity has an acute phase (beginning after two to three days) and a delayed phase (two weeks after application) and it seems questionable whether the reported biomarker adequately reflects the occurrence of this adverse effect. To summarise, one trial reported a clinical benefit (less severe diarrhoea) with selenium supplementation for women during radiotherapy of the pelvic region. Other clinical trials and one systematic review do not support the regular use of selenium supplements during cancer therapy. Is it safe? Adverse events Early signs of selenium toxicity (garlic breath, hair and nail changes, upset stomach) were observed in participants of a clinical trial who received 1600µg or 3200µg selenised yeast/day for up to 24 months. 24 In the Selenium and Vitamin E Cancer Prevention Trial, 25 which used 200 µg/day selenomethionine for 7 12 years, the rate of alopecia (overall incidence: 3% of participants) and mild dermatitis (7% of participants) was higher than in the placebo group (relative risk increase: +28% and +17%, respectively). Neither trial reported more severe adverse effects or signs of chronic toxicity. Chronic selenium poisoning (selenosis) has been seen in seleniferous areas of North America and China, but has also been attributed to commercially available selenium supplements. 24 Symptoms of selenosis include hair loss, thickened nails, nausea, vomiting, fatigue and paresthesia and paralysis. The EU Scientific Committee on Food considers an upper selenium limit (for adults) of 300µg/day (including supplements) to be acceptable for the avoidance of selenosis. 26 The US Food and Nutrition Board, Institute of Medicine, have set the tolerable upper level of selenium intake to 400µg/day. 3 However, there are concerns that long-term selenium supplementation may increase the risk of developing type 2 diabetes mellitus in selenium-replete populations. The relative risk for male selenium users in the SELECT trial was 1.07 (95% confidence interval (CI) ), when compared to the placebo group; this meant that there were six additional cases of diabetes in every 1000 selenium users per year (diabetes risk: +7% in the selenium group compared to placebo). 25 In the Nutritional Prevention of Cancer Trial (NPCT), the risk of developing diabetes mellitus in the selenium group was 1.55 (95% CI: ); this meant that there were four additional cases of diabetes in 1000 selenium users per year (diabetes risk: +55% in the selenium group). 27 Lethal and non-lethal acute poisoning related to use of selenium as a complementary alternative medicine has been reported in a number of cases. 28,29 The lethal dose of selenium in humans is unknown, but is estimated to be between 0.12g and 1g ( mg). 26 Acute poisoning is characterised by vomiting, garlic breath, abdominal pain, hypersalivation, cardiac arrhythmia, haemolysis, necrosis of the liver, cerebral and pulmonary oedema, coma and death / 10

7 Contraindications Chronic overexposure to selenium (selenosis). According to the NPCT, selenium may increase the risk of non-melanoma cancer recurrenceselenium supplementation may therefore be problematic, especially for light-skinned people. 31 Interactions Vitamin C can lower the intestinal absorption of selenium. 32 Other problems or complications Severe complications have been reported because not only consumers, but also healthcare professionals, have confused the measurements milligram (mg) and microgram (µg). Also, a number of websites mistakenly recommend milligrams of selenium instead of micrograms, the ingestion of which may result in a thousand-fold overdose. No controlled data are available on the effects of selenium supplements in non-selenium-deficient women during pregnancy or lactation. Citation Gabriele Dennert, CAM-Cancer Consortium. Selenium during cancer treatment [online document]. October 20, Document history Summary first published in November 2010, authored by Gabriele Dennert. Original summary divided into Selenium prevention and Selenium during cancer treatment, fully revised and updated in October 2013 by Gabriele Dennert. References Rayman MP, Infante HG, Sargent M. Food-chain selenium and human health: spotlight on speciation. Br J Nutr 2008; 100: Rayman MP. The use of high-selenium yeast to raise selenium status: how does it measure up? Br J Nutr 2004; 92(4): accessed 13 August 2013 Biologische Krebsabwehr: Selen. (last access 7 / 10

8 /06/2013). Fakih MG, Pendyala L, Brady W, Smith PF, Ross ME, Creaven PJ, Badmaev V, Prey JD, Rustum YM. A Phase I and pharmacokinetic study of selenomethionine in combination with a fixed dose of irinotecan in solid tumors. Cancer Chemother Pharmacol 2008; 62(3): Reilly C. Selenium in food and health. 2nd Edition. New York: Springer Rayman, MP: Selenium and human health. Lancet 2012; 379: National Cancer Institute: Antioxidants and Cancer Prevention: Fact Sheet (last access 29/06/2013). Nagel G, Hoyer H, Katenkamp D. Use of complementary and alternative medicine by patients with breast cancer: observations from a health-care survey. Support Care Cancer 2004; 12(11): Bruns F, Glatzel M, Schönekaes K, Riesenbeck D, Mücke R, Büntzel J, Micke P, Schäfer U, Kisters K, Micke O. Complementary and alternative medicine experience in radiation oncology patients: first results of a multi-center approach. Trace Elements & Electrolytes 2006; 23(4): Sehouli J, David M, Kaufmann B, Lichtenegger W. Unkonventionelle Methoden in der Krebsmedizin - Postoperative Nutzung durch Patientinnen mit gynäkologischen Malignomen [Use of alternative treatments by patients after surgery for gynecologic malignancies]. Geburtsh Frauenheilk 2000; 60: Bishop FL, Rea A, Lewith H, Chan YK, Saville J, Prescott P, von Elm E, Lewith GT: Complementary medicine use by men with prostate cancer: a systematic review of prevalence studies. Prostate Cancer and Prostatic Diseases 2011:14, OTC ingredient tables. (accessed 29/06/2013). Asfour IA, Fayek M, Raouf S, Soliman M, Hegab HM, El-Desoky H, Saleh R, Moussa MA. The impact of high-dose sodium selenite therapy on Bcl-2 expression in adult non-hodgkin's lymphoma patients: correlation with response and survival. Biol Trace Elem Res 2007; 120(1-3): Karp DD, Lee SJ, Keller SM et al. Randomized, double-blind, placebo-controlled, phase III chemoprevention trial of selenium supplementation in patients with resected stage I non-small-cell lung cancer: ECOG J Clin Oncol 2013;31(33): Dennert G, Horneber M. Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD Kasseroller R. Sodium selenite as prophylaxis against erysipelas in secondary lymphedema. Anticancer Res 1998; 18(3C): Zimmermann T, Leonhardt H, Kersting S, Albrecht S, Range U, Eckelt U. Reduction of postoperative lymphedema after oral tumor surgery with sodium selenite. Biol Trace Elem Res 2005; 106(3): Mücke R, Schomburg L, Glatzel M, Berndtskorka R, Baaske D, Reichl B, Büntzel J, Kundt G, Prott FJ, DeVries A, Stoll G, Kisters K, Bruns F, Schaeffer U, Willich N, Micke O, German Working Group Trace Elements and Electrolytes in Oncology - AKTE: Multicenter phase 3 trial comparing selenium supplementation with observaton in gynecologic radiation oncology. Int J Radiat Oncol Biol Phys 2010; 78: ; doi: /j.ijrobp Buentzel J, Micke O, Glatzel M, Bruns F, Kisters K, Muecke R: Evaluation of the effect of selenium on radiation-induced toxicities in head neck cancer patients (abstract). J Clin Oncol 27, 2009 (suppl; abstr e20698); (last accessed 29/06/2013) 8 / 10

9 Büntzel, J, Riesenbeck, D, Glatzel, M, Berndt-Skorka, R, Riedel, T, Mücke, R, Kisters, K, Schönekaes, KG, Schäfer, U, Bruns, F, Micke, O: Limited effect of selenium substitution in the prevention of radiation-associated toxicities. Results of a randomized study in head and neck cancer patients. Anticancer Res 2010; 30: Büntzel, J, Micke, O, Kisters, K, Bruns, F, Glatzel, M, Schönekaes, K, Kundt, G, Schäfer, U, Mücke, R: Selenium substitution during radiotherapy of solid tumours laboratory data from two observation studies in gynaecological and head and neck cancer patients. Anticancer Res 2010; 30: Hu YJ, Chen Y, Zhang YQ, Zhou MZ, Song XM, Zhang BZ, Luo L, Xu PM, Zhao YN, Zhao YB, et al. The Protective Role of Selenium on the Toxicity of Cisplatin-Contained Chemotherapy Regimen in Cancer Patients. Biol Trace Elem Res 1997; 56: Reid ME, Stratton MS, Lillico AJ, Fakih M, Natarajan R, Clark LC, Marshall JR: A report of high-dose selenium supplementation: response and toxicities. J Trace Elem Med Biol 2004; 18(1): Lippman SM, Klein EA, Goodman PJ, et al: Effect of Selenium and Vitamin E on Risk of Prostate Cancer and Other Cancers: The Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2009; 301(1):39-51 Sutter ME, Thomas JD, Brown J, Morgan B. Selenium toxicity: a case of selenosis caused by a nutritional supplement. Ann Intern Med 2008;148(12): Stranges S, Marshall JR, Natarajan R, Donahue RP, Trevisan M, Combs GF, Cappuccio FP, Ceriello A, Reid ME: Effects of Long-Term Selenium Supplementation on the Incidence of Type 2 Diabetes: A Randomized Trial. Ann Intern Med 2007; 147: Pfeffer H. Schwerwiegender Zwischenfall bei Selen-Medikation. Hamburger Zahnärzteblatt 2002;42(3): 3. See KA, Lavercombe PS, Dillon J, Ginsberg R. Accidental death from acute selenium poisoning. Med J Aust 2006; 185(7): SCF (Scientific Committee on Food): Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Selenium (accessed 01/10/2012). Duffield-Lillico AJ, Reid ME, Turnbull BW, Combs GF, Jr., Slate EH, Fischbach LA, Marshall JR, Clark LC. Baseline characteristics and the effect of selenium supplementation on cancer incidence in a randomized clinical trial: A summary report of the Nutritional Prevention of Cancer Trial. Cancer Epidemiol Biomarkers Prev 2002; 11(7): Sandström B: Micronutrient interactions: effects on absorption and bioavailability. Br J Nutr 2001; 85: S181-S185. Legal notice The present documentation has been compiled by the CAM-CANCER Project with all due care and expert knowledge. However, the CAM-CANCER Project provides no assurance, guarantee or promise with regard to the correctness, accuracy, up-to-date status or completeness of the information it contains. This information is designed for health professionals. Readers are strongly advised to discuss the information with their physician. Accordingly, the CAM-CANCER Project shall not be liable for damage or loss caused because anyone relies on the information. 9 / 10

10 Please visit the CAM-Cancer website for more information about the project: 10 / 10