Multicenter, Phase III Trial Comparing Selenium ...

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concluded that the Se compounds methylseleninic acid and selenodiglutathione induce cell death in lymphoma cell lines and primary lymphoma cultures, which ...

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ICTXXX10.1177/1534735414541963Integrative Cancer TherapiesMuecke et al

Article

Multicenter, Phase III Trial Comparing Selenium Supplementation With Observation in Gynecologic Radiation Oncology: Follow-Up Analysis of the Survival Data 6 Years After Cessation of Randomization

Integrative Cancer Therapies 2014, Vol. 13(6) 463­–467 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1534735414541963 ict.sagepub.com

Ralph Muecke, MD1,2, Oliver Micke, MD3, Lutz Schomburg, PhD4, Michael Glatzel, MD5, Berthold Reichl6, Klaus Kisters, MD7, Ulrich Schaefer, MD1, Jutta Huebner, MD8, Hans T. Eich, MD9, K. Fakhrian, MD2, Irenaeus A. Adamietz, MD2, and Jens Buentzel, MD10, on Behalf of the German Working Group Trace Elements and Electrolytes in Oncology—AKTE

Abstract Purpose. In 2010, we reported that selenium (Se) supplementation during radiation therapy (RT) is effective for increasing blood Se levels in Se-deficient cervical and uterine cancer patients, and reduced the number of episodes and severity of RT-induced diarrhea. In the current study, we examine whether of Se supplementation during adjuvant RT affects longterm survival of these patients. Patients and Methods. Former patients were identified and questioned with respect to their health and well-being. Results. A total of 81 patients were randomized in the initial supplementation study, 39 of whom received Se (selenium group, SeG) and 42 of whom served as controls (control group, CG). When former patients were reidentified after a median follow-up of 70 months (range = 0-136), the actuarial 10-year disease-free survival rate in the SeG was 80.1% compared to 83.2% in the CG (P = .65), and the actuarial 10-year overall survival rate of patients in the SeG was 55.3% compared to 42.7% in the CG (P = .09). Conclusions. Our extended follow-up analysis demonstrates that Se supplementation had no influence on the effectiveness of the anticancer irradiation therapy and did not negatively affect patients’ long-term survival. In view of its positive effects on RT-induced diarrhea, we consider Se supplementation to be a meaningful and beneficial adjuvant treatment in Se-deficient cervical and uterine cancer patients while undergoing pelvic radiation therapy. Keywords long-term data, selenium supplementation, gynecologic radiation oncology, overall survival, disease-free survival

Introduction The essential trace element selenium (Se), which is a crucial constituent of the most important endogenous antioxidative enzymes in the human body, has attracted increasing attention from both lay and expert groups. Among other important functions, Se has been shown to possess cancerpreventive and cytoprotective activities in both animal models and humans. Selenium plays a key role in redox regulation and antioxidant function, and hence in membrane integrity, energy metabolism, and protection against DNA damage. These functions are mediated through approximately 120 different selenoproteins encoded by 25 separate human selenoprotein genes, which require adequate

1

Lippe Hospital, Lemgo, Germany Marien Hospital Herne, Ruhr University, Bochum, Germany 3 Franziskus Hospital, Bielefeld, Germany 4 Charité, Berlin, Germany 5 Municipal Hospital, Erfurt, Germany 6 Municipal Hospital, Weiden, Germany 7 St. Anna Hospital, Herne, Germany 8 Working Group Integrative Oncology, German Cancer Society, Berlin, Germany 9 University, Muenster, Germany 10 Suedharz Hospital, Nordhausen, Germany 2

Corresponding Author: Oliver Micke, Department of Radiotherapy and Radiation Oncology, Franziskus Hospital Bielefeld, Kiskerstrasse 26, D-33615 Bielefeld, Germany. Email: [email protected]

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Se availability for their regular biosynthesis and expression. Selenoproteins include several forms of the enzymes glutathione peroxidase, thioredoxin reductase, and iodothyronine deiodinase.1-4 Besides the disease itself, radiation and chemotherapy, as well as suboptimal nutrition, in cancer patients in the clinic might aggravate the situation in a Se-deficient patient and increase the likelihood of radiation-induced side effects. In 2010, a Brazilian prospective study showed a significant reduction in plasma levels of selenium in breast cancer patients undergoing radiotherapy, suggesting attention to the nutritional status of this micronutrient and other antioxidant agents.5 The thoughtful radiation oncologist is thus mainly concerned with the following clinical aspects: radioprotection of normal tissues, radio-sensitizing of malignant tumor cells, protection from edematous effects, and adjuvant measures for primary and secondary cancer prevention.6 Clinical and experimental evidence indicates that Se could address most of these issues because it functions as a radio- and chemoprotector with the ability to alleviate the side effects of tumor-specific chemotherapy or radiotherapy treatments.7-9 In 2003, a British retrospective study showed a positive correlation between initial serum Se levels and the dose delivery of chemotherapy and outcome of patients with aggressive non-Hodgkin’s lymphoma. In light of the results of a subsequent experimental study, the authors concluded that the Se compounds methylseleninic acid and selenodiglutathione induce cell death in lymphoma cell lines and primary lymphoma cultures, which may be partly attributable to the generation of reactive oxygen species.10,11 Between 2000 and 2006, the German Working Group Trace Elements and Electrolytes in Oncology (AKTE) conducted the first worldwide randomized phase III clinical study to examine the radioprotective properties of sodium selenite in postoperative radiation therapy of pelvic tumors. We observed that Se supplementation during radiation therapy effectively improved blood Se status in Se-deficient cervical and uterine cancer patients and reduced the number of episodes and severity of radiation therapy–induced diarrhea.12 Despite the positive results of this study, some oncologists suspected that Se may protect tumor cells from therapeutic radiation damage and were concerned about the long-term effects of Se supplementation during radiation therapy. Hence, we examined whether there was an impact of Se supplementation during adjuvant radiation therapy on the long-term survival of these patients.

confirmed cervical and uterine cancer after surgical treatment. Patients with initial Se concentrations less than 84 µg/L were randomized into the Se group (SeG) or a control group (CG). During radiation therapy, patients in the SeG received 500 µg of Se (as inorganic sodium selenite; selenase®) per os on the days of radiation therapy and 300 µg of Se on the days without treatment until the last day of radiation therapy. In the control group, adjuvant radiation therapy was given without Se supplementation. The cumulative Se dose given to the patients in the SeG was 17 mg of sodium selenite over an average treatment period of 38 days. After a maximal time period of 136 months (average = 70 months), former patients were identified and questioned with respect to their health and well-being. Results from these interviews were used to compare longterm survival in the SeG with those in the CG.

Patients and Methods

Survival Data

Between January 2000 and June 2006, whole blood Se concentrations were measured in patients with histopathologically

Survival data for 81 of the 81 patients initially randomized into the SeG and CG were available.

Statistics All data were stored and analyzed using the SPSS statistical package 15.0 (SPSS Inc, Chicago, IL). Descriptive statistics were computed for continuous and categorical variables. The statistics computed included mean and standard deviations of continuous variables, and frequencies and relative frequencies of categorical factors. Testing for differences in continuous variables between the groups was accomplished by the 2-sample t test for independent samples or the Mann–Whitney U test, as appropriate. The period of time to cancer recurrence or death was estimated using the Kaplan–Meier method. Differences between curves were assessed by Mantel’s log-rank test for censored data. All P values were 2-sided statistical tests, and values of P < .05 were considered to be statistically significant.

Results Patients A total of 81 patients (mean age = 64.3 ± 10.1; range = 31-80) with carcinomas of the cervix or corpus uteri with significant whole blood Se deficiency after curative surgical treatment were randomized to the SeG (n = 39) or the CG (n = 42). Patients with metastatic disease, diarrhea before radiotherapy, radiochemotherapy, receiving Se supplementation before radiation therapy, and patients who had undergone previous pelvic radiation therapy as described earlier were excluded.12

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Figure 1.  Univariate analysis (log-rank) for disease-free survival according to Se supplementation.

Figure 2.  Univariate analysis (log-rank) for overall survival according to Se supplementation.

Thin line = without Se; thick line = with Se.

Thin line = without Se; thick line = with Se.

Disease-Free Survival

assumed and suspected by many oncologists. This finding may be related to a number of selective Se-mediated processes recently identified. Besides the anti-oxidative capacity in healthy tissue, an unusual selective activation of wild-type p53 by Se-dependent reduction of 2 critical cysteine residues by redox effector factor-1 might contribute to efficient activation of DNA-repair in healthy cells of the small intestinal mucosa.13-15 Furthermore, it is possible that patients with improved Se status may have benefited from a selective increase in cell death in postoperative backward tumor cells by an increase in the Se metabolism-related generation of reactive oxygen species.11,16 Above all, the 10-year overall survival rate in patients receiving Se supplementation, and who consequently had increased whole blood Se levels up to a mean of 90.9 µg/L (corresponding to approximately 72.1 µg/L in serum), is higher, with a borderline level of statistical significance (P = .09) compared with the control group who did not receive Se supplementation and had a mean whole blood Se level at the end of radiation therapy of 61.4 µg/L (corresponding to approximately 48.7 µg/L in serum). From these results, a positive impact of Se supplementation could also be discussed. A nonlinear association between serum Se levels and all-cause and cancer mortality was published by Bleys et al in 2008 based on the analysis of a representative sample of the US population, with 13 887 adult participants. Increased serum Se levels were associated with decreased mortality up to concentrations of 130 µg/L.17 If we consider the causes of death in our study, it also shows an advantage for the SeG (Table 1). These results are also in line with a recently published retrospective study on renal cancer patients reporting a strong dependence of cancer-related mortality with the Se status of patients.18 Whether or not the effects of Se were elicited directly during tumor radiation therapy or during the recovery phase thereafter remains to be determined. However, despite

With a median follow-up of 49 months (range = 0-75), the actuarial 5-year disease-free survival rate was 80.1% in patients in the SeG compared to 83.2% in the CG (P = .74, log-rank test).12 With a median follow-up of 67 months (range = 0-136 months), the actuarial 10-year disease-free survival rate was 80.1% in patients in the SeG compared to 83.2% in the CG (P = .65, log-rank test; Figure 1).

Overall Survival With a median follow-up of 51 months (range = 6-75), the actuarial 5-year overall survival rate was 91.9% in patients in the SeG compared to 83.1% in the CG (P = .34, log-rank test).12 With a median follow-up of 70 months (range = 6-136 months), the actuarial 10-year overall survival rate was 55.3% in patients in the SeG compared to 42.7% in the CG (P = .09, log-rank test; Figure 2).

Discussion In 2010, we published the results of the effects of Se supplementation during radiation therapy in a group of patients with initially low Se serum levels after surgery.12 Se supplementation improved the Se levels in patients under the therapy conditions and yielded a significant reduction in diarrhea. Because concerns were raised with respect to the safety of Se supplementation and the potential tumor-sparing side effect of Se-dependent protective enzyme systems, we report the long-term follow-up of these patients. These concerns proved not to apply, and the calculated long-term survival rates did not differ between the 2 groups, indicating that Se was not protective of tumor cells, as was often

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Table 1.  Causes of Death According to Se Supplementation.

References

Causes of Death

1. Micke O, Muecke R, Buentzel J, Kisters K, Schaefer U. Some more steps on the way to clinical elementology. Trace Elem Electrolytes. 2010;27:29-34. 2. Rayman MP. Selenium and human health. Lancet. 2012;379:1256-1268. 3. Schomburg L, Schweizer U, Koehrle J. Selenium and selenoproteins in mammals: extraordinary, essential, enigmatic. Cell Mol Life Sci. 2004;61:1988-1995. 4. Hoefig CS, Renko K, Koehrle J, Birringer M, Schomburg L. Comparison of different selenocompounds with respect to nutritional value vs. toxicity using liver cells in culture. J Nutr Biochem. 2011;22:945-955. 5. Franca CA, Nogueira CR, Ramalho A, Carvalho AC, Vieira SL, Penna AB. Serum levels of selenium in patients with breast cancer before and after treatment of external beam radiotherapy. Ann Oncol. 2011;22:1109-1112. 6. Muecke R, Micke O, Schomburg L, Buentzel J, Kisters K, Adamietz IA. Selenium in radiation oncology—experiences and prospects. Trace Elem Electrolytes. 2011;28:168-177. 7. Asfour IA, El-Tehewi MM, Ahmed MH, et al. High-dose sodium selenite can induce apoptosis of lymphoma cells in adult patients with non-Hodgkin’s lymphoma. Biol Trace Elem Res. 2009;127:200-210. 8. Buentzel J, Micke O, Glatzel M, et al. Selenium substitution during radiotherapy in head and neck cancer. Trace Elem Electrolytes. 2010;27:235-239. 9. Sieja K, Talerczyk M. Selenium as an element in the treatment of ovarian cancer in women receiving chemotherapy. Gynecol Oncol. 2004;93:320-327. 10. 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. 2003;21:2335-2341. 11. Last K, Maharaj L, Perry J, et al. The activity of methylated and non-methylated selenium species in lymphoma cell lines and primary tumours. Ann Oncol. 2006;17:773-779. 12. Muecke R, Schomburg L, Glatzel M, et al. Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology. Int J Radiat Oncol Biol Phys. 2010;70:828-835. 13. Gudkov AV. Converting p53 from a killer to a healer. Nat Med. 2002;8:1196-1198. 14. Fischer JL, Mihelc EM, Pollok KE, Smith ML. Chemotherapeutic selectivity conferred by selenium: a role for p53-dependent DNA repair. Mol Cancer Ther. 2007;6:355-361. 15. Lanfear J, Fleming J, Wu L, Webster G, Harrison PR. The selenium metabolite selenodiglutathione induces p53 and apoptosis: relevance to the chemopreventive effects of selenium? Carcinogenesis. 1994;15:1387-1392. 16. Gonzalez-Moreno O, Segura V, Serrano D, Nguewa P, de las Rivas J, Calvo A. Methylseleninic acid enhances the effect of etoposide to inhibit prostate cancer growth in vivo. Int J Cancer. 2007;121:1197-1204. 17. Bleys J, Navas-Acien A, Guallar E. Serum selenium levels and all cause, cancer and cardiovascular mortality among US adults. Arch Intern Med. 2008;168:404-410. 18. Meyer HA, Endermann T, Stephan C, et al. Selenoprotein P status correlates to cancer-specific mortality in renal cancer patients. PLoS One. 2012;7:e46644.

Primary tumor or metastases Secondary tumors Heart diseases Total

Without Selenium

With Selenium

6

4

3 6 15

1 5 10

the low number of patients, we conclude that, at the very least, the short-term high-dose Se supplementation during radiation therapy was safe for patients in our study and successfully reduced radiation therapy-associated side-effects. Our results support the 2003 findings published by Last et al and highlight that in patients with higher blood Se levels, radiation therapy was significantly better tolerated.10 Therefore, we strongly advocate taking the Se status of patients under therapy more seriously, determine the patient’s Se status prior to therapy and to consider Se supplementation when the current Se status appears to be insufficient before applying radiation therapy.19

Conclusions Our results demonstrate that Se supplementation neither influenced the effectiveness of the anticancer radiation therapy nor negatively affected long-term survival. In view of the positive effects on radiation therapy–induced diarrhea, we consider Se supplementation a meaningful and beneficial adjuvant treatment measure in cervical and uterine cancer patients when they exhibit low Se baseline levels prior to undergoing adjuvant pelvic radiation therapy. It is unlikely that our data can be directly extrapolated to cancer patients with better Se status, as they do not present or develop a Se deficiency. However, given the strong cytotoxic effects of radiation therapy in combination with the increased production of reactive oxygen species, a respective supplementation study with Se might still be considered in case a deficit has been diagnosed, in contrast to cancer prevention trials where supplemental Se was recently proven ineffective in US patients with good baseline nutritional Se status.20 Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Ralph Muecke has had conference and travel expenses reimbursed and has received lecture fees from the pharmaceutical company biosyn-Arzneimittel GmbH to help run the study.

Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Supported by a grant from the pharmaceutical company biosynArzneimittel GmbH Fellbach, Germany.

Muecke et al 19. Muecke R, Schomburg L, Buentzel J, Kisters K, Micke O. Selenium or no selenium—that is the question in tumor patients: a new controversy. Integr Cancer Ther. 2010;9: 136-141.

467 20. Lippmann 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;301:39-51.

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