Multicenter, Phase 3 Trial Comparing Selenium Supplementation With Observation in Gynecologic Radiation Oncology

doi:10.1016/j.ijrobp.2009.08.013

International Journal of Radiation OncologyBiologyPhysics

Volume 78, Issue 3, 1 November 2010, Pages 828-835

Presented at the 47th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Denver, CO, October 16–20, 2005, and at the 49th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Los Angeles, CA, October 28–November 1, 2007.

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https://doi.org/10.1016/j.ijrobp.2009.08.013 Get rights and content

Purpose

We assessed whether adjuvant supplementation with selenium improves the selenium status and reduces side effects of patients treated by radiotherapy (RT) for cervical and uterine cancer.

Methods and Materials

Whole-blood selenium concentrations were measured in patients with cervical cancer (n = 11) and uterine cancer (n = 70) after surgical treatment, during RT, at the end of RT, and 6 weeks after RT. Patients with initial selenium concentrations of less than 84μg/L were randomized before RT either to receive 500 μg of selenium (in the form of sodium selenite [selenase®, biosyn Arzneimittel GmbH, Fellbach, Germany]) by mouth on the days of RT and 300 μg of selenium on the days without RT or to receive no supplement during RT. The primary endpoint of this multicenter Phase 3 study was to assess the efficiency of selenium supplementation during RT; the secondary endpoint was to decrease radiation-induced diarrhea and other RT-dependent side effects.

Results

A total of 81 patients were randomized. We enrolled 39 in the selenium group (SG) and 42 in the control group (CG). Selenium levels did not differ between the SG and CG upon study initiation but were significantly higher in the SG at the end of RT. The actuarial incidence of diarrhea of Grade 2 or higher according to Common Toxicity Criteria (version 2) in the SG was 20.5% compared with 44.5% in the CG (p = 0.04). Other blood parameters, Eastern Cooperative Oncology Group performance status, and self-reported quality of life were not different between the groups.

Conclusions

Selenium supplementation during RT is effective in improving blood selenium status in selenium-deficient cervical and uterine cancer patients and reduces the number of episodes and severity of RT-induced diarrhea.

Introduction

The essential trace element selenium is of fundamental importance to human health 1, 2. As a constituent of the small group of selenocysteine-containing selenoproteins, selenium elicits important structural and enzymatic functions (3). A number of epidemiologic, experimental, and case–control studies have indicated an inverse association between selenium concentrations in blood and cancer risk 1, 4, 5, 6, 7, 8, 9.

Although the mode of action of selenium as a chemopreventive supplement is still enigmatic, its high potential as a natural anticancer agent for selenium-deficient individuals is well documented by clinical interventional trials 10, 11. The issue of whether this difference is due to the malignancy or represents a predisposing risk factor leading to higher cancer incidence is at present still unresolved. To date, there are no general recommendations in favor of or against selenium supplementation in cancer patients (12). Radiotherapy (RT) and chemotherapy, as well as the suboptimal nutrition of cancer patients in clinics, might aggravate the situation in selenium-deficient patients even further and increase the likelihood of radiation-induced side effects during and after therapy 13, 14, 15.

Supplementation of cancer patients with selenium at dosages of up to 2,000 μg/d alone or in combination with vitamins has been reported in only a few studies as a way to improve quality of life 16, 17, 18, 19, 20.

Preliminary experimental and clinical evidence indicates that selenium might function as an effective cytoprotector with the ability to alleviate side effects of tumor-specific chemotherapy or RT treatments 21, 22, 23, 24, 25, 26, 27, 28, 29. It is assumed by various working groups that an increased selenium supply elevates the antioxidant capacity in the healthy tissue via increased biosynthesis of the different glutathione peroxidase and thioredoxin reductase isozymes.

Randomized clinical studies with supplementation of selenium during RT are missing. To this end, we conducted a randomized multicenter study in patients with squamous cell carcinoma and adenocarcinoma of the uterus after curative surgical treatment. As the primary endpoint, we verified that selenium supplementation was effective in compensating for the selenium deficiency in the selenium group (SG). As the secondary endpoint, we observed a significant reduction of radiation-induced diarrhea in the selenium-treated patients.

Section snippets

Methods and Materials

The study was approved by the International Ethics Committee in Freiburg, Germany (No. 2000-D-7251). Each patient gave written informed consent before being accrued. The study was performed in full accordance with the Declaration of Helsinki.

Patients were also assured of the anonymity and confidentiality of their data. In addition, they were assured that refusal to participate in the study would not affect their future care in any way.

Patients

Between January 2000 and June 2006, whole-blood selenium levels before RT were measured in 135 patients from 10 RT departments in Germany. In 108 patients whole-blood selenium deficiency was diagnosed; 27 patients of these were ineligible. Of these 27 patients, 26 did not consent to take part in the study and 1 did not undergo irradiation. Figure 1 shows the progress of all patients during the trial. A total of 81 patients (mean age, 64.3 ± 10.1 years; range, 31–80 years) were randomized. Of

Discussion

Our study describes the effects of selenium supplementation in a group of patients with an initially low selenium status after surgery during RT treatment. We were able to improve the selenium status of our patients under the therapy conditions, thus achieving the primary endpoint of the study. We are not aware of comparable results from other studies under similar RT conditions. The SG achieved a mean blood selenium level of 90.9 μg/L, which corresponds roughly to the lower limit of the

Conclusions

For the first time, the significant benefit of sodium selenite supplementation with regard to selenium deficiency and RT-induced diarrhea in patients with cervical and uterine cancer has been shown in a prospective randomized trial. Disease-free survival and overall survival data imply that supplementation with selenium does not interfere with the positive biological effects of RT and might constitute a valuable adjuvant therapy option especially in marginally supplied individuals.

Acknowledgments

The authors thank Mrs. Simone Steinert for data monitoring and documentation.

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: Supported by a grant from biosyn Arzneimittel GmbH, Fellbach, Germany.

: Conflict of interest: none.

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Clinical InvestigationMulticenter, Phase 3 Trial Comparing Selenium Supplementation With Observation in Gynecologic Radiation Oncology

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Methods and Materials

Patients

Discussion

Conclusions

Acknowledgments

Lancet

J Urol

Int J Radiat Oncol Biol Phys

Eur J Cancer

Mutat Res

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Selenium: Benefits and risks

MMW Fortschr Med

From selenium to selenoproteins: Synthesis, identity, and their role in human health

Antioxid Redox Signal

Serum selenium levels, glutathione peroxidase activities and serum redox potential levels in patients with untreated non-small cell lung cancer and adenocarcinoma of the rectum

Trace Elem Electrolytes

Blood selenium concentrations and glutathione peroxidase activities in patients with breast cancer and with advanced gastrointestinal cancer

J Trace Elem Electrolytes Health Dis

Serum selenium and subsequent risk of cancer among Finnish men and woman

J Natl Cancer Inst

Serum selenium levels in various cancer types

Trace Elem Electrolytes

Selenium is inversely associated with bladder cancer risk: A report from the Belgian case-control study on bladder cancer

Int J Urol

Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin

JAMA

A preliminary report on the intervention trials of primary liver cancer in high-risk populations with nutritional supplementation of selenium in china

Biol Trace Elem Res

Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients

Cochrane Database Syst Rev

From the radiolysis of water to the role of trace elements in radiobiology and clinical radiation therapy: Following a logical chain

Trace Elem Electrolytes

Mineral status and enzymatic antioxidative capacities during radiochemotherapy in patients with advanced head and neck cancer

Trace Elem Electrolytes

Amifostine and selenium during simultaneous radiochemotherapy in head and neck cancer—Redox status data

Trace Elem Electrolytes

Experiences with sodium selenite in treatment of acute and late adverse effects of radiochemotherapy of head-neck carcinomas. Cytoprotection Working Group in AK Supportive Measures in Oncology within the scope of MASCC and DKG

Med Klin

Selenium supplementation in head and neck surgery

Trace Elem Electrolytes

Clinical elementology in oncology: Experiences and proposals from Germany

Trace Elem Electrolytes

Clinical Investigation
Multicenter, Phase 3 Trial Comparing Selenium Supplementation With Observation in Gynecologic Radiation Oncology