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

Authors:

Abstract

Background: Selenium supplements are frequently used by cancer patients. Selenium is an essential trace element and is involved in antioxidant protection and redox-regulation in humans. Several adverse effects of radiotherapy and chemotherapy in cancer patients as well as cellular processes that maintain chronic lymphoedema have been linked to oxidative cell damage in the human body. Selenium has recently been investigated as a remedy against chemotherapy and radiotherapy-associated side effects as well as its effects on lymphoedema. Objectives: This review assessed the effects of supplementary selenium on adverse effects of conventional radiotherapy, chemotherapy, or surgery, in oncologic patients and on quality of life or performance status during and after oncologic treatment. Search strategy: We searched the Cochrane Pain, Palliative & Supportive Care Trials Register, the Cochrane Database of Systematic Reviews (The Cochrane Library , Issue 2, 2004), Medline (1966 - Sep 2004), Embase (1980 - 2004 week 12), SIGLE (October 2004), Cancerlit (October 2004), Clinical Contents in Medicine CCMed (October 2004), the German Register of Cancer Studies (October 2004), the NCI Clinical Trials Register (October 2004), the International Standard Randomised Controlled Trial Number Register ISRCTN (October 2004) and the Meta-Register of Controlled Trials mRCT (October 2004), reference lists and the archive of our working group. We contacted manufacturers of selenium supplements and investigators. Selection criteria: Randomised-controlled trials of selenium mono-supplements in cancer patients undergoing tumour specific therapy such as chemotherapy, radiotherapy or surgery. Data collection and analysis: Two review authors independently checked trials for eligibility, extracted data and assessed trial quality. We sought additional information from investigators when required. Main results: Two trials have been included, a randomised controlled trial with 60 participants at the beginning of the study investigating secondary lymphoedema and an ongoing trial with preliminary results of 63 participants investigating radiotherapy induced diarrhoea as a secondary outcome. Both trials had drawbacks with regard to study quality and reporting. The trial on secondary lymphoedema reported a decreased number of recurrent erysipela infections in the selenium supplementation group compared to placebo. However, results must be interpreted with caution and cannot be generalised to other populations. The ongoing trial on radiotherapy associated diarrhoea preliminarily reported a lower incidence of diarrhoea in patients receiving selenium supplementation concomitant to pelvic radiation, however, no data were presented. Publication of final results must be awaited to discuss these findings in detail. No randomised controlled trials were found studying the effect of selenium supplementation on other therapy-associated toxicities or quality of life or performance status in cancer patients. Authors' conclusions: There is insufficient evidence at present that selenium supplementation alleviates the side effects of tumour specific chemotherapy or radiotherapy treatments. Or, that it improves the after effects of surgery, or improves quality of life in cancer patients or reduces secondary lymphoedema. To date research findings do not provide a basis for any recommendation in favour or against selenium supplementation in cancer patients. Potential hazards of supplementing a trace mineral should be kept in mind.
Selenium for alleviating the side effects of chemotherapy,
radiotherapy and surgery in cancer patients (Review)
Dennert G, Horneber M
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2009, Issue 2
http://www.thecochranelibrary.com
Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
T A B L E O F C O N T E N T S
1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
25WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
iSelenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]
Selenium for alleviating the side effects of chemotherapy,
radiotherapy and surgery in cancer patients
Gabriele Dennert1, Markus Horneber2
1Medizinische Klinik 5, Klinikum Nord, Nuernberg, Germany. 2Medizinische Klinik 5 - Schwerpunkt Onkologie/Haematologie,
Klinikum Nord, Nuernberg, Germany
Contact address: Gabriele Dennert, Medizinische Klinik 5, Klinikum Nord, Prof.-Ernst-Nathan-Str. 1, Nuernberg, D-90419, Germany.
Gabriele.Dennert@klinikum-nuernberg.de. (Editorial group: Cochrane Pain, Palliative and Supportive Care Group.)
Cochrane Database of Systematic Reviews, Issue 2, 2009 (Status in this issue: New search for studies completed, conclusions not changed)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DOI: 10.1002/14651858.CD005037.pub2
This version first published online: 19 July 2006 in Issue 3, 2006.
Last assessed as up-to-date: 16 February 2009. (Help document - Dates and Statuses explained)
This record should be cited as: Dennert G, Horneber M. Selenium for alleviating the side effects of chemotherapy, radio-
therapy and surgery in cancer patients. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD005037. DOI:
10.1002/14651858.CD005037.pub2.
A B S T R A C T
Background
This is an updated version of the original Cochrane review published in Issue 3, 2006. Selenium supplements are frequently used
by cancer patients. Selenium is an essential trace element and is involved in antioxidant protection and the redox-regulation in
humans. Several adverse effects of radiotherapy and chemotherapy in cancer patients as well as cellular processes that maintain chronic
lymphoedema have been linked to oxidative cell processes in the human body. Selenium has been claimed to alleviate side effects of
conventional cancer therapy and recently been investigated as a remedy against chemotherapy and radiotherapy-associated side effects
and secondary lymphoedema.
Objectives
This review assessed the effects of supplementary selenium on adverse effects of conventional radiotherapy, chemotherapy, or surgery
in oncology patients and on quality of life/performance status during and after oncological treatment.
Search strategy
The Cochrane Pain, Palliative & Supportive Care Trials Register, the Cochrane Database of Systematic Reviews, the Database of
Abstracts of Reviews of Effects (DARE), CENTRAL, MEDLINE, EMBASE, SIGLE, Cancerlit, CCMed, the German online register
for cancer trials, the ISRCTN, the mRCT, the NCI Clinical Trials register databases were searched and most updated in July 2007.
Selection criteria
Randomised controlled trials (RCTs) of selenium mono-supplements in cancer patients undergoing tumour specific therapy, such as
chemotherapy, radiotherapy or surgery.
Data collection and analysis
Two review authors independently checked trials for eligibility, extracted data and assessed trial quality.
Main results
One new included study as well as further participants to a study already included was added to this update involving a further 39
participants. There were a total of three studies included involving 162 participants for this update.
1Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
For this review two RCTs were included investigating secondary lymphoedema in 60 women after breast cancer surgery and 20 men and
women after head and neck cancer surgery. One ongoing trial with preliminary results of 82 participants was also identified studying
radiotherapy induced diarrhoea as a secondary outcome. All studies had considerable drawbacks with regards to quality and reporting.
One study on secondary lymphoedema reported a decreased number of recurrent erysipela infections in the selenium supplementation
group compared to placebo. The second study reported a decreased facial swelling in the selenium group in a two-week period following
surgical tumour resection. However, results must be interpreted with caution and cannot be generalised to other populations.
The ongoing trial on radiotherapy associated diarrhoea preliminarily reported a lower incidence of diarrhoea in participants receiving
selenium supplementation concomitant to pelvic radiation, however, no data were presented. We must await publication of final results
to discuss these findings in detail.
No RCTs were found studying the effect of selenium supplementation on other therapy-associated toxicities or quality of
life/performance status in cancer patients.
Authors’ conclusions
There is insufficient evidence at present that selenium supplementation alleviates the side effects of tumour specific chemotherapy or
radiotherapy treatments or that it improves the after-e ffects of surgery, or improves quality-of-life in cancer patients or reduces secondary
lymphoedema. To date, research findings do not provide a basis for any recommendation in favour or against selenium supplementation
in cancer patients. Potential hazards of supplementing a trace mineral should be kept in mind. Since the last version of this review, the
one new additional study has not provided information to change the conclusions of the original review.
P L A I N L A N G U A G E S U M M A R Y
Selenium supplements for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients
There is no evidence that selenium supplements reduce side effects of chemotherapy, radiotherapy or the effects of surgery in cancer
patients. Selenium is a mineral necessary for human health. Selenium acts against cell damage in the body and might help to alleviate
the side effects of therapies in cancer patients, such as nausea, diarrhoea or the lymph retention in limbs. Selenium supplements are
frequently used by cancer patients. This systematic review looked at studies providing selenium supplements to cancer patients and
found no clear evidence that selenium supplements improve side effects of cancer therapy. No adverse effects were reported in the
studies, but evidence of overdosing, all be it unintentional and selenium intoxication has occurred in several selenium users. More
research is needed to find out which doses of selenium supplements can be reasonably used by cancer patients and whether selenium
supplements can affect the side effects of cancer therapy.
B A C K G R O U N D
This review is an update of a previously published review in The
Cochrane Database of Systematic Reviews (Issue 3, 2006) on ’Se-
lenium for alleviating the side effects of chemotherapy, radiother-
apy and surgery in cancer patients’.
Selenium is an essential trace element for humans. It is involved
in antioxidant protection and redox regulation as a component
of seleno-proteins and as a source of seleno-metabolites (Hatfield
2001). Adverse effects of radiotherapy and chemotherapy in can-
cer patients have been linked to the formation of free radicals and
the related oxidative damage to normal cells (Weijl 1997). Lately,
intervention strategies have been investigated to use biological re-
sponse modifiers, such as selenium compounds, as toxicity antago-
nists for prevention of chemotherapy and radiotherapy associated
side effects.
Acute mucositis is a severe condition seen frequently in patients
undergoing radiotherapy. A recent review found that about 80%
of ENT radiotherapy patients developed mucositis, about half of
them experienced a severe form (grade three to four) which lead to
treatment interruption or alteration in one in ninepatients (Trotti
2003). Patients undergoing pelvic radiation for e.g. gynecological
malignancies are at risk for developing acute intestinal mucositis,
enteritis, and diarrhoea. Atrophy of the salivary glands and xe-
rostomia are long-term sequelae of a radiogenic sialadenitis after
ENT radiotherapy, which can only be controlled insufficiently by
symptomatic interventions, such as saliva substitutes or stimulants
2Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Groetz 2003).
Both in acute and long-term side effects of radiotherapy, selenium
has been discussed as a preventive agent. In vitro experiments
found a cytoprotective effect of sodium selenite on human fibrob-
lasts and endothelial cells without reducing radiotherapy activity
against cancer cells (Rodemann 1999;Schleicher 1999). Sagowski
2004 showed that administration of parenteral sodium selenite
reduced radiogenic damage to parotid glands in rats, which was
confirmed by better gland function after irradiation.
A number of chemotherapy toxicities and adverse effects have been
linked to the formation of free radicals by cytostatics (Weijl 1997).
A protective effect of ebselen against doxorubicin induced cell
damage was seen in rat cardiomyocytes in vitro (Kotamraju 2000).
Animal studies suggested that sodium selenite may decrease cis-
platin induced nephrotoxicity (Baldew 1989;Francescato 2001;
Yoshida 2000) and myelotoxicity (Ohkawa 1988) in rats and mice.
Cardiac sensitivity to ischemia after adriamycin treatment was re-
duced by sodium selenite supplementation in rats (Boucher 1995).
Secondary lymphoedema is a common complication after sur-
gical and radiological therapy of breast and ENT cancer (Dietz
1998;Erickson 2001). Patients with lymphoedema of the upper
extremity and the head and neck region can experience a sub-
stantial degree of functional impairment and psychological mor-
bidity. Endolaryngeal oedema and swelling may even lead to air-
way obstruction and require tracheostomy. The development of
oedema is indicated by surgical or radiological damage to the lym-
phatic system resulting in fluid retention (Zimmermann 2005).
Higher interstitial pressure lessens oxygen supply to oedematous
tissue and chronic inflammatory processes lead to fibrosis of small
lymph vessels. Highly reactive oxygen containing radicals (reac-
tive oxygen species) are claimed to have a crucial role in develop-
ment and maintenance of lymphoedema. Selenium compounds
may improve redox balance in sparsely perfused oedematous tis-
sue and, hence, be effective in control and therapy of secondary
lymphoedema (Micke 2003;Zimmermann 2005).
The role of the complementary use of selenium in cancer patients
is unclear. Some publications report a positive effect of selenium
supplementation on radio/chemotherapy associated side effects
and lymphoedema following surgical cancer treatment. However,
trial evidence is inconsistent, and a systematic review on this topic
has not been conducted.
Surveys in Canada, UK, Austria and Germany found that four to
12% of breast cancer and prostate cancer patients used selenium
supplements during and after cancer therapy to alleviate adverse
effects of conventional therapy and to improve quality of life (
Cheetham 2001;Nam 1999;Petru2001;Sehouli 2000). This high
number of cancer patients using selenium supplements contrasts
with the little clear evidence in this field thus justifying the need
to update this Cochrane review.
O B J E C T I V E S
The aim of this review was to assess the effects of supplementary
selenium, given at any dose, on:
adverse effects of conventional radiotherapy, chemo-
therapy, and/or oncological surgery;
quality of life and performance status during and after
conventional oncological therapy.
A further aim was to make recommendations for future research.
M E T H O D S
Criteria for considering studies for this review
Types of studies
Randomised-controlled trials (RCTs) were included in this review
which studied the efficacy of selenium supplementation as sup-
plementary cancer treatment. No restriction was made regarding
publication status, year or language of publication.
Types of participants
Study participants were patients of any age with malignant diseases
(regardless of the stage of disease) who were undergoing tumour
specific therapy (chemotherapy, radiotherapy or surgery).
Types of interventions
Studies that assessed selenium supplements or selenium prepara-
tions at any dose, duration, and route of administration compared
with placebo or no intervention/routine care were eligible. Studies
using selenium supplements as part of a multicomponent prepa-
ration in which there was no study arm testing for selenium sup-
plements alone were not included in this review. Collateral inter-
ventions (e.g. manual therapy for lymphoedema) were allowed if
adequately controlled for, and used in, all arms of the study.
Types of outcome measures
Data on the following outcomes were collected:
the effect of selenium on the incidence and severity of
chemotherapy or radiotherapy related toxicities if they
were reported according to internationally accepted cri-
teria for common toxicities (e.g. WHO, ECOG or NIH
criteria for adverse effects; DCTD 2004;Miller 1981;
Oken 1982);
the effect of selenium on the incidence and severity
of lymphoedema following surgical treatment or radio-
therapy;
3Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
patient-reported levels of physical and psychological in-
dices of symptom distress (measured using reliable and
valid assessment tools);
quality of life, as measured by a validated instrument;
incidence and type of adverse effects.
Search methods for identification of studies
Electronic searches
For this updatewe searched the foll owing databases, sources of grey
literature and registers of clinical trials with the reported search
strategies:
the Cochrane Pain, Palliative & Supportive Care Trials
Register (July 2007),
the Cochrane Database of Systematic Reviews (The
Cochrane Library, Issue 2, 2007),
the Database of Abstracts of Reviews of Effects (DARE)
(The Cochrane Library, Issue 2, 2007),
the Cochrane Central Register of Controlled Trials
CENTRAL (The Cochrane Library, Issue 2, 2007),
MEDLINE (1966 to July 2007),
EMBASE (1980 to 2007 week 28),
SIGLE (October 2004; database discontinued in 2005),
Cancerlit (July 2007),
CCMed (Clinical Contents in Medicine,German) (Oc-
tober 2004),
the German online register for cancer trials (July 2007),
the International Standard Randomised Controlled
Trial Number Register ISRCTN (October 2004),
the Meta-Register of Controlled Trials mRCT (October
2004),
the NCI Clinical Trials register (October 2004).
The search for the original review was run in 2004, subsequent
searches for the update were run in 2007. CCMed database - a
database of German journals - search was omitted in 2007 as the
relevant journals for this review are now indexed in MEDLINE,
which they were not in 2004. ISRCTN, mRCT and NCI Clinical
Trials are online registers for cl inical studies and helpful to identify
ongoing RCTs. We considered a time interval of three years too
short for an update search in these online resources taking into
account a reasonable balance of resources and expected outcome.
We used the MEDLINE search strategy as outlined in Appendix
1(via PubMed - 1966 to July 2007), its strategy was adapted
and developed for other databases searched which can be seen in
Appendix 2.
Searching other resources
We contacted the Chinese Cochrane Center and the Russian
Branch of the Nordic Cochrane Center, but due to limited re-
sources we were not able to have the Moscow Medical Library or
the Chinese Biomedical Database searched for publications.
Additionally, we checked the reference lists of retrieved publica-
tions for further studies and searched the archive of our work
group. Manufacturers of selenium supplements and authors of
publications were contacted and asked to contribute additional
data.
Data collection and analysis
Selection of studies
Identified publications were checked for eligibility by both review
authors. A publication was obtained in full text if it could not be
rejected with certainty on the basis of its title or abstract. Stud-
ies of possible relevance were also obtained in full text for further
evaluation. If inclusion or exclusion could not be assessed from
the publication alone, first authors were contacted for additional
information. Reasons for excluding trials from the review are re-
ported in the ’Characteristics of excluded studies’ table.
The review authors were not blinded to authors´ names, institu-
tion and source of publication. Any disagreement was resolved by
discussion between the review authors.
Data extraction and management
Both review authors independently extracted and documented
data using a pre-tested extraction form. The following information
was collected:
study methods (randomisation, allocation conceal-
ment, blinding, eligibility criteria, follow-up);
participants (patient characteristics, age, gender, cancer
type, other cancer management/treatment, comorbid-
ity) and additional treatments/medication;
interventions (selenium dose, regimen, duration of
treatment, route of administration) and placebo
outcome measures;
study withdrawals, drop-outs and protocol deviations;
adverse effects;
informed consent, ethic board approval.
Discrepancies were resolved by discussion between both review
authors.
We contacted all primary study authors of included studies for
additional information and data. Details of all eligible studies are
summarised in the ’Characteristics of included studies’ table.
Methodological quality
Review authors assessed studies for methodological quality using
a critical appraisal checklist according to Juni 2001.
4Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
This checklist included the following aspects of methodological
quality:
randomisation, allocation concealment,
blinding,
specification of eligibility criteria,
equal provision of care (apart from selenium supple-
mentation) and equal follow-up,
similarity of groups at baseline,
reporting of protocol deviations, withdrawals and drop-
outs,
reporting of outcome measures and adverse effects,
statistical procedures (intention-to-treat analysis).
Additionally, completed studies were rated according to the Ox-
ford Quality Scale (Jadad 1996) and the Delphi list (Verhagen
1998).
Analysis
We planned to calculate a summary statistic and its 95% confi-
dence interval (CI) for each outcome and to perform a meta-anal-
ysis of summary statistics if appropriate. Due to the small number
of included studies, their methodological limitations and clinical
heterogeneity, we considered summary statistics not to be appro-
priate. Study results are reported as presented in the original pub-
lication along with information on adverse effects.
R E S U L T S
Description of studies
See: Characteristics of included studies;Characteristics of excluded
studies;Characteristics of ongoing studies.
Results of the search
For this update review one new included study (Zimmermann
2005) was included and more participants were added to the
Mücke 2007 study adding a further 39 participants to the total
participants included within the review. The previous review iden-
tified an ongoing study which has been completed since the orig-
inal publication of this review and is now excluded (Schumacher
2003). The total number of participants considered within the
included studies is 162.
Our search returned 1981 studies of possible relevance. Of these,
1943 studies could be excluded based on title or abstract. The ap-
parently high number of screened studies was due to our intensive
literature search in databases that did not allow the use of a search
strategy other than the main topic “selenium”. After screening, the
remaining 38 publications were obtained in full text. Following
the inclusion criteria of this review, a further 30 papers (represent-
ing 26 studies) had to be excluded. The main reasons for exclusion
were that the publications described a non-randomised study or
the study investigated laboratory parameters, e.g. the change of
serum selenium status after supplementation. (see Characteristics
of excluded studies).
The remaining eight publications represented four studies (
Büntzel 2004;Kasseroller 1998;Mücke 2007;Zimmermann
2005). Two of these studies were completed (Kasseroller 1998;
Zimmermann 2005) and intermediate results have been published
for one of the ongoing studies (Mücke 2007) (see Characteristics
of included studies’). One study is ongoing (Büntzel 2004) and no
preliminary results have been published so far. All study authors
were contacted and provided additional papers or information for
this review.
All four studies were or are being conducted in Germany and Aus-
tria as a cooperation between different clinicians and one Ger-
man pharmaceutical company, which manufactures sodium selen-
ite products for clinical application.
Included studies
1) Effects on the incidence and severity of lymphoedema
Two completed RCTs could be identified for this outcome (
Kasseroller 1998;Zimmermann 2005):
Kasseroller 1998 was described as a placebo-controlled ran-
domised, double blind trial. Sixty female cancer patients were in-
cluded in the study and results were presented for 57. The ob-
jective was to investigate the efficacy of sodium selenite applica-
tion in combination with physical therapy to relieve secondary
lymphoedemas after breast cancer surgery; recurrence of erysipela
infection in the oedematous limb was reported as the primary
outcome. Participants in the intervention group received sodium
selenite per os for 15 weeks with a sum dose of 19.600 µg to
28.000 µg (19.6 mg to 28 mg, depending on body weight). All
participants were treated with a combined physical congestion-
relief programme.
Preliminary results of this study were published in 1996 giving
data for 34 female cancer patients, including 25 women after breast
cancer surgery and nine women after pelvic surgery. According to
our correspondence with the author, all 25 breast cancer patients
reported in 1996 were participants of this later study (Kasseroller
1998). We could not obtain additional information on the re-
maining participants with other gynecologic malignancies.
Zimmermann 2005 was also described as a placebo-controlled ran-
domised, double-blind trial. Twenty participants (18 male, two fe-
male) with head-and-neck cancer undergoing curatively intended
tumour resection were included. The objective was to investigate
blood selenium concentration and different enzyme activities and
postoperative lymphoedema. Only the latter outcome is of in-
terest for this systematic review. Participants in the intervention
5Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
group received 3000 µg sodium selenite intravenously on the day
of surgery and 1000 µg sodium selenite daily (i.v. or per os(p.o.))
on days one to 21 after surgery.
2) Effects on the incidence and severity of chemo- or
radiotherapy related toxicities
One ongoing RCT with published preliminary results could be
identified for this outcome:
Mücke 2007 investigated the use of sodium selenite supplements
in female cancer patients during adjuvant radiotherapy in an on-
going randomised, unblinded two-armed multi-center study with
a no-treatment control group. Study objectives were the assess-
ment of the efficacy of sodium selenite p.o. for normalization of
selenium deficiency during adjuvant radiotherapy (primary out-
come) and, secondarily, its effect on the incidence and severity of
radiotherapy toxicities (e.g. diarrhoea according to common tox-
icity criteria (CTC), changes in body weight and blood count).
The intervention group received a sum dosage of approximately
15,900 to18,000 µg sodium selenite p.o. (15.9 to18 mg) during
radiotherapy (ca. 5 weeks). According to the study protocol, the
trial will randomise 200 participants to intervention and control
group. Intermediate results have been published for 41 partici-
pants (Mücke 2004b) and 63 participants (Mücke 2004a), 77
participants (Mücke 2006b), 79 participants (Mücke 2006a), 80
participants (Micke 2007), and 82 participants (Mücke 2007a;
Mücke 2007b) (Mücke 2007).
Risk of bias in included studies
Details of the methodological quality of included studies are given
in an additional table (see Additional Table 1: ’Quality Assessment
of Included Studies’).
Table 1. Quality assessment of included studies
Study Allocation Conceal-
ment
Study
groups
Eligibility Blinding Attrition Delphi list Jadad
score
Comment
Kasseroller
1998
random al-
location;
method of
sequence
gen-
eration not
reported
unclear no infor-
mation
on compa-
rabil-
ity of study
groups re-
garding
risk factors
at baseline
eli-
gibility cri-
teria speci-
fied; num-
ber of el-
igible pa-
tients not
stated
patient:
yes; care
provider:
yes; out-
come as-
sessor: yes -
un-
blinding of
treatment
status after
3 dropouts 1-0-0-1-1-
1-1-0-0
1-1-1 Selection
bias possi-
ble: alloca-
tion con-
cealment
unclear, no
infor-
mation on
distribu-
tion of risk
6Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 1. Quality assessment of included studies (Continued)
end of in-
tervention
factors at
baseline.
Observer/detection
bias possi-
ble:
no control
procedure
reported
whether
blinding
was suc-
cessful, de-
tails on
outcome
assess-
ment not
reported
Performance
bias pos-
sible: con-
comi-
tant treat-
ment not
sufficiently
described
Mücke
2007
random al-
location;
method of
sequence
gen-
eration not
reported
serially
numbered,
sealed,
opaque en-
velopes
no infor-
mation
on compa-
rabil-
ity of study
groups re-
garding
risk factors
at baseline
eli-
gibility cri-
teria speci-
fied; num-
ber of el-
igible pa-
tients not
stated
patient:
no; care
provider:
no; out-
come as-
sessor: no
dropouts /
with-
drawals
not
reported
in most re-
cent publi-
cations
-- -- Prelimi-
nary
results of
an ongoing
study
(Delphi
List
and Jadad
Score will
be given
when final
report is
available)
Selection
bias un-
likely, but
pos-
sible: allo-
cation con-
7Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 1. Quality assessment of included studies (Continued)
ceal-
ment ade-
quate, but
no infor-
mation on
distribu-
tion of risk
factors for
outcome.
Observer/detection
bias possi-
ble: no
blinding.
Perfor-
mance bias
possible:
concomi-
tant treat-
ment un-
clear
Zimmermann
2005
random al-
location;
method of
sequence
gen-
eration not
reported
unclear no infor-
mation
on compa-
rabil-
ity of study
groups re-
garding
risk factors
at baseline
eli-
gibility cri-
teria speci-
fied; num-
ber of el-
igible pa-
tients not
stated
pa-
tient: un-
clear; care
provider:
un-
clear; out-
come as-
sessor: un-
clear
no
dropouts
or with-
drawals
1-0-0-1-0-
0-0-0-0
1-1-1 Selection
bias possi-
ble: alloca-
tion con-
cealment
unclear, in-
formation
on distri-
bution of
risk factors
at baseline.
Observer/detection
bias possi-
ble: study
was
reported as
double-
blinded
- informed
consent
form, how-
ever, con-
tained in-
forma-
8Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 1. Quality assessment of included studies (Continued)
tion on in-
tervention
status, reli-
ability and
validity of
outcome
assessment
unclear.
Performance
bias pos-
sible: con-
comi-
tant treat-
ment not
sufficiently
described.
Randomisation
and blind-
ing
unclear:
informed
con-
sent form
for partici-
pants con-
tains the
sentence
“you have
been al-
located to
the group
receiving
sele-
nium sup-
plements”,
while study
is reported
as double-
blinded
No study described the method of sequence generation for ran-
dom allocation. Mücke 2007 reported an adequate procedure of
allocation concealment (personal communication); methods of al-
location concealment in Kasseroller 1998 and Zimmermann 2005
remained unclear. All studies specified criteria for inclusion and
exclusion of participants, but information on intervention and
control groups’ characteristics at baseline was not provided. There-
fore, unequal distribution of risk factors for the outcomes of in-
terests cannot be ruled out. Treatment allocation was described as
blinded to participants, doctors, care-givers and outcome assessors
in Kasseroller 1998, but a control procedure checker as to whether
blinding was successful was not reported. Zimmermann 2005 was
described as a double-blinded, placebo-controlled trial. However,
the informed consent form for participants indicated that they had
been allocated to the selenium group (see: Leonhardt 2002, p. 79
(Zimmermann 2005)). We were not able to clarify the actual pro-
9Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
cedure of treatment allocation and blinding with the investigators
of this study. Mücke 2007 is an unblinded trial.
According to Kasseroller 1998, all participants received compa-
rable physical treatment for lymphoedema. However, details on
concomitant treatments such as high-voltage therapy and infor-
mation on additional medication that might influence erysipela
incidence (e.g. corticosteroids) were not provided. All participants
in Zimmermann 2005 underwent curatively intended oral tu-
mour surgery with bilateral neck dissection. Information on fac-
tors that might influence postsurgical local swelling, such as the ex-
tent of intraoperative tissue trauma, postoperative complications
or comorbidity was not reported. In the ongoing trial by Mücke
2007, participants are excluded who receive specific medication at
study commencement (antibiotics, antacids, adsorbents, 5-HT3-
antagonists). If started after study inclusion, concomitant intake
of these drugs should be avoided according to the study proto-
col, but will not result in exclusion from the study group. Other
drugs that might influence diarrhoea, especially opioid analgesics,
are not mentioned in the study protocol and not reported in the
preliminary data.
Kasseroller 1998 gave no details for methods of outcome assess-
ment or criteria of erysipela diagnosis. Especially the assessment
of erysipela infections after dismissal from hospital remained un-
clear. Zimmermann 2005 reported three distances in the face (tra-
gus - nostril, tragus - tip of chin, tragus - corner of mouth), each
distance measured both directly and circumferentially. The mea-
surements were manually undertaken by one investigator before
surgery and repeated immediately after, one and two weeks af-
ter tumour resection. Reliability of measurements was unclear.
Study investigators equated the measurement of postsurgical face
swelling within the first two weeks after surgery with the assess-
ment of postoperative secondary lymphoedema. The validity of
this procedure seems questionable as the short interval between
surgery and outcome assessment does not allow for postsurgical
traumatic swelling to disappear and for lymphoedema to develop.
In addition, Zimmermann and colleagues themselves stated that
the “measuring distances chosen only partly describe the extent of
the lymphedema” (Zimmermann 2005, p. 199). Measurements of
caudal to mandible, where lymphoedema would be most promi-
nent according to Zimmermann and colleagues, were not con-
ducted. In Mücke 2007, incidence and severity of diarrhoea are
diagnosed by the radiologist on a weekly basis based on partici-
pants’ self-reports.
Kasseroller 1998 reported findings for recurrence of erysipela in-
fection. In contrast to the study objectives, results on the devel-
opment of lymphoedema with and without selenium supplemen-
tation were not reported. Results of a data analysis (i.e OR/CI
or t-test/P) were not presented. Zimmermann 2005 reported the
measurements for three distances in the face at four time points
as raw data. Results were presented as graphs only; Cross-tables
or absolute numbers of results were not provided. Results were
tested for differences between intervention and control group and
significance levels were reported; the related test was not specified.
Mücke 2007 reported preliminary data on incidence and severity
of radiation-induced diarrhoea and chi-square test and t-test were
performed to investigate differences in the occurrence of diarrhoea
according to CTC.
Effects of interventions
After a comprehensive literature search, we located two completed
studies investigating the effect of selenium supplementation on
secondary lymphoedema. Another ongoing study examines radio-
therapy-associated diarrhoea as a secondary outcome; with the pri-
mary objective being the evaluation of sodium selenite supplemen-
tation for compensation of pre-existing selenium deficiency. We
could not identify trials covering other outcomes of this review,
such as quality of life or chemotherapy toxicities.
1) Effects of selenium with physical therapy on the
incidence and severity of lymphoedema
Kasseroller 1998 measured the recurrence of erysipela infections
of lymphoedematous upper limbs after breast cancer treatment.
During the three-week treatment in the hospital no erysipela oc-
curred in the intervention group, and one erysipela occurred in
the control group. During the entire intervention and follow-up
period of 15 weeks no participant in the intervention group de-
veloped recurrent erysipela while in the placebo group 14 partici-
pants (50 % of n = 28) were diagnosed with erysipela infections.
These findings suggest that there might be a lower incidence of
recurrent erysipela infections in the selenium group compared to
placebo in the 15 weeks’ period. However, this study has severe
methodological limitations, as described earlier in this review. Due
to these methodological problems, no conclusions on the effect
of selenium supplementation on the recurrence of erysipelas in
the intervention group can be drawn and generalisations to other
cancer patients seem questionable.
Zimmermann 2005 reported the extent of facial swelling after
oral tumour surgery for head and neck cancer. The control group
showed the peak in facial swelling at the measuring point one
week after surgery. In the selenium group, the maximum swelling
was seen directly after surgery. The circumferential distance tra-
gus/tip of chin was significantly shorter one week and two weeks
after surgery in the intervention group, indicating a lesser facial
swelling than in the control group. Taking into consideration the
low number of participants and the limitations in methodology
and reporting, both internal validity of results and external gener-
alisability to other patients seems questionable.
2) Effects of selenium on the incidence and severity of
chemo- or radiotherapy related toxicities
Mücke 2007 investigated radiotherapy associated diarrhoea as
a secondary outcome in selenium deficient women undergoing
pelvic radiation. The latest publication of this study provided data
on 82 female participants with a median age of 66 years (range 31
10Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
to 80). Authors reported a statistically significant lower incidence
and severity of diarrhoea in weeks four to six of radiotherapy in the
intervention group. The overall incidence of radiation-induced di-
arrhoea grade CTC two or higher was 21% in the selenium group
compared to 47 % in the control group. Further data on incidence
or severity of diarrhoea, cross-tables, additional data analysis (e.g.
OR with CI) or results (e.g. blood count) have not yet been pre-
sented. Also, distribution of risk factors for diarrhoea at baseline
and concomitant medication that might influence diarrhoea have
not been reported. A conclusive discussion of this trial will need
to await the publication of detailed final results.
In all three studies, no adverse effects of selenium supplementation
were observed.
D I S C U S S I O N
After a comprehensive literature search, we were able to locate only
two completed RCTs (Kasseroller 1998;Zimmermann 2005) that
fulfilled the inclusion criteria of this review and another ongoing
study (Mücke 2007) with published preliminary results. All three
included studies used inorganic sodium selenite as medication.
Another study not included within the included studies is currently
ongoing (Büntzel 2004).
Due to methodological limitations it is not possible to draw con-
clusions on the effect of selenium supplementation on the re-
currence of erysipela infections in women with secondary lym-
phoedema in the Kasseroller 1998 study. This study has been in-
cluded in another Cochrane Review assessing the efficacy of anti-
inflammatories for reducing acute inflammatory episodes in lym-
phoedema of the limbs (Badger 2004), which came to a similar
conclusion regarding trial quality and the subsequent limitations
in the interpretation of trial results. However, Badger 2004 re-
ported two publications of Kasseroller 1996 and Kasseroller 1998
as two distinct studies. Having been able to make contact with
Kasseroller, it was confirmed that the publication Kasseroller 1996
reported preliminary results of Kasseroller 1998.
Zimmermann 2005 reported a lesser facial swelling after head and
neck tumour resection in one (of three) measurements in a two
week follow-up in a group of 20 participants. Considering the
unclear reliability and validity of outcome measurements, it is un-
clear whether the measured differences really reflect a reduction
in postoperative lymphoedema in the selenium group. Generali-
sation to other cancer patients seems questionable. Furthermore,
the clinical relevance of these measurements remained unclear.
The findings of Kasseroller have been cited in a number of
secondary publications and non-systematic reviews. In 2000
Kasseroller/Schrauzer published an overview with pooled results
from different studies that investigated the efficacy of selenium
supplementation in female breast cancer patients with secondary
lymphoedema (Kasseroller 2000). We obtained confirmation from
Kasseroller that his study data (Kasseroller 1998) were included in
this summary report, but could not clarify where the remaining
data stemmed from. It is doubtful that all data in this overview
originated from RCTs. Kasseroller/Schrauzer inferred that clinical
“studies with lymphedema of the arm after breast cancer surgery
document that sodium selenite increases the efficacy of physical de-
congestion therapy and prevents erysipela infections” (Kasseroller
2000). Another summary of current treatment options for sec-
ondary lymphoedema (Bruns 2003) arrived at a similar positive
conclusion regarding selenium supplementation: “Present data
demonstrate that selenium can enhance the benefits of physical
therapy in radiation-induced lymphedemas. The very low toxic-
ity profile of selenium and its cost effectiveness are further argu-
ments for its use in lymphedema treatment” (Bruns 2003). Au-
thors backed their approval with a reference to the Kasseroller 1998
study and asserted that “Kasseroller [...] reported promising results
of a placebo-controlled, double-blind study of selenium in 179
postmastectomy patients”. However, the Kasseroller 1998 study
included only 60 participants and the above described overview
by Kasseroller/Schrauzer (Kasseroller 2000), which reported data
of 179 participants altogether,did not describe a RCT, but pooled
data of predominantly unknown origin.
More recent publications also referred to Zimmermann 2005 to
back their approval of selenium supplementation (Beuth 2007)
claiming that “[r]andomized controlled clinical trials have demon-
strated significant benefits for cancer patients receiving Se dur-
ing chemo and radiotherapy, such as reduction of lymphedema in
head and neck” cancer patients (p. 427).
Considering the lack of evidence from studies with a design that
aimed to minimise possible sources of bias and the low quality of
reporting in the two completed trials, this systematic review does
not support the conclusions in the above cited secondary publica-
tions on the efficacy of selenium supplementation in patients with
secondary lymphoedema.
To date no completed RCT is available that investigates the effi-
cacy of selenium supplements to ameliorate side effects of conven-
tional cancer chemo- or radiotherapy. Intermediate results from
one study using sodium selenite to diminish diarrhoea in women
undergoing pelvic radiation were included in this review, but have
not yet been published in sufficient detail for a conclusive dis-
cussion (Mücke 2007). Another study is currently ongoing with
toxicities of conventional therapy as outcomes of interest: Büntzel
2004 has a design comparable to that of Mücke 2007 and in-
cludes participants with a pre-existing selenium deficiency who are
undergoing radiotherapy for ENT-malignancies. This study has
been recruiting since 2000 and aims to include 200 participants
randomly allocated to intervention (oral administration of sodium
selenite) or control group (without selenium supplementation).
Primary outcome measure is the normalisation of selenium defi-
ciency in the blood, and secondary outcomes include radiotherapy
11Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
toxicities.
In contrast to the complete lack of evidence from RCTs regarding
the efficacy of selenium supplements against radio-/chemotherapy
associated side-effects, selenium supplements are frequently rec-
ommended for this indication in secondary publications (Arnold
2001;Beuth 2002) and claimed that “a protective effect against
chemotherapy toxicities” has been proven in clinical studies and
observations (Sill-Steffens 2003). Considering the lack of evi-
dence, no recommendation can currently be given regarding the
use of selenium supplements to ameliorate radio- or chemother-
apy associated side effects.
Authors of secondary publications frequently emphasize that sele-
nium supplementation seems to be a safe intervention as no side
effects have been reported in clinical studies. In both RCTs that
are included in this review no side effects attributable to selenium
supplementation were reported at average dosages between 100
to1000 µg sodium selenite daily over a period of five to 15 weeks.
Inorganic selenium compounds have known acute and chronic
toxicities (selenosis) at high dosages. The recommended daily al-
lowance for adults varies between 30 to100 µg daily depending
on country and gender. 200 µg to 300 µg are considered the max-
imally safe daily intake over longer periods (Baehr 1999), but
dosages of 1000 µg daily have been used in clinical investigations
with sepsis patients for up to four weeks without signs of selenosis
(Zimmermann 1997).
A few cases of acute and chronic selenosis in patients due to acci-
dental overdosage of selenium-containing medication have been
reported in the literature. In the year 2000 two severe incidents
occurred in Germany and Austria when physicians mistakenly pre-
scribed milligrams of sodium selenite instead of micrograms caus-
ing one death in Austria after parenteral administration of about
200 mg selenium (Pfeffer 2002). In 2006, the case of an Australian
man with an adenocarcinoma of the prostate was published, who
ingested 10 g of sodium selenite after reading on the internet about
selenium as putative treatment for prostate cancer. He died some
hours later of selenium intoxication (See 2006). Several cases of
chronic selenosis have been reported in persons using non-pre-
scribed nutritional supplements with inaccurate specification of
selenium content. Individuals had a daily intake of ca. 1000 µg/d
selenium up to 27,000 µg/d in the form of organic or inorganic
selenium compounds over several weeks resulting in chronic se-
lenium intoxication with partly severe symptoms (nausea, vomit-
ing, loss of nails and hair, and halitosis) (Helzlsouer 1985;Jensen
1984).
Apart from acute and chronic toxicity of selenium, long-term
effects of selenium supplementation are still controversially dis-
cussed (Vinceti 2001). Evidence from observational and interven-
tion trials regarding the effect of selenium on cancer incidence
and mortality is contradictory; a Cochrane review on the cancer-
preventive efficacy of selenium is in process (Dennert 2005). In
Germany, inorganic selenium compounds are currently classified
as potential workplace cancerogenics (Greim 1999;Greim 2003).
Whether short or long-term selenium supplementation bears any
protective or harmful effect on cancer diseases, is still open to ques-
tion.
To summarise, the current evidence is insufficient to provide
guidelines for clinical practice. The lack of primary study data
contrasts remarkably with the amount of secondary publications
and the proportion of cancer patients using selenium supplements,
especially in German-speaking countries. It remains to be seen
whether the ongoing studies will be able to add substantially to
the current body of evidence.
A U T H O R S ’ C O N C L U S I O N S
Implications for practice
The currently available evidence is insufficient to assess reliably
the possible role of selenium supplementation on toxicities related
to oncology treatments, on the development and severity of sec-
ondary lymphoedema and on quality of life during antineoplastic
treatments. The quality of the studies prohibits us from extrapo-
lating any effects observed to the general population level. Cur-
rently, research findings do not provide a basis for any recommen-
dation in favour or against selenium supplementation in cancer
patients. Nevertheless, the potential hazards of supplementing a
trace mineral should always be kept in mind.
Since the last version of this review the additional participants have
not provided additional information to change the conclusions.
Implications for research
As it is likely that a considerable number of cancer patients will seek
“complementary” treatments to alleviate adverse effects connected
with conventional therapy, further research is desirable.
Supplementation with sodium selenite is currently under inves-
tigation in RCTs and robust and sound replication of the exist-
ing trial might be useful. However, no systematic dosage-finding
study has been reported so far. An adequate dosage-finding study
seems as desirable as adequate reporting of completed, ongoing
and future trials.
A C K N O W L E D G E M E N T S
We thank all authors, clinicians and investigators who provided us
with additional information and publications for this review. The
AG Biologische Krebstherapie is funded by the German Cancer
Aid.
12Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
R E F E R E N C E S
References to studies included in this review
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Kasseroller 1995 {published data only}
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[Natriumselenitin der Therapie des c hronischenLymphödems]. Der
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Kiremidjian-Schumacher L, Roy M. Effect of selenium on the im-
munocompetence of patients with head and neck cancer and on
adoptive immunotherapy of early and established lesions. BioFactors
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Lasch K, Brasel C, Jahn H. Selenium therapy in colorectal tu-
mors? [Selentherapie bei kolorektalen Tumoren?]. Medizinische
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Lasch K, Bräsel C, Jahn H. Selenium therapy for colorectalcarcinoma
[Poster: Selentherapie bei kolorektalen Karzinomen]. Poster. ——.
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Schumacher K. Influence of selenium on the adverse effect pro-
file of adjuvant chemotherapy in patients with mammacarcinoma.
Prospective, controlled, open, multi-center clinical study phase II
[Einfluss von Selen auf das Nebenwirkungsprofil von adjuvanter
Chemotherapie bei Patientinnen mit Mammakarzinom. Prospek-
tive, kontrollierte, offene, multizentrische klinische Prüfung der
Phase II]. www.studien.de (download 16.01.2004) 2002.
Schumacher K, Biosyn Arzneimittel GmbH. Study plan - Influence
of selenium on the adverse effect profile of adjuvant chemotherapy in
patients with mammacarcinoma. Prospective, randomised, 4-armed,
controlled, open, multi-center clinical study phase II [Prüfplan –
Einfluss von Selen auf das Nebenwirkungsprofil von adjuvanter
Chemotherapie bei Patientinnen mit Mammakarzinom. Prospek-
tive, randomisierte, vierarmige, kontrollierte, offene, multizentrische
klinische Prüfung der Phase II]. biosyn Arzneimittel GmbH 2003.
Sieja 2000 {published data only}
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chemotherapy in patients with ovarian cancer. Pharmazie 2000;55
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Sundström 1984 {published data only}
Sundström H, Korpela H, Viinikka L, Kauppila A. Serum selenium
and glutathione peroxidase, and plasma lipid peroxides in uterine,
ovarian or vulvar cancer, and their responses to antioxidants in pa-
tients with ovarian cancer. Cancer Letters 1984;24(1):1–10.
Sundström 1989 {published data only}
Sundström H, Korpela H, Sajanti E, Kauppila A. Supplementation
with selenium, vitamin E and their combination in gynaecological
cancer during cytotoxic chemotherapy. Carcinogenesis 1989;10(2):
273–8.
Wagler 2000 {published data only}
Wagler E, Schwokowski C, Schönfelder M. Poster: first results of
selenium supplementation in patients with gastrointestinal tumours
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gastrointestinalen Tumoren]. Poster. Universitätsklinikum Leipzig,
2000.
Xu 1990 {published data only}
Xu H, Mei W, Dong Z, Liao B. Study of the oxidative metabolic
function and chemotaxis of neutrophils from patients with cancer
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25(3):201–9.
Xu 1999 {published data only}
Xu B, Sun Y. Randomized double-blind placebo-controlled phase
II clinical trial of kappa-selenocarrageenan in cancer chemotherapy
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Yu 1996 {published data only}
Yu B, Wang M, Li D. [The relationship between selenium and im-
munity in large bowel cancer]. Zhonghua Wai Ke Za Zhi 1996;34
(1):50–3.
References to ongoing studies
Büntzel 2004 {published data only}
Büntzel 2002: Büntzel J. Use of selenase as complementary treatment
to radiotherapy for tumours of the head and neck region [Einsatz von
selenase als Zusatztherapie zur Radiotherapie bei Tumoren im Hals–
Nasen–Ohrenbereich]. www.studien.de (retrieved on 16.01.2004)
2002.
Büntzel J, Biosyn Arzneimittel GmbH. Observation plan of a post-
marketing surveillance study. Use of selenase as complementary treat-
ment to radiotherapy of tumours ofthe head and neck region (version
1.4) [Beobachtungsplan der Anwendungsbeobachtung (AWB). Ein-
satz von selenase als Zusatztherapie zur Radiotherapie bei Tumoren
14Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
im Hals–Nasen–Ohrenbereich (version 1.4.)]. biosyn Arzneimittel
GmbH 2004.
Micke 2003b: Micke O, Riesenbeck D, Büntzel J. Importance of
selenium supplementation in postoperative radiotherapy of head-
neck-tumours and gynecological tumours of the pelvis - A multi-
centre phase III study [Stellenwert der Selen–Substitution bei
der postoperativen Strahlentherapie bei Kopf–Hals–Tumoren und
gynäkologischen Beckentumoren – Eine multizentrische Phase–
III–Studie]. www.uni-muenster.de’/rektorat/forschungsberichte-
2001-2002/fo05aka15.htm (download 09.01.2004). Münster:
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16Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
References to other published versions of this review
Dennert 2006
Dennert G, Horneber M. Selenium for alleviating the side ef-
fects of chemotherapy, radiotherapy and surgery in cancer patients.
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Indicates the major publication for the study
17Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Kasseroller 1998
Methods Randomised placebo-controlled, double-blind trial with two parallel arms
Recruitment period: July 1994 - September 1995
Observation period: 15 weeks
Ethical approval: yes
Participants Number of patients: eligible/accrued: unclear - included: 60 - reported: 57
Drop Outs: “During the treatment, some of the patients were excluded from the study since they did not
meet the criteria for study inclusion, namely, too short a period of stay.” (Kasseroller 1998, p. 2228)
Inclusion criteria: female cancer patients with one-sided secondary lymphoedema (arm) after mastectomy
with axillar dissection and recurrent erysipela infections (> = 3 in the year before admission) who were
admitted to the hospital for lymphoedema treatment
Exclusion criteria: current treatment with antibiotics, NSAIDs or antioxidant medication
Demographics: women, average age = 60.5 years
Recruitment and setting: patients admitted to Wittlinger´ s therapy center, Walchsee, Austria (private
rehab clinic) for lymphoedema treatment
Informed consent: yes
Interventions Intervention: week 1: sodium selenite solution 1000 µg/d p.o.; week 2-3: 300 µg/d p.o.; week 4-15: 200
µg/d p.o. (body weight > 70 kg), 100 µg/d p.o. (body weight < 70 kg)
Control: identically looking placebo (sodium chloride p.o.)
Concomitant treatment: combined physical congestion-relief program (manual lymph drainage twice
daily, compressive bandages, high-voltage therapy, therapeutic exercise, meticulous skin care)
Outcomes Primary outcome measure: incidence of recurrent erysipelas in a 15-week follow-up period
Outcome assessment: diagnosis of erysipela infection based on clinical examination, blood sedimentation
rate and CRP titer
Notes Post-marketing surveillance study in Austria
Participants: no data on stage of lymphoedema, comorbidity given
Number of participants: inconsistent data: results reported for n = 57 participants in text, but for n = 60
participants in table
Intervention: application of 1000 mg sodium selenite reported (misprint instead of 1000 µg)
Outcomes: criteria for erysipela diagnosis unclear, diagnosis might differ between in-hospital treatment
and follow-up after dismissal
Investigator provided additional information on study methods
Risk of bias
Item Authors’ judgement Description
18Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Kasseroller 1998 (Continued)
Allocation concealment? Unclear B - Unclear
Mücke 2007
Methods Ongoing randomised placebo-controlled, open label trial with 2 parallel arms
Recruitment period: December 2000 - ongoing
Observation period: December 2000 - ongoing
most recent publication reports on December 2000 to May 2007
Ethical approval: yes
Participants Number of patients eligible: unclear - blood tested for selenium deficiency: unclear - selenium deficiency
in blood: unclear - included: unclear
reported: 82
Drop Outs: unclear
Inclusion criteria: female cancer patients with cervical or endometrial cancer after surgery and with pre-
existing selenium deficiency in whole blood/serum receiving adjuvant percutaneous radiotherapy
Exclusion criteria: distant metastases; patients receiving combined radio-/ chemotherapy; patients with
prior pelvic/ abdominal radiation; current diarrhea; use of antibiotics, antacids, astringents, adsorbents,
intestinal desinfectants or 5-HT3-antagonists at the beginning of the study; use of selenium supplements;
use of cytoprotectants
Demographics: women, age 31 to 80 years (median: 66 years).
Recruitment and setting: multicenter study, Germany
Informed consent: yes
Interventions Intervention: sodium selenite solution 500 µg/d for two days before start of radiotherapy, 500 µg/d on
days of radiation, 300 µg/d on days without radiation (weekend)
Control: no supplementation
all patients: percutaneous adjuvant radiotherapy with total doses between 45 to 50 Gy and single doses
between 1.8 to 2.0 Gy
supportive medication: not reported
Outcomes Primary outcome measure: compensation of selenium deficiency as measured in whole blood
other: incidence and severity of diarrhoea
Outcome assessment: weekly examination by physician; blood tests; participants diary of well-being and
physical problems
Notes Post-marketing surveillance study in Germany
Intervention: concomitant medication with influence on diarrhea (opioids etc.) not reported
Investigators provided a study plan and additional information on study methods
Actual intervention deviated from study protocol: sodium selenite prior to radiotherapy was omitted in a
number of patients (see: recent publications, confirmed by investigators)
Risk of bias
19Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Mücke 2007 (Continued)
Item Authors’ judgement Description
Allocation concealment? Yes A - Adequate
Zimmermann 2005
Methods Randomised placebo-controlled, double-blind trial with 2 parallel arms
Recruitment period: unclear
Observation period: 2 weeks (for postoperative face swelling)
Ethical approval: yes
Participants Number of patients:
eligible: unclear - included: unclear - reported: 20
Drop outs: unclear
Inclusion criteria: female and male patients, age >18, with carcinoma of the tongue or floor of the mouth
(clinical stage T3 or T4)
Exclusion criteria: clinical tumour stage T1 or T2; second malignancy; cardiac oedema; hypoproteinic
oedema; acute infections during the past 6 months; regular intake of antioxidants; chronic renal failure;
intellectual disability; pregnant women; prison inmates; participants of other clinical studies.
Demographics: 18 men - 2 women; age 30 - 74 (mean: 57) years; all patients had histologically confirmed
squamous cell cancer (2 pT2, 7 pT3, 8 pT4)
Recruitment and setting: monocenter study, Dresden, Germany
Informed consent: yes
Interventions Intervention: 3000 µg sodium selenite solution i.v. on day of surgery; 1000 µg sodium selenite solution
i.v. or p.o. on days 1 to 21 after surgery
Control: placebo (0.9% sodium chloride solution)
all patients: surgical tumour resection in curative intention with bilateral neck dissection
Outcomes Primary outcome measures: three defined distances and circumferences in the face; selenium levels in
whole blood and several other laboratory parameters
Assessment of outcome of interest: manual measurement by one investigator at four time points (prior
to, immediately after, one week after and two weeks after surgical intervention)
Notes Intervention: concomitant surgical and non-surgical interventions with influence on lymphoedema not
reported
Investigators provided additional information on their interpretation of study results
All patients who refused the continuation of study medication due to perceived adverse effects would
have been excluded from the final study report according to Leonhardt 2002; according to personal
communication no drop-outs occurred.
Risk of bias
Item Authors’ judgement Description
20Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Zimmermann 2005 (Continued)
Allocation concealment? Unclear B -Unclear
CRP: C-reactive protein
d: day
Gy: Gray
µg: microgram
NSAID: non-steroidal antiinflammatory drugs
p.o.: per os
Characteristics of excluded studies [ordered by study ID]
Asfour 2006 RCT, outcome:apoptosis in polymorphonuclear leucocytes; also infections in selenium and control group re-
ported, authors contacted. Study excluded because assessment is not possible on the basis of available information
Badger 2004 Cochrane Review: includes patients with malignant and non-malignant diseases
Büntzel 1999 Case series
Elango 2006 Clinical trial; outcome:plasma selenium level and activity of selenium-dependent enzymes
Fakih 2006 Phase I clinical trial to determine the maximum tolerated dose of irinotecan in combination with a fixed dose
of selenomethionine
Federico 2001 RCT, zinc/selenium combination supplement
Fraunholz 2001 Non-randomized clinical trial
Hoenjet 2005 RCT with multi component supplement; only non-clinical outcomes
Hu 1997 RCT, outcome: treatment toxicities of chemotherapy; data not presented according to toxicity scale; author
contacted, but no reply obtained
Kasseroller 1995 RCT, participants with malignant and non-malignant diseases
Kiremidjian 2000 RCT, outcome: reaction of peripheral lymphocytes to mitogen stimulation after selenium supplementation
Kreienberg 2003 Study title mentioned in University of Heidelberg´ s trials´ register of the year 2003; hospital contacted, but no
answer obtained
21Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)
Lasch 1999 Clinical controlled trial: study not described as randomized, all ocation to study and control group was per formed
according to date of birth
Schumacher 2003 Planned RCT, so far not recruiting patients
Sieja 2000 Multi component drug, study not described as randomised
Sundström 1984 No RCT, outcome: change in selenium-related biomarkers
Sundström 1989 No RCT, outcome: change in selenium-related biomarkers
Wagler 2000 RCT, outcome: change in selenium-related biomarkers - author contacted, but no reply obtained
Xu 1990 RCT, outcome: change of chemiluminescence measurement after selenium supplementation
Xu 1999 RCT, outcome: immunomodulation following selenium supplementation
Yu 1996 Outcome: selenium-related biomarkers; author contacted, but no answer obtained
Characteristics of ongoing studies [ordered by study ID]
Büntzel 2004
Trial name or title Einsatz von selenase als Zusatztherapie zur Radiotherapie bei Tumoren im Hals-Nasen-Ohrenbereich.
[Use of selenase as complementary therapy for radiotherapy in ENT tumours)
Methods
Participants 200 female and male patients with selenium deficiency in whole blood receiving radiotherapy for ENT
carcinomas
Interventions Supplementation of sodium selenite solution p.o.
Intervention: 500 µg/d for two days before start of radiotherapy, 500 µg/d on days of radiation, 300 µg/d on
days without radiation (weekend)
Control: no supplementation
all patients: percutaneous adjuvant radiotherapy with total doses between 45 to 50 Gy and single doses
between 1.8 and 2.0 Gy
Outcomes Primary outcome measure: normalisation of pre-existing selenium deficiency in whole blood
other: radiotherapy toxicities
Starting date 01.09.2000
22Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Büntzel 2004 (Continued)
Contact information Dr Jens Büntzel, Südharzkrankenhaus Nordhausen, Klinik für HNO-Erkrankungen, Dr.-Robert-Koch-Str.
29, 99734 Nordhausen, Germany
Notes Information taken from study protocol version 1.4/01.03.2004
Study is recruiting according to authors
23Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
D A T A A N D A N A L Y S E S
This review has no analyses.
A P P E N D I C E S
Appendix 1. MEDLINE search strategy
1. selen* OR seleno* OR selenium[mesh] OR selenium compounds[mesh] OR organoseleno compounds[mesh]
2. epidemiologic study characteristics[mesh] OR random* OR placebo* OR clinical trial* OR double blind method OR single
blind method
3. neoplasms[mesh] OR stem cell transplantation[mesh] OR therapeutics[mesh] OR antineoplastic agents[mesh] OR quality
of life[mesh]
4. cancer* OR malignan* OR carcino* OR neoplasm* OR tumor* OR tumour*
5. radioth* OR radiat* OR irradiat* OR radiochemo* OR radio-chemo* OR chemotherap*
6. melanoma* OR sarcoma* OR adenoma* OR adenosarcoma* OR adenocarcinoma* OR carcinosarcoma* OR chondrosar-
coma* OR fibrosarcoma* OR dermatofibrosarcoma* OR neurofibrosarcoma* OR hemangiosarcoma* OR leiomyosarcoma*
OR liposarcoma* OR myosarcoma* OR rhabdomyosarcoma* OR myxosarcoma* OR osteosarcoma* OR lymphoma* OR
stem cell transplant* OR stem-cell transplant* OR bone marrow transplant*
7. lymphedem* OR lymphoedem* OR cardiotox* OR nausea* OR vomit* OR hair loss* OR leukopenia* OR neutropenia*
OR thrombopenia* OR anemia*
8. #3 OR #4 OR #5 OR #6 OR #7
9. #1 AND #2 AND #8
10. animals[mh] NOT humans[mh]
11. #9 NOT #10
Appendix 2. Additional search strategies
Database Time Search Strategy
EMBASE 1980 - 2007 week 28 1 selenium/ or selen$.mp.
2 exp Selenium Derivative/
3 methylseleninic acid/ or methylselenium.mp.
4 exp Organoselenium Derivative/
5 exp Clinical Study/
6 exp NEOPLASM/
7 Selenium 75/
8 1 or 2 or 3 or 4
9 8 and 5 and 6
10 9 not 7
11 limit 10 to human
24Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)
SIGLE [ www.fiz- informationsdienste.de]
[the database was discontinued]
October 2004 ?selen?
with restriction to subject group “06 Biological and Medical
Sciences (without Botanics, Zoology, Biophysics)”
Cancerlit July 2007 1 random* OR placebo* OR clinical trial* OR randomized
controlled trial* OR controlled clinical trial* OR double blind
OR single blind
2 selen* OR organoselen*
3 1 AND 2
Clinical Contents in Medicine CCMed October 2004 selen* OR organoselen* OR natriumselen*
NCI Clinical Trials [ www.cancer.gov] October 2004 medication=selenium
ISRCTN and mRCT [ www.controlled-
trials.com]
October 2004 selenium AND cancer
German Register of Cancer Studies [
www.studien.de]
July 2007 selen
Cochrane Pain, Palliative & Supportive
Care Trials Register
July 2007 selen*
The Cochrane Database of Systematic Re-
views; The Database of Abstracts of Re-
views of Effects (DARE); The Cochrane
Central Register of Controlled Trials
(CENTRAL)
Issue 2, 2007 selen*
W H A T ’ S N E W
Last assessed as up-to-date: 16 February 2009.
25Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
17 February 2009 New search has been performed For this update review one new included study (Zimmermann 2005) was
included adding a further 20 participants of head and neck cancer patients
to the total participants included within the review. The Mücke 2007 latest
data included a further 19 participants. The previous review identified an
ongoing study which has been completed since the original publication of
this review and is now excluded (Schumacher 2003). The list of excluded
studies, background and discussion chapter was also revised. The search for
this update was run in July 2007. The new included and excluded studies
did not change the original conclusions of this review.
H I S T O R Y
Protocol first published: Issue 4, 2004
Review first published: Issue 3, 2006
22 April 2008 Amended Converted to new review format.
C O N T R I B U T I O N S O F A U T H O R S
GD, MH: protocol development, study assessment, data extraction, data analysis, discussion.
GD: literature search, data management, review coordination, contact with first authors, writing, review update.
D E C L A R A T I O N S O F I N T E R E S T
None known
S O U R C E S O F S U P P O R T
Internal sources
No sources of support supplied
26Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
External sources
Dr Ernst and Anita Bauer Stiftung, Germany.
EU Project: Concerted action for complementary and alternative medicine in the cancer field (EU CAM-Cancer) (contract
no.: QLG4-CT-2002-00786), Not specified.
I N D E X T E R M S
Medical Subject Headings (MeSH)
Antineoplastic Agents [adverse effects]; Antioxidants [therapeutic use]; Diarrhea [prevention & control]; Lymphedema [prevention
& control]; Neoplasms [drug therapy; radiotherapy; surgery]; Postoperative Complications [prevention & control]; Radiotherapy
[adverse effects]; Randomized Controlled Trials as Topic; Sodium Selenite [therapeutic use]
MeSH check words
Humans
27Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
... Sodium selenite has been found to have chemoprotective and antitumor capacities at non-toxic doses [1,2]. Some studies have shown that a low dose of selenite in supplementation with chemotherapy could help to reduce its side effects [1,3,4]. In addition, selenite has been found to possess a potent antitumor capacity and selectivity for tumor cells. ...
... Specifically, sodium selenite (SeO3 2-) is reduced to selenide (HSe -) by GSH, which is expelled due to cellular detoxification processes via the MRP system. (4). Once inside the cell cytoplasm, selenite depletes GSH and reduced thioredoxin (TRX-H), leaving the cell defenseless against reactive oxygen species (ROS) and increasing them. ...
... Specifically, sodium selenite (SeO 3 2-) is reduced to selenide (HSe -) by GSH, which is expelled due to cellular detoxification processes via the MRP system. (4). Once inside the cell cytoplasm, selenite depletes GSH and reduced thioredoxin (TRX-H), leaving the cell defenseless against reactive oxygen species (ROS) and increasing them. ...
Article
Full-text available
Sodium selenite acts by depleting enzymes that protect against cellular oxidative stress. To determine its effect alone or in combination with gemcitabine (GMZ) in pancreatic cancer, we used PANC-1 and Pan02 cell lines and C57BL mice bearing a Pan02-generated tumor. Our results demonstrated a significant inhibition of pancreatic cancer cell viability with the use of sodium selenite alone and a synergistic effect when associated with GMZ. The molecular mechanisms of the antitumor effect of sodium selenite alone involved apoptosis-inducing factor (AIF) and the expression of phospho-p38 in the combined therapy. In addition, sodium selenite alone and in association with GMZ significantly decreased the migration capacity and colony-forming ability, reduced tumor activity in multicellular tumor spheroids (MTS) and decreased sphere formation of cancer stem cells. In vivo studies demonstrated that combined therapy not only inhibited tumor growth (65%) compared to the untreated group but also relative to sodium selenite or GMZ used as monotherapy (up to 40%), increasing mice survival. These results were supported by the analysis of C57BL/6 albino mice bearing a Pan02-generated tumor, using the IVIS system. In conclusion, our results showed that sodium selenite is a potential agent for the improvement in the treatment of pancreatic cancer and should be considered for future human clinical trials.
... El selenio, un microelemento, es importante para las defensas antioxidantes del cuerpo como un componente integral de las enzimas metaloproteicas. (27) ...
... El selenio disminuyó significativamente la incidencia de carcinoma hepatocelular en grupos de pacientes de alto riesgo, el selenio es el único suplemento antioxidante probado que puede presentar efectos beneficiosos sobre la incidencia de carcinoma hepatocelular. (27) Se han realizado varios estudios relacionados con el uso de vitamina E en pacientes con neuropatía periférica inducida por cisplatino, donde se evaluó su efecto neuroprotector. Pace y otros evaluaron el efecto neuroprotector de la vitamina E como suplemento antioxidante en 27 pacientes con Melanoma tratados con Cisplatino, y se constató disminución de la neurotoxicidad en los pacientes tratados con vitamina E en comparación con los que recibieron Cisplatino solamente. ...
Article
Full-text available
El estrés oxidativo es un desequilibrio bioquímico entre los radicales libres y los mecanismos de defensa antioxidantes de una célula. El cáncer es per se, una enfermedad inductora de estrés oxidativo debido a las alteraciones metabólicas de las células neoplásicas, la malnutrición y los tratamientos oncoespecíficos. El uso de antioxidantes podría evitar sus efectos sobre las células normales, pero al anular los efectos nocivos del estrés oxidativo sobre las células neoplásicas impediría la muerte celular programada y podría reducir la eficacia de los tratamientos. El artículo tiene como objetivo exponer los beneficios/perjuicios de la ingesta de agentes antioxidantes en los pacientes oncológicos. Se consultaron las bases de datos, PubMed, MedLine, BioMed Central y SciELO. Se seleccionaron artículos de revisión sobre el tema en los últimos cinco años, así como revisiones clásicas y meta-análisis que evaluaron la utilización de suplementos antioxidantes durante el tratamiento oncológico.
... According to reports, there were 17.5 million cancer patients existing in 2015 (Javadi, 2018). At present, conventional interventions such as chemotherapy, surgery, and radiation are often used to help cancer patients get rid of the disease (Dennert & Horneber, 2006). Although these interventions are available, the applications of which are also accompanied by some side effects (Dennert & Horneber, 2006). ...
... At present, conventional interventions such as chemotherapy, surgery, and radiation are often used to help cancer patients get rid of the disease (Dennert & Horneber, 2006). Although these interventions are available, the applications of which are also accompanied by some side effects (Dennert & Horneber, 2006). For safety concerns, there is a great need to look for effective and safe methods for cancer treatment. ...
Article
Full-text available
Previously, beetroot is mainly consumed as a food additive. In recent years, the beetroot, especially the betalains (betanin) and nitrates it contains, now has received increasing attention for their effective biological activity. Betalains have been proven to eliminate oxidative and nitrative stress by scavenging DPPH, preventing DNA damage, and reducing LDL. It also has been found to exert antitumor activity by inhibiting cell proliferation, angiogenesis, inducing cell apoptosis, and autophagy. In some chronic diseases, nitrate is the main component for lowing blood lipids, glucose, and pressure, while its role in treating hypertension and hyperglycemia has not been clearly stated. Moreover, the intake of nitrate-rich beetroot could enhance athletic performance and attenuate muscle soreness in certain types of exercise. The objective of this review is to provide sufficient evidence for the clarification of health benefits of beetroot, especially in the aspect of biooxidation, neoplastic diseases, some chronic diseases, and energy supplementation.
... One trial [49] failed to demonstrate selenium supplements reduced side effects of CT and RT, or the effects of surgery. Further investigation agreed that selenium supplementation during radiation had no effect on the severity/incidence of OM [22]. ...
Article
Full-text available
Purpose To evaluate the effectiveness of antioxidants in the prevention and management of oral mucositis in adults undergoing radiotherapy and/or chemotherapy with diagnosed head and neck cancer (HNC) compared to placebo intervention. Methods Cochrane, EMBASE, PubMed, and Web of Science databases were used to search for randomized controlled trials (RCTs) comparing oral or topical antioxidants with placebo in clinically diagnosed HNC adult patients receiving radiotherapy with/without chemotherapy. The primary outcome was to assess the efficacy of the antioxidant to prevent and decrease the incidence/prevalence and severity of oral/oropharyngeal mucositis. The risk of bias was assessed following Cochrane’s guidelines. Results The database search resulted in 203 records up to February 19, 2021. Thirteen RCTs were included with 650 HNC-diagnosed patients. Included studies showed a statistically significant improvement in mucositis severity score for all antioxidants except melatonin. However, further studies are needed as only one study reported outcomes for zinc, propolis, curcumin, and silymarin. Patients receiving vitamin E were 60% less likely to develop severe mucositis grade 2 or higher than those receiving placebo in one study (P = 0.040). Patients receiving zinc were 95% less likely to develop severe mucositis (grades 3–4) in one study compared to placebo (P = 0.031). One meta-analysis showed no statistical difference in the risk of having severe mucositis (grades 3–4) with 199 patients compared to placebo for honey (n = 2 studies, P = 0.403). Meta-analyses could not be conducted for zinc, propolis, curcumin, melatonin, silymarin, and selenium due to the lack of studies reporting similar outcomes for the same intervention. Conclusion Though oral and topical antioxidants significantly improved mucositis severity scores in HNC patients receiving radiotherapy with/without chemotherapy in individual studies, the quality of the evidence was low due to the small number of studies and unclear/high-risk bias. Additionally, large RCTs are needed to confirm these results.
... Dietary selenium is obtained chiefly from the following food groups: meat and fish, eggs and dairy products, and bread and cereals [6]. For clinical application, selenium can be used to treat erosive oral lichen planus [7] and relieve side effects in cancer patients after chemotherapy and radiotherapy [8]. In addition, selenium nanoparticles can be used as cancer-targeted drugs [9]. ...
Article
Full-text available
Non-alcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease without effective therapy. Selenium, as an essential trace element for humans, is notable for its antioxidant properties. The previous study shows that selenium levels in NAFLD patients are lower than normal ones. Selenium supplementation can effectively alleviate metabolic disorders by relieving anti-oxidative stress and anti-inflammatory regulation. However, the correlation between selenium and NAFLD has not been fully clarified. Herein, we review the current studies on selenium in regulating the different stages of NAFLD and summarize relevant clinical trials to highlight the potential roles of selenium in NAFLD treatment.
... Cisplatin, a chemotherapy agent used to treat ovarian, bladder, lung, and other cancers can reduce selenium levels in hair, plasma, and serum [239,240]. Some studies have examined whether selenium supplementation helps reduce the side effects of cisplatin and other chemotherapy agents, but the evidence is uncertain [240,241]. ...
Article
Full-text available
COVID-19, the disease caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in 2019 and has infected over 230 million people worldwide as of October 1, 2021. Common initial signs and symptoms include cough, fever, fatigue, headache, muscle aches and pain, and diarrhea [2]. Some individuals with COVID-19 become severely ill, usually starting about 1 week after symptom onset; severe COVID-19 often involves progressive respiratory failure and may also result in life-threatening pneumonia, multiorgan failure, and death. In addition, thousands of individuals-possibly 10% to 75%-who have had COVID-19 report symptoms of “long COVID” (including fatigue, muscle weakness, sleep difficulties, and cognitive dysfunction) for several months after the acute stage of illness has passed. Currently, data are insufficient to support recommendations for or against the use of any vitamin, mineral, herb or other botanical, fatty acid, or other dietary supplement ingredient to prevent or treat COVID-19. And by law, dietary supplements are not allowed to be marketed as a treatment, prevention, or cure for any disease; only drugs can legally make such claims. Nevertheless, sales of dietary supplements marketed for immune health increased after the emergence of COVID-19 because many people hoped that these products might provide some protection from SARS-CoV-2 infection and, for those who develop COVID-19, help reduce disease severity. The immune system defends the body against pathogens that cause disease and is comprised of innate responses, which are the first line of defense, and adaptive responses, which become engaged later.
... Drug therapy can result in damage to normal tissues and organs such as bone marrow, kidney, and oral mucosa and can hinder the normal metabolism. In addition, these three methods may cause inflammation and secondary lymphedema during treatment (Dennert and Horneber, 2006 ...
Article
Full-text available
Lactic acid bacteria (LAB) are a kind of Gram-positive bacteria which can colonize in the biological gastrointestinal tract and play a variety of probiotic roles. LAB have a wide range of applications in industry, animal husbandry, planting, food safety, and medical science fields. Previous studies on LAB have typically concentrated on their effects on improving the digestion and absorption of the gastrointestinal tract, regulating the balance of the microflora, and inhibiting the production and accumulation of toxic substances. The resistance of LAB to cancer is a topic of growing interest and relevance. This paper provided a summary of bio-active substances of LAB when they act against cancer, as well as the safety of LAB in clinical cancer treatment. Moreover, this paper further discussed several possible directions for future research and the potential application of LAB as anti-cancer therapy.
... In a six-month observational study, children undergoing treatment for acute lymphoblastic leukemia and with an inadequate intake of antioxidants (vitamin A, E, and carotenoids) were faced with increased chemotherapy-related adverse effects [237]. In his study, Nicolson claimed that antioxidant supplementation could decrease chemotherapyinduced side effects through the restoration of mitochondrial function, but should not be taken at the same time of day as the therapy [238].A meta-analysis of randomized clinical trials led to insufficient evidence for the alleviation of chemotherapy-and radiotherapyinduced side effects or improvement of the after-effects of surgery with selenium monotherapy [239]. ...
Article
Full-text available
Colorectal carcinogenesis is the second most common cause of mortality across all types of malignancies, followed by hepatic and stomach cancers. Chemotherapy and radiotherapy are key approaches to treating cancer patients, but these carry major concerns, such as a high risk of side effects, poor accessibility, and the non-selective nature of chemotherapeutics. A number of natural products have been identified as countering various forms of cancer with fewer side effects. The potential impact of vitamins and minerals on long-term health, cognition, healthy development, bone formation, and aging has been supported by experimental and epidemiological studies. Successful treatment may thus be highly influenced by the nutritional status of patients. An insufficient diet could lead to detrimental effects on immune status and tolerance to treatment, affecting the ability of chemotherapy to destroy cancerous cells. In recent decades, most cancer patients have been taking vitamins and minerals to improve standard therapy and/or to decrease the undesirable side effects of the treatment together with the underlying disease. On the other hand, taking dietary supplements during cancer therapy may affect the effectiveness of chemotherapy. Thus, micronutrients in complementary oncology must be selected appropriately and should be taken at the right time. Here, the potential impact of micronutrients on gastro-intestinal and hepatic cancers is explored and their molecular targets are laid down.
Chapter
Рhytосhemiсаls аs biоасtive соmроnents of plants shows promising results in curing many diseases. Therefore, the demand for these natural medicines increases day by day. Phytochemicals such as phenols and flavonoids seem to act in various ways to protect health. Protection of cells can be done through different types of means such as change of reactive oxygen species to non-radicle type by breaking sequencing of auto oxidative reactions commenced by reactive oxygen species and by lowering the oxygen saturation of diseased area. Many phytochemicals balance antioxidants and free radicals in our bodies. Some recent studies have shown that intake of synthetic antioxidants for a long duration may cause many health problems, like allergies, digestive problems, and according to few studies may also increase the chances of cancer.
Article
Full-text available
Introduction Antioxidant dietary supplements are used by many patients with cancer to reduce the side effects of chemotherapy and improve prognosis. While some research indicates oral antioxidant supplementation reduces side effects and improves patient survival, other studies suggest the use of antioxidant dietary supplements may interfere with chemotherapy and reduce its curative effects. There is a need to clarify the evidence base on the impact of dietary antioxidant supplementation during chemotherapy on both side effect and treatment efficacy outcomes. We will use a scoping review approach to identify what systematic review evidence exists regarding beneficial and harmful effects of dietary antioxidant supplements when used during cancer treatment. Methods and analysis We will use Arksey & O’Malley and Joanna Briggs Institute methods for scoping reviews. We will systematically search PubMed, Embase, CINAHL, Scopus, Dissertations & Theses Global and the Cochrane Library from inception to October 2020. Systematic reviews of randomised controlled trials of oral dietary antioxidant supplements used by participants receiving curative chemotherapy, radiotherapy or other biological therapy for cancer will be eligible. Two reviewers will screen citations and full texts for inclusion and chart data on research questions from included reviews. Two reviewers will assess the overall confidence in systematic review results using A Measurement Tool to Assess Systematic Reviews-2 (AMSTAR-2), and summarised evidence will focus on reviews rated at high or moderate overall confidence. Tables will be used to map existing evidence and identify evidence gaps for safety and effectiveness outcomes. Ethics and dissemination This scoping review does not require ethical approval as it is a secondary assessment of available literature. The results will be presented at conferences and submitted for publication in a peer-reviewed journal. We will also disseminate results to community and clinical stakeholders and involve them in developing subsequent research to address critical existing gaps in the evidence as identified by the scoping review.
Article
Full-text available
Background: This review is the third update of the Cochrane review "Selenium for preventing cancer". Selenium is a naturally occurring element with both nutritional and toxicological properties. Higher selenium exposure and selenium supplements have been suggested to protect against several types of cancer. Objectives: To gather and present evidence needed to address two research questions:1. What is the aetiological relationship between selenium exposure and cancer risk in humans?2. Describe the efficacy of selenium supplementation for cancer prevention in humans. Search methods: We updated electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), MEDLINE (Ovid, 2013 to January 2017, week 4), and Embase (2013 to 2017, week 6), as well as searches of clinical trial registries. Selection criteria: We included randomised controlled trials (RCTs) and longitudinal observational studies that enrolled adult participants. Data collection and analysis: We performed random-effects (RE) meta-analyses when two or more RCTs were available for a specific outcome. We conducted RE meta-analyses when five or more observational studies were available for a specific outcome. We assessed risk of bias in RCTs and in observational studies using Cochrane's risk assessment tool and the Newcastle-Ottawa Scale, respectively. We considered in the primary analysis data pooled from RCTs with low risk of bias. We assessed the certainty of evidence by using the GRADE approach. Main results: We included 83 studies in this updated review: two additional RCTs (10 in total) and a few additional trial reports for previously included studies. RCTs involved 27,232 participants allocated to either selenium supplements or placebo. For analyses of RCTs with low risk of bias, the summary risk ratio (RR) for any cancer incidence was 1.01 (95% confidence interval (CI) 0.93 to 1.10; 3 studies, 19,475 participants; high-certainty evidence). The RR for estimated cancer mortality was 1.02 (95% CI 0.80 to 1.30; 1 study, 17,444 participants). For the most frequently investigated site-specific cancers, investigators provided little evidence of any effect of selenium supplementation. Two RCTs with 19,009 participants indicated that colorectal cancer was unaffected by selenium administration (RR 0.99, 95% CI 0.69 to 1.43), as were non-melanoma skin cancer (RR 1.16, 95% CI 0.30 to 4.42; 2 studies, 2027 participants), lung cancer (RR 1.16, 95% CI 0.89 to 1.50; 2 studies, 19,009 participants), breast cancer (RR 2.04, 95% CI 0.44 to 9.55; 1 study, 802 participants), bladder cancer (RR 1.07, 95% CI 0.76 to 1.52; 2 studies, 19,009 participants), and prostate cancer (RR 1.01, 95% CI 0.90 to 1.14; 4 studies, 18,942 participants). Certainty of the evidence was high for all of these cancer sites, except for breast cancer, which was of moderate certainty owing to imprecision, and non-melanoma skin cancer, which we judged as moderate certainty owing to high heterogeneity. RCTs with low risk of bias suggested increased melanoma risk.Results for most outcomes were similar when we included all RCTs in the meta-analysis, regardless of risk of bias. Selenium supplementation did not reduce overall cancer incidence (RR 0.99, 95% CI 0.86 to 1.14; 5 studies, 21,860 participants) nor mortality (RR 0.81, 95% CI 0.49 to 1.32; 2 studies, 18,698 participants). Summary RRs for site-specific cancers showed limited changes compared with estimates from high-quality studies alone, except for liver cancer, for which results were reversed.In the largest trial, the Selenium and Vitamin E Cancer Trial, selenium supplementation increased risks of alopecia and dermatitis, and for participants with highest background selenium status, supplementation also increased risk of high-grade prostate cancer. RCTs showed a slightly increased risk of type 2 diabetes associated with supplementation. A hypothesis generated by the Nutritional Prevention of Cancer Trial - that individuals with low blood selenium levels could reduce their risk of cancer (particularly prostate cancer) by increasing selenium intake - has not been confirmed. As RCT participants have been overwhelmingly male (88%), we could not assess the potential influence of sex or gender.We included 15 additional observational cohort studies (70 in total; over 2,360,000 participants). We found that lower cancer incidence (summary odds ratio (OR) 0.72, 95% CI 0.55 to 0.93; 7 studies, 76,239 participants) and lower cancer mortality (OR 0.76, 95% CI 0.59 to 0.97; 7 studies, 183,863 participants) were associated with the highest category of selenium exposure compared with the lowest. Cancer incidence was lower in men (OR 0.72, 95% CI 0.46 to 1.14, 4 studies, 29,365 men) than in women (OR 0.90, 95% CI 0.45 to 1.77, 2 studies, 18,244 women). Data show a decrease in risk of site-specific cancers for stomach, colorectal, lung, breast, bladder, and prostate cancers. However, these studies have major weaknesses due to study design, exposure misclassification, and potential unmeasured confounding due to lifestyle or nutritional factors covarying with selenium exposure beyond those taken into account in multi-variable analyses. In addition, no evidence of a dose-response relation between selenium status and cancer risk emerged. Certainty of evidence was very low for each outcome. Some studies suggested that genetic factors might modify the relation between selenium and cancer risk - an issue that merits further investigation. Authors' conclusions: Well-designed and well-conducted RCTs have shown no beneficial effect of selenium supplements in reducing cancer risk (high certainty of evidence). Some RCTs have raised concerns by reporting a higher incidence of high-grade prostate cancer and type 2 diabetes in participants with selenium supplementation. No clear evidence of an influence of baseline participant selenium status on outcomes has emerged in these studies.Observational longitudinal studies have shown an inverse association between selenium exposure and risk of some cancer types, but null and direct relations have also been reported, and no systematic pattern suggesting dose-response relations has emerged. These studies suffer from limitations inherent to the observational design, including exposure misclassification and unmeasured confounding.Overall, there is no evidence to suggest that increasing selenium intake through diet or supplementation prevents cancer in humans. However, more research is needed to assess whether selenium may modify the risk of cancer in individuals with a specific genetic background or nutritional status, and to investigate possible differential effects of various forms of selenium.
Book
As discussed in this book, a large body of evidence indicates that selenium is a cancer chemopreventive agent. Further evidence points to a role of this element in reducing viral expression, in preventing heart disease, and other cardiovascular and muscle disorders, and in delaying the progression of AIDS in HIV infected patients. Selenium may also have a role in mammalian development, in male fertility, in immune function and in slowing the aging process. The mechanism by which selenium exerts its beneficial effects on health may be through selenium-containing proteins. Selenium is incorporated into protein as the amino acid selenocysteine. Selenocysteine utilizes a specific tRNA, a specific elongation factor, a specific set of signals, and the codeword, UGA, for its cotranslational insertion into protein. It is indeed the 21st naturally occurring amino acid to be incorporated into protein and marks the first and only expansion of the genetic code since the code was deciphered in the mid 1960s.
Article
To evaluate the clinical usefulness of K - selenocarrageenan (Se - C) in immunomodulation, a total of 42 patients were enrolled in a randomized, double -blind, placebo - controlled phase II clinical trial. Of them 26 patients were given oral administration of 100mg Se - C capsule and 16 patients were given oral administration of placebo once a day for two consecutive weeks and was repeatedly administered in the subsequent cycle in the same manner. Immune functions were assessed after six-weeks. The results showed that the percentage of T4 cells was increased from 27. 9 ± 7. 4 to 38.1 ± 10. (P < 0.05) and T4/T8 ratio was increased from O. 92 ± 0. 23 to 1.27 ± 0.50 (P < 0.01) in treatment group. Percentage of phagocytosis of macrophages was increased from 24. 5 ± 19.4 to 31.9 ± 15.3 (P < 0. 01) in treatment group and decreased from 25.4 ± 15.4 to 21. 6 ± 22.3 (P < 0.01) in control group. NK cell activity, Ig contents, response rate and adverse effects were comparable in both groups. Conclusion: Se - C is an effective immunomodulatory agent.
Article
Background: The aim of this prospective phase III study was to evaluate whether sodium selenite is able to compensate a preexisting selenium deficiency in adjuvant radiotherapy (RT) for pelvic gynecologic malignancies. Further, we proved the use of sodium selenite in prevention of radiation-induced diarrhea. Material and methods: Whole blood selenium levels were measured in patients undergoing adjuvant RT after curative surgical resection of a pelvic gynecologic tumor before RT, after completing 50% of RT, at the end of RT and 6 weeks after RT depending on supplementation of sodium selenite in the verum group till the end of RT. Data were calculated for the patients that completed study protocol. Results: From December 2000 to November 2002, 41 patients (median age: 64.5 years) completed the protocol. All patients with histologically proven squamous cell carcinoma and adenocarcinoma of the uterine cervix or corpus had decreased whole blood selenium levels. There is a significant increase of the mean level of whole blood selenium in supplementation group reaching the lower border of normal range and a decrease after cessation of selenium intake. In control group we could not see any change of investigated mean selenium levels. Concerning diarrhea, there is a non-significant trend towards a lower incidence of diarrhea CTC 2 with selenium supplementation at present. Conclusion: Our first data may serve as evidence for a successful supplementation of selenium during radiotherapy of patients with gynecological tumors. No selenium-related side effects were observed.
Article
Background: Is the complementary supplementation of selenium useful in the therapy of colorectal cancer? □Patients and Methods: Fifty-three patients with primary colorectal cancer received a selenium treatment for 19 days in addition to a complete in-patient rehabilitation cure based on a behavioural approach. A comparative control group consisted of 41 patients. Measured factors were the selenium content in serum and whole blood, GSH-Px activity and TBARS in serum. Both the intake of selenium by nutrition and the patients’ life quality were determined additionally on day 1 and 19. The tumor marker CA 19-9 was measured only on day 1. □Results: A latent selenium deficiency was observed while gsh-px activity or concentration of TBARS were normal. The selenium status corresponds to the concentration of the tumor marker CA 19-9. The selenium status improves through supplementation, accompanied by a further increase of GSH-Px activity. During supplementation the patients’ life quality improves; subjective physical complaints decrease. □Conclusion: Further research will be necessary on both the dependency of the selenium status on the tumor marker concentration and on the development of the cancer. Optimum GSH-Px activity and individually different responses also need additional investigation. The influence of selenium on the patients’ life qualitiy should be investigated in the context of immunomodulation.
Article
Fragestellung: Das Zytostatikum Vinorelbin ist eine bei verschiedenen Tumorerkrankungen wirksame Substanz aus der Reihe der Vincaalkaloide. Auch bei sachgerechter Applikation werden in der Literatur [[1], [3], [4]] lokale Phlebitiden als Ausdruck einer mikroangiopathischen Inflammation mit einer Inzidenz von 10-26 % beschrieben. Wir gingen der Frage nach, ob die prophylaktische, unmittelbar vor der intravenösen Zytostatikaapplikation verabreichte Gabe von hochdosiertem Natriumselenit die Inzidenz und den Schweregrad der lokalen Phlebitis beeinflußen kann. Patienten: Im Rahmen dieser Untersuchung wurden 69 Patienten dokumentiert, bei denen eine Chemotherapie mit Vinorelbin durchgeführt wurden. Dem Wirkungsspektrum dieser Substanz entsprechend wurden Patienten mit Mammakarzinom, nichtkleinzelligem Bronchialkarzinom, Prostatakarzinom und Cervixkarzinom eingeschlossen. Methode: Bei 20 von 69 auswertbaren Patienten (29 %) trat eine Phlebitis ab Schweregrad 2 auf. Diese Patienten erhielten vor der nächsten Vinorelbininfusion 1000 μg Natriumselenit als Kurzinfusion in 500 ml NaCl 0,9 %. Ergebnisse: Nach prophylaktischer intravenöser Gabe von 1000 μg Natriumselenit konnte bei 16 von 20 Patienten das Auftreten einer lokalen Phlebitis bei allen nächsten Vinorelbingaben verhindert werden. Schlußfolgerung: Wir schließen daraus, daß die prophylaktische Gabe von Natriumselenit unmittelbar vor der intravenösen Vinorelbinapplikation eine wirkungsvolle supportive Therapieoption zur Vermeidung einer chemotherapieassoziierten Phlebitis darstellen kann.