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Jahangard-Rafsanjani et al. (2013): The efficacy of selenium in prevention of oral mucositis in patients undergoing hematopoietic SCT: a randomized clinical trial

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Title The efficacy of selenium in prevention of oral mucositis in patients undergoing hematopoietic SCT: a randomized clinical trial
Topic Selenium
Author Jahangard-Rafsanjani, Z, Gholami, K, Hadjibabaie, M, Shamshiri, AR, Alimoghadam, K, Sarayani, A, Mojtahedzadeh, M, Ostadali-Dehaghi, M, Ghavamzadeh, A
Year 2013
Journal Bone Marrow Transplantation
DOI https://doi.org/10.1038/bmt.2012.250

Brief summary

This study included 77 patients with acute lymphoblastic or myeloid leukemia who were undergoing high-dose chemotherapy and subsequent stem cell transplantation. The aim of the study was to find out whether the intake of selenium can influence the occurrence of mucositis. Other laboratory parameters and symptoms of the patients were also recorded. For the study, the patients were randomly divided into two arms, so that one arm (38 participants) received 200 mcg of selenium twice a day during chemotherapy and up to 14 days after the transplant, while the other arm received a placebo. Overall, there were no differences in the onset, frequency, or duration of mucositis between the two arms. However, there were significantly fewer severe cases of mucositis in the selenium arm, and the duration of the more severe cases in the selenium arm was also shorter compared to the placebo arm. There were no differences in length of hospital stay, duration of fever, frequency of immunologic response to the transplant, mortality, or other laboratory parameters related to liver or kidney function. The study is methodologically well conducted, but provides little information about the sample included (few demographic details). An existing selenium deficiency can be deduced from the available values despite the absence of a direct mention of it. The use of medication for the general prevention of mucositis could also have affected the direct influence of selenium on mucositis.


In dieser Studie wurden 77 Patienten mit akuter lymphatischer oder myeloischer Leukämie eingeschlossen, welche sich einer hochdosierten Chemotherapie und anschließend einer Stammzelltransplantation unterzogen. Ziel der Studie war es herauszufinden, ob die Einnahme von Selen das Auftreten von Mukositis beeinflussen kann. Es wurden zudem weitere Laborparameter und Symptome der Patienten erhoben. Für die Studie wurden die Patienten zufällig in zwei Gruppen eingeteilt, so dass eine Gruppe (38 Probanden) während der Chemotherapie und bis 14 Tage nach der Transplantation jeden Tag 2x täglich 200mcg Selen erhielten und die andere Gruppe ein Placebo. Insgesamt gab es keine Unterschiede über den Beginn, die Häufigkeit oder die Dauer der Mukositis zwischen den beiden Gruppen. Es gab allerdings bedeutsam weniger schwere Fälle von Mukositis in der Selen-Gruppe, und auch die Dauer der schwereren Fälle in der Selengruppe war kürzer im Vergleich zur Placebogruppe. Es gab keine Unterschiede bezüglich Länge des Krankenhausaufenthaltes, Dauer des aufgetretenen Fiebers, der Häufigkeit der immunologischen Abwehrreaktion auf das Transplantat oder der Sterblichkeit, sowie weitere Laborparameter bezüglich der Leber- oder Nierenfunktion. Die Studie ist methodisch gut durchgeführt, gibt aber wenig Informationen über die einbezogene Stichprobe (wenig demographische Angaben). Ein vorliegender Selenmangel kann trotz Fehlens eines direkten Erwähnens dessen aus den vorliegenden Werten abgeleitet werden. Auch der Einsatz von Medikamenten zur generellen Mukositisprävention könnte den direkten Einfluss von Selen auf die Mukositis beeinträchtigt haben.

Study Design

Prospective / Retrospective Prospective: forward-looking, examples include clinical trials, cohort studies, and long-term observational studies;</br>Retrospective: backward-looking, relying on existing data, examples include case-control studies and retrospective cohort studies Prospective
Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals Monocentric
Blinding No: Open, all parties are aware of group assignments;</br>Single: one party is unaware of group assignments (generally participants);</br>Double: two parties are unaware of group assignments (generally the participants and the researchers); </br>Triple: concealing group assignment from additional parties Double
Is randomized Yes
Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control No
Number of arms 2

Study characteristics

Inclusion criteria Patients with Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia, undergoing allogenic Hematopoietic Stem Cell Transplantation, all patients had adequate cardiac, pulmonary, renal, and hepatic function as determined by the institutional protocol

+ baseline indicates a mild selenium deficiency

Exclusion criteria Patients were excluded if they had a Karnofsky performance status under 70%
N randomized 77
Analysis PP: Per Protocol analysis, i.e. only participants included who adhered to the study protocol.</br>ITT: Intention-to-treat analysis, i.e. all randomized participants included regardless of any drop-outs or changes in assignment.</br>mITT: modified Intention-to-treat analysis can refer to analyses in which participants with missing outcome data are excluded or it can refer to analyses in which only participants who received at least one treatment dose are included. In this case, participants dropped out of the study prematurely for reasons unrelated to the treatment. PP Analysis
Specifications on analyses analyzed n=74
Countries of data collection Iran
LoE Level of evidence 2b Oxford 2009
Outcome timeline Data collection times T0: Baseline (start of chemotherapy)

T1: End of chemotherapy (6 days)

T2: +1 day: transplantation

T3: 21 days after transplantation

T4: Follow-up after 3 months

Characteristics of participants

Setting Refers to cancer therapy setting.</br>- Curative therapy: aims to completely eradicate a disease and achieve a full recovery; </br>- Neo-adjuvant therapy: form of curative therapy, given before the primary treatment for cancer (usually surgery); </br>- Adjuvant therapy: form of curative therapy, given after the primary treatment for cancer (usually surgery); </br>- Palliative therapy: focuses on providing relief from symptoms and improving the quality of life for patients, without necessarily targeting the underlying disease; </br>- Active surveillance: involves close monitoring of disease progression without any intervention (typically used for prostate cancer);</br>- No therapy setting: Patients who completed therapy/are currently not in cancer treatment, cancer survivors. Curative
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included Hematologic Cancers - Leukemia (Acute Lymphocytic/Acute Myeloid/Chronic Lymphocytic/Chronic Myeloid)
Cancer stages Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;</br>Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis NA
Specifications on cancer stages Patients in different stages of complete remission: CR1, CR2, CR3
Comorbidities NI
Current cancer therapies Chemotherapy, Stem cell or bone marrow transplant
Specifications on cancer therapies The high-dose chemotherapy included busulfan 4 mg/kg p.o. in divided doses daily for 4 days (total dose 16 mg/kg) followed by cyclophsophamide 60 mg/kg once daily i.v. for 2 days (total dose 120 mg/kg) + peripheral blood hematopoietic stem cells 1 day after completion of chemotherapy
Previous cancer therapies NI
Gender Mixed
Gender specifications 43.2% female
Age groups Adults (18+)
Age groups specification Mean; median; range in years:

Intervention arm 33.3; 32; 18-55 and placebo arm 34; 32; 18-55

Arms

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment Intervention
Number of participants (arm) N randomized 38
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date 1
Drop-out reasons Patient was non-adherent
Intervention Selenium tablet

+ every arm similar regime for prevention oc mucositis: 20 drops of nystatin every 3h, a chewable tablet of sucralfate 500mg every 8h and mouth washes containing 10 cc chlorhexidine 0.02% plus 10 cc diluted povidone iodine every 3h

Dosage and regime Selenium tablet (Webber Naturals, Coquitlam, BC, Canada, 200 mcg) twice daily, from the starting day of HDC to 14 days after transplantation
One-time application No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information. 21
Side effects / Interactions NI
Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment Placebo
Number of participants (arm) N randomized 39
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date 2
Drop-out reasons N=1 patient died, n=1 patient was non-adherent
Intervention Placebo

+ every arm similar regime for prevention oc mucositis: 20 drops of nystatin every 3 h, a chewable tablet of sucralfate 500mg every 8 h and mouth washes containing 10 cc chlorhexidine 0.02% plus 10 cc diluted povidone iodine every 3h

Dosage and regime Placebo twice daily, from the starting day of HDC to 14 days after transplantation
One-time application No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information. 21
Side effects / Interactions NI

Outcomes

Mucositis

Outcome type As specificed by the authors Primary
Outcome specification Oral Mucositis
Type of measurement WHO-Scale (World Health Organisation)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". Onset of mucositis after transplantation comparable in both selenium and placebo arm; p=0.81
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". Overall: Cumulative incidence (grade 1-4) comparable in both selenium arm (83.8%) and placebo arm (81.1%); p=0.76; grade 3-4 mucositis significantly lower in selenium arm (10.8%) compared to placebo arm (35.1%); p=0.013 (grade 4: 2x in placebo arm, 0x in selenium arm)


Mean duration comparable (p=0.048), only duration of objective mucositis from grade 2 to 4 and back was significantly shorter in the selenium arm (3.6±1.84 days) than in the placebo arm (5.3±2.2 days); p=0.014

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process some concerns
Bias due to deviation from intended intervention (assignment to intervention) some concerns
Bias due to deviation from intended intervention (adhering to intervention) NA
Bias due to missing outcome data low risk
Bias in measurement of the outcome some concerns
Bias in selection of the reported result some concerns
Other sources of bias some concerns
Overall RoB judgment high risk

Haematological indices

Outcome type As specificed by the authors Secondary
Outcome specification Neutrophil and platelet engraftment time (the time point after transplantation at which a patient can maintain a sustained ANC of 4500 cells/mm3 and a sustained platelet count of at least 20 000/mm3 lasting 3 consecutive days without transfusions during hospital stay)
Type of measurement Blood Test
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". No difference between arms (p=0.32, p=0.87)
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". NA
Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process some concerns
Bias due to deviation from intended intervention (assignment to intervention) some concerns
Bias due to deviation from intended intervention (adhering to intervention) NA
Bias due to missing outcome data low risk
Bias in measurement of the outcome low risk
Bias in selection of the reported result some concerns
Other sources of bias some concerns
Overall RoB judgment some concerns

Fever

Outcome type As specificed by the authors Secondary
Outcome specification Duration of fever
Type of measurement Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". Fever above 38.3°C in 72 patients (97.3%) during neutropenia; duration of fever comparable in both selenium and placebo arm ; p=0.98
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". NA
Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process some concerns
Bias due to deviation from intended intervention (assignment to intervention) some concerns
Bias due to deviation from intended intervention (adhering to intervention) NA
Bias due to missing outcome data low risk
Bias in measurement of the outcome low risk
Bias in selection of the reported result some concerns
Other sources of bias some concerns
Overall RoB judgment some concerns

Length of hospital stay

Outcome type As specificed by the authors Secondary
Outcome specification NA
Type of measurement Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". No difference between selenium arm (26.92±6.26 days) and placebo arm (25.81±4.33 days); p=0.38
Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process some concerns
Bias due to deviation from intended intervention (assignment to intervention) some concerns
Bias due to deviation from intended intervention (adhering to intervention) NA
Bias due to missing outcome data low risk
Bias in measurement of the outcome low risk
Bias in selection of the reported result some concerns
Other sources of bias some concerns
Overall RoB judgment some concerns

Incidence of acute GVHD (Graft-Versus-Host Disease)

Outcome type As specificed by the authors Secondary
Outcome specification Graft-versus-host disease is a condition where the donated stem cells (graft) attack the recipient's body (host)
Type of measurement Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". Overall: No difference between the arms; p= 0.35
Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process some concerns
Bias due to deviation from intended intervention (assignment to intervention) some concerns
Bias due to deviation from intended intervention (adhering to intervention) NA
Bias due to missing outcome data low risk
Bias in measurement of the outcome low risk
Bias in selection of the reported result some concerns
Other sources of bias some concerns
Overall RoB judgment some concerns

Mortality rate

Outcome type As specificed by the authors Secondary
Outcome specification At 3 months
Type of measurement Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". No difference between the arms; p= 0.69
Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process some concerns
Bias due to deviation from intended intervention (assignment to intervention) some concerns
Bias due to deviation from intended intervention (adhering to intervention) low risk
Bias due to missing outcome data low risk
Bias in measurement of the outcome some concerns
Bias in selection of the reported result some concerns
Other sources of bias some concerns
Overall RoB judgment some concerns

Non-haematological indices

Outcome type As specificed by the authors Secondary
Outcome specification Serum creatinine level and blood urea nitrogen test for renal function assessment and aspartate aminotransferase and alanine transaminase for liver function assessment, recorded daily
Type of measurement Blood Test
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". Overall: No difference between arms for increase in serum creatinine; p=0.31 or increase in aspartate aminotransferase and alanine transaminase: p=0.62
Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process some concerns
Bias due to deviation from intended intervention (assignment to intervention) some concerns
Bias due to deviation from intended intervention (adhering to intervention) NA
Bias due to missing outcome data low risk
Bias in measurement of the outcome low risk
Bias in selection of the reported result some concerns
Other sources of bias some concerns
Overall RoB judgment some concerns

Selenium level

Outcome type As specificed by the authors Others
Outcome specification NA
Type of measurement Blood Test
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall". Significant difference in mean serum selenium level between two arms at 14 days after transplantation (8.34 mcg/dL in the selenium arm vs 7.36 mcg/dL in the placebo arm), p=0.018
Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process some concerns
Bias due to deviation from intended intervention (assignment to intervention) some concerns
Bias due to deviation from intended intervention (adhering to intervention) NA
Bias due to missing outcome data low risk
Bias in measurement of the outcome low risk
Bias in selection of the reported result some concerns
Other sources of bias some concerns
Overall RoB judgment some concerns

Funding and Conflicts of Interest

Funding NI
Conflicts of Interest According to authors no conflict of interest.

Further points for assessing the study

Sample

Power analysis performed Yes
- Sample size corresponds to power analysis Yes
- Reasons for insufficient sample size based on power analysis NA
If no power analysis performed: at least moderate sample size (n >= 30 per arm) NA
Ethnicity mentioned No

Alternative Explanation

Other explanations for an effect besides the investigated intervention No
- Possibility of attention effects NA
- Possibility of placebo effects NA
- Other reasons NA

Statistics

Correct use of parametric and non-parametric tests Testing for normal distribution only necessary if parametric tests are used, NI: use of parametric tests without report of normal distribution testing NI
Correction for multiple testing No
Measurement of compliance No
Consistent reporting in numbers (figures, flowchart, abstract, results) Yes
Comprehensive and coherent reporting Yes
Cross-over No
- Sufficient washout period NA
- Tested for carry-over effects NA
- Tested for sequence effects NA

Interpretation of results

Effect sizes reported (clinical vs. statistical significance) No
Side effects systematically recorded No
Side effects considered in result interpretation NA
Ethics votum Yes


Additional Notes

PRO:

  • Ethics approval obtained.
  • Placebo-controlled and double-blind.
  • Power analysis and adherence to sample size.
  • Detailed protocol description.
  • Measurement of selenium levels.


CONTRA:

  • No compliance verification.
  • No information on side effects or potential interactions with medications for mucositis prevention.
  • Focus on small effects rather than clinically relevant ones and those corresponding to the predefined research question.
  • Despite stating that previous studies show most stem cell transplant patients suffer from selenium deficiency, this was not tested or described here.
  • Very few demographic variables provided.
  • No verification of successful blinding.
  • No information on whether participants could or did take other supplements.
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