Muecke et al. (2010): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology

Reference ↗
Title	Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology
Topic	Selenium
Author	Muecke, R, Schomburg, L, Glatzel, M, Berndt-Skorka, R, Baaske, D, Reichl, B, Buentzel, J, Kundt, G, Prott, FJ, Devries, A, Stoll, G, Kisters, K, Bruns, F, Schaefer, U, Willich, N, Micke, O
Year	2010
Journal	International Journal of Radiation Oncology – Biology – Physics
DOI	https://doi.org/10.1016/j.ijrobp.2009.08.013

Study Note

One study with a subgroup-analysis of the sample was published: Muecke et al. (2013): Impact of treatment planning target volumen (PTV) size on radiation induced diarrhoea following selenium supplementation in gynecologic radiation oncology-a subgroup analysis of a multicenter, phase III trial and one follow-up study: Muecke et al. (2014): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology: follow-up analysis of the survival data 6 years after cessation of randomization

Brief summary

This study included 81 patients with uterine or cervical cancer. They were randomly divided into two arms and received either 500µg selenium in addition to radiotherapy or no additional preparations. All participants had a selenium deficiency at the beginning of the study. After about seven weeks and thus the end of radiotherapy, a significantly increased selenium concentration was found in the selenium arm compared to the control arm. There was also a lower incidence of radiotherapy-induced diarrhea in the selenium arm compared to the control arm. However, no differences were found with regard to performance status, quality of life, overall survival or disease-free survival after five years. The study impresses with a clear presentation of the results and an examination of the selenium concentration of the participants. However, little information is given about the patients beyond their disease and selenium status and accordingly none can be included in the interpretation of the results. Overall, however, the study can be regarded as methodologically sound.

Diese Studie schloss 81 Patientinnen mit Gebärmutter- oder Gebärmutterhalskrebs ein. Sie wurden zufällig in zwei Gruppen eingeteilt und erhielten entweder zusätzlich zur Radiotherapie 500µg Selen oder keine zusätzlichen Präparate. Alle Probanden hatten zu Beginn der Studie ein Selendefizit. Nach etwa sieben Wochen und damit dem Ende der Radiotherapie zeigte sich eine bedeutsam erhöhte Selenkonzentration in der Selen-Gruppe im Vergleich zur Kontrollgruppe. Es zeigte sich zudem eine geringere Häufigkeit von durch die Radiotherapie verursachtem Durchfall in der Selengruppe im Vergleich zur Kontrollgruppe. Es konnten allerdings keine Unterschiede bezüglich dem Performanz-status, der Lebensqualität oder dem Gesamtüberleben oder dem Krankheitsfreien-Überleben nach fünf Jahren festgestellt werden. Die Studie überzeugt durch eine übersichtliche Darstellung der Ergebnisse und einer Prüfung der Selenkonzentration der Probanden. Allerdings werden über Krankheit- und Selenstatus hinaus wenig Informationen zu den Patientinnen gegeben und dementsprechend können auch keine in die Interpretation der Ergebnisse einbezogen werden. Im Ganzen kann die Studie aber als methodisch solide betrachtet werden.

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	Multicentric
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	No
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 histopathologically confirmed carcinomas of the cervix or corpus uteri with a significant whole-blood selenium deficiency (i.e., concentration <85 µg/L) after curative surgical treatment
Exclusion criteria	Patients with metastatic disease, diarrhea before radiotherapy, radiochemotherapy, or supplementation of selenium before radiotherapy, as well as patients who had undergone previous pelvic radiotherapy
N randomized	81
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.	NI
Specifications on analyses	No information about possible drop-out
Countries of data collection	Germany
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1: Half of the radiotherapy (about 4 weeks) T2: End of radiotherapy T3: 6 weeks after radiotherapy

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, Adjuvant
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Gynecologic Cancers - Cervical Cancer
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	Early Stage, Advanced Stage
Specifications on cancer stages	FIGO Stadium I-IV
Comorbidities	Selenium concentration (whole-blood) lower than 84µg/L
Current cancer therapies	Radiation therapy
Specifications on cancer therapies	External radiotherapy was delivered with a 6- to 18-MV linear accelerator. Five fractions per week were planned. Treatment was given with a three- to four-field box technique. Radiotherapy was given as three-dimensional conformal radiotherapy. Computed tomography–based treatment planning was performed in all cases. The clinical target volume encompassed the primary tumor region and the pelvic regional lymph nodes. High-dose rate brachytherapy of the vagina was considered optional in accordance with German evidence-based guidelines. Brachytherapy was delivered by iridium 192 afterloading.
Previous cancer therapies	Surgery
Gender	Mixed
Gender specifications	NA
Age groups	Adults (18+)
Age groups specification	Mean (SD), range: 64.3 (10.1), 31–80 years

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	39
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	0
Drop-out reasons	NA
Intervention	Sodium Selenite
Dosage and regime	500 µg selenium in the form of sodium selenite (selenase®), orally on radiotherapy days and 300 µg on days without radiotherapy
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.	56
Side effects / Interactions	No side effects

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Passive control
Number of participants (arm) N randomized	42
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	0
Drop-out reasons	NA
Intervention	Usual Care
Dosage and regime	NA
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.	56
Side effects / Interactions	NA

Outcomes

Selenium level

Outcome type As specificed by the authors	Primary
Outcome specification	Efficiancy of supplementation
Type of measurement	GFAAS (Graphite Furnace Atomic Absorption Spectrometry)
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 at baseline, but significantly higher in the intervention arm than the control arm at mid-study (intervention arm: 93.2 µg/L vs. control arm: 67.3 µg/L) and end of study (intervention arm: 90.9±19.9 µg/L vs. control arm: 61.4±15.5 µg/L; p < 0.001)
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".	After 6 weeks post radiotherapy, levels between arms were comparable

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)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	some concerns
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

Toxicity

Outcome type As specificed by the authors	Secondary
Outcome specification	Diarrhea
Type of measurement	CTCAE (Common Terminology Criteria of Adverse Events)
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".	Lower incidence of grade 1-3 diarrhea at mid-study in the intervention arm compared to the control arm; p = 0.01
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 incidence of grade 2 diarrhea: intervention arm 20.5% vs. control arm 44.5% (p = 0.04)

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)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	some concerns
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

Performance Status

Outcome type As specificed by the authors	Secondary
Outcome specification	NA
Type of measurement	ECOG Performance Status Scale (Eastern Cooperative Oncology Group)
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
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 arms

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)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	some concerns
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

Quality of life

Outcome type As specificed by the authors	Secondary
Outcome specification	NA
Type of measurement	VAS (Visual Analogue Scale)
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
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 arms

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)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	some concerns
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

DFS (Disease-Free Survival)

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".	Median follow-up of 49 months (range, 0-75): 5-year disease free survival in the intervention arm was 80.1% vs. 83.2% in the control arm, no significant difference; p = 0.74

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)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	some concerns
Bias in measurement of the outcome	some concerns
Bias in selection of the reported result	some concerns
Other sources of bias	low risk
Overall RoB judgment	some concerns

OS (Overall Survival)

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".	Median follow-up of 51 months (range 6-75): 5-year overall survival in the intervention arm was 91.9% vs. 83.1% in the control arm, no significant difference; p = 0.34

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)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	some concerns
Bias in measurement of the outcome	some concerns
Bias in selection of the reported result	some concerns
Other sources of bias	low risk
Overall RoB judgment	some concerns

Funding and Conflicts of Interest

Funding	"Supported by a grant from biosyn Arzneimittel GmbH, Fellbach, Germany"
Conflicts of Interest	The authors declare 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	Yes
- Possibility of attention effects	NA
- Possibility of placebo effects	Yes
- Other reasons	Open study design (knowledge of group assigment)

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	Yes
Correction for multiple testing	No
Measurement of compliance	NI
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	NI
Side effects considered in result interpretation	Yes
Ethics votum	Yes

Additional Notes

PRO:

• Ethics approval obtained.
• Testing for selenium deficiency.
• Power analysis conducted.
• Comparability of arms established.
• Very detailed and clear presentation of results.

CONTRA:

• No placebo control.
• No information on possible blinding.
• No information on potential dropouts.
• "Total dose of external radiotherapy (Gy)" at p=0.06 — close to significance between arms.
• No testing whether selenium significantly decreases in the control arm.
• No verification of supplementation outside the study.
• Few demographic variables provided.