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

Reference ↗
Title	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
Topic	Selenium
Author	Muecke, R, Micke, O, Schomburg, L, Buentzel, J, Glatzel, M, Baaske, D, Berndt-Skorka, R, Prott, FJ, Reichl, B, Kisters, K, Schaefer, U, Huebner, J, Eich, HT, Kundt, G, Adamietz, IA
Year	2013
Journal	Radiation Oncology
DOI	https://link.springer.com/article/10.1186/1748-717X-8-72

Study Note

This study is a subgroup-analysis of Muecke et al. (2010): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology. There is a follow-up study to the 2010 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. This is a further analysis of Muecke et al. (2010): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology - in this study the arm was divided into those with a large target volume and those with a small one. This showed that the reduction in diarrhea due to selenium was only significant in the arm with a large target volume, i.e. the irradiated part of the pelvis. This indicates that the effect originally found is significantly influenced by the size of the target volume.

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. Es ist eine weitere Analyse der Studie Muecke et al. (2010): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology - in dieser Studie wurde die Gruppe geteilt, in jeden mit einem großen Zielvolumen und jeden mit einem kleinen. Hierbei zeigte sich, dass die Reduzierung des Durchfalls durch Selen nur noch bedeutsam in der Gruppe mit einem großen Zielvolumen, also dem bestrahlten Anteil des Beckens ist. Was darauf hinweist, dass der ursprünglich gefundene Effekt von der Größe des Zielvolumens maßgeblich beeinflusst wird.

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	NA
Exclusion criteria	NA
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	NA

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 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	Female
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

Toxicity

Outcome type As specificed by the authors	Primary
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".	Overall Analysis: Median PTV in both arms: 1302 ml (916-4608); mean PTV in the intervention arm: 1604 ml vs. 1447 ml in the control arm; p=0.55 If PTV ≤ 1302 ml (n=41), then occurrence of at least grade 2 diarrhea in the intervention arm was 22.3% (4/18 patients) vs. 34.8% (8/23 patients) in the control arm; p=0.50 With PTV > 1302 ml (n=40), the intervention arm had 19.1% (4/21 patients) vs. the control arm with 52.6% (10/19 patients); p=0.046
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)	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 by the pharmaceutical company biosyn, Fellbach, Germany.“
Conflicts of Interest	„RM has had conference and travel expenses reimbursed and has received lecture fees from the pharmaceutical company biosyn-Arzneimittel GmbH, biosyn-Arzneimittel GmbH is not financing this manuscript. The other authors declare that they have no competing interests.“

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	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	No
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.