Mix et al. (2015): Randomized phase II trial of selenomethionine as a modulator of efficacy and toxicity of chemoradiation in squamous cell carcinoma of the head and neck

Reference ↗
Title	Randomized phase II trial of selenomethionine as a modulator of efficacy and toxicity of chemoradiation in squamous cell carcinoma of the head and neck
Topic	Selenium
Author	Mix, M, Singh, AK, Tills, M, Dibaj, S, Groman, A, Jaggernauth, W, Rustum, Y, Jameson, MB
Year	2015
Journal	World journal of clinical oncology
DOI	https://doi.org/10.5306/wjco.v6.i5.166

Brief summary

In this study, 18 patients with squamous cell carcinoma of the head and neck who were undergoing chemotherapy and radiotherapy were randomly assigned to two arms in which they either received selenium seven days before, during and three weeks after treatment or a placebo. The results after seven weeks showed no differences between the arms in the development of oral mucosal inflammation or tumor response to treatment. There were also no differences in overall survival, progression-free survival or quality of life at twelve months. There were a number of side effects of chemotherapy and radiotherapy in both arms. However, no direct comparison was carried out here. Overall, the sample is very small, which may well mean that differences were not significant, but as described, comparisons were not always made. Overall, the reporting is very superficial in view of the general study descriptions/framework conditions and in particular the description of the results.

In dieser Studie wurden 18 Patienten mit Plattenepithelkarzinom des Kopf-Hals-Bereiches, welche sich einer Chemo- und Radiotherapie unterzogen zufällig zwei Gruppen zugeordnet, in der sie entweder Selen sieben Tage vor, während der Behandlung und drei Wochen danach bekamen oder ein Placebo. Die Ergebnisse nach sieben Wochen zeigen keine Unterschiede zwischen den Gruppen bezüglich der Entwicklung von Mundschleimhautentzündung, oder der Tumorantwort auf die Behandlung. Es zeigen sich auch keine Unterschiede im Gesamtüberleben oder dem Progressionsfreien-Überleben, sowie der Lebensqualität nach zwölf Monaten. Es zeigten sich eine Reihe von Nebenwirkungen der Chemo- und Radiotherapie in beiden Gruppen. Hier wurde allerdings kein Gruppenvergleich durchgeführt. Insgesamt ist die Stichprobe sehr klein, dies kann durchaus dazu führen, dass Unterschiede nicht signifikant geworden sind, allerdings wurden wie beschrieben auch nicht immer Vergleiche durchgeführt. Insgesamt ist die Berichterstattung sehr oberflächlich in Anbetracht der allgemeinen Studienbeschreibungen/ Rahmenbedingungen und insbesondere der Ergebnisbeschreibung.

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	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 stage III or IV Head and Neck Squamous Cell Carcinoma scheduled for 7 weeks of concurrent cisplatin and radiation, biopsy-proven locally advanced Head and Neck Squamous Cell Carcinoma, in oral cavity, oropharynx, hypopharynx, larynx, nasopharynx, or paranasal sinuses, Eastern Cooperative Oncology Group performance status of 0-2
Exclusion criteria	Patients who underwent definitive surgery (anything beyond excisional biopsy), those with Stage IVc disease (nonregional metastatic disease), those with malignancy within the previous five years, prior radiotherapy, HIV or hepatitis C positivity, platinum hypersensitivity, inability to tolerate oral medications (in absence of feeding tube), symptomatic peripheral neuropathy, planned use of amifostine, and significant comorbidity
N randomized	18
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.	ITT Analysis
Specifications on analyses	Three interim analyses were planned: the first after 20 patients have completed Chemo-Radiotherapy to ensure toxicity in the selenium arm was not unacceptably high and the second and third after one third and two thirds of the patients had been followed for at least 18 months
Countries of data collection	NI
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1: Week 4 T2: Week 7 during treatment T3: Week 6-8 post-treatment T4: Follow-up 3 months after completion of the study and then at further 3-month intervals over 2 years, then every 6 months until 5 years thereafter

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	Skin Cancer - Squamous Cell Carcinoma
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	Advanced Stage
Specifications on cancer stages	Head and Neck region; stage III or IV
Comorbidities	No selenium deficit at baseline
Current cancer therapies	Chemotherapy, Radiation therapy
Specifications on cancer therapies	Radiotherapy: 70 Gy at 2 Gy per fraction in 35 daily treatments, 5 days a week for 7 weeks, chemotherapy: Cisplatin dosed at 100 mg/m² intravenously over 3h in 1000mL saline on days 1, 22, and 43 of radiotherapy
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	17/18 male
Age groups	Adults (18+)
Age groups specification	Median: 57 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	10
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 complained of "bad taste" and withdrew from the trial
Intervention	Selenomethionine
Dosage and regime	Selenomethionine 3600 µg/m²(in 800 µg tablets) 2x daily 7 days before chemotherapy, during chemotherapy 1x daily, and daily for 3 weeks after chemotherapy
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.	49
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	8
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	Placebo
Dosage and regime	2x daily 7 days before chemotherapy, during chemotherapy 1x daily, and daily for 3 weeks after chemotherapy
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.	49
Side effects / Interactions	NI

Outcomes

Mucositis

Outcome type As specificed by the authors	Primary
Outcome specification	Grade 3 or 4
Type of measurement	NI
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 significant differences between arms (grade 3 intervention arm 2x, placebo arm 3x, no grade 4)

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	low risk
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	low risk
Bias in measurement of the outcome	some concerns
Bias in selection of the reported result	low risk
Other sources of bias	some concerns
Overall RoB judgment	some concerns

Tumor response

Outcome type As specificed by the authors	Secondary
Outcome specification	Complete response rate (CR)
Type of measurement	RECIST 1.0 Criteria (Response Evaluation Criteria in Solid Tumors)
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".	Only one patient from the intervention arm did not reach CR and died

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	low risk
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	low risk
Bias in measurement of the outcome	low risk
Bias in selection of the reported result	low risk
Other sources of bias	some concerns
Overall RoB judgment	low risk

PFS (Progression-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".	After 12 months: No significant differences between arms

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	low risk
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	low risk
Bias in measurement of the outcome	low risk
Bias in selection of the reported result	low risk
Other sources of bias	some concerns
Overall RoB judgment	low risk

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".	After 12 months: No significant differences between arms

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	low risk
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	low risk
Bias in measurement of the outcome	low risk
Bias in selection of the reported result	low risk
Other sources of bias	some concerns
Overall RoB judgment	low risk

Quality of life

Outcome type As specificed by the authors	Secondary
Outcome specification	Measured with EORTC C-30 Version 3 and EORTC QLQ - H&N35
Type of measurement	EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire)
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 significant difference for the 7 weeks of intervention
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 significant difference for week 6-8 post-treatment and Follow-up within a year

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	low risk
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	low risk
Bias in measurement of the outcome	some concerns
Bias in selection of the reported result	low risk
Other sources of bias	some concerns
Overall RoB judgment	some concerns

Toxicity

Outcome type As specificed by the authors	Secondary
Outcome specification	Other treatment-associated side effects such as xerostomia, renal impairment, hearing dysfunction, and myelosuppression
Type of measurement	NI
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: Hearing dysfunction n=1 each in the intervention arm and placebo arm; elevated creatinine n=1 in the placebo arm; myelosuppression: anemia in the placebo arm n=1; leukopenia in the intervention arm n=3 and placebo arm n=2; dermatitis in the intervention arm n=2; dry mouth in the placebo arm n=2; dysgeusia in the intervention arm n=2, placebo arm n=1; odyno-/dysphagia in the intervention arm n=1, placebo arm n=2; oral/throat pain in the placebo arm n=2; mucus/sputum intervention arm n=3, placebo arm n=1

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	low risk
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	low risk
Bias in measurement of the outcome	some concerns
Bias in selection of the reported result	low risk
Other sources of bias	some concerns
Overall RoB judgment	some concerns

Funding and Conflicts of Interest

Funding	“Supported by A grant from the Health Research Council of New Zealand (in part).“
Conflicts of Interest	Authors declare no conflict of interest.

Further points for assessing the study

Sample

Power analysis performed	Yes
- Sample size corresponds to power analysis	No
- Reasons for insufficient sample size based on power analysis	"The trial was planned to recruit 80 patients but, due to funding constraints, recruitment was suspended after 18 patients and an interim analysis was performed to see if a sufficiently promising effect could be discerned to warrant further funding."
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	No
Ethnicity mentioned	Yes

Alternative Explanation

Other explanations for an effect besides the investigated intervention	Yes
- Possibility of attention effects	NA
- Possibility of placebo effects	NA
- Other reasons	Small sample size, possibility of beta error

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	Yes
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

Note: Chemotherapy compliance: 8x every 3 cycles of cisplatin, 6x 2 cycles, 2x 1 cycle, 1x, 1x no chemotherapy

PRO:

• Ethics approval obtained.
• Participants were instructed to keep a diary of tablet intake.
• Intent-to-treat analysis conducted.
• Sample size calculation performed.
• Measurement of selenium concentration at baseline (no group difference).
• Comparability of groups at baseline established.

CONTRA:

• Very small sample size.
• No indication of selenium deficiencies present.
• Very superficial reporting, particularly in the results section, with little information on blinding.
• No group comparison for number of chemotherapy/radiotherapy side effects or selenium concentration.