Walsh et al. (2010): Use of alpha,25-dihydroxyvitamin D3 treatment to stimulate immune infiltration into head and neck squamous cell carcinoma

Reference ↗
Title	Use of alpha,25-dihydroxyvitamin D3 treatment to stimulate immune infiltration into head and neck squamous cell carcinoma
Topic	Vitamin D
Author	Walsh, JE, Clark, A-M, Day, TA, Gillespie, MB, Young, MRI
Year	2010
Journal	Human immunology
DOI	https://doi.org/10.1016/j.humimm.2010.04.008

Brief summary

In this study, two groups of neck and head tumor patients were compared with regard to the progression-free interval. One group received vitamin D for 3 weeks before the tumor operation and the other group received nothing. In the vitamin D group, it took significantly longer for the disease to progress. As only a very small sample was examined (16 patients per group), this study only provides initial indications of the effectiveness of vitamin D prior to surgery.

In dieser Studie wurden zwei Gruppen von Hals-Kopf Tumor Patienten hinsichtlich des progressionsfreien Intervalls miteinander verglichen. Eine Gruppe bekam 3 Wochen vor der der Tumoroperation 3 Wochen lang Vitamin D und die andere Gruppe bekam nichts. Bei der Vitamin-D-Gruppe dauerte es bedeutsam länger bis zum Fortschreiten der Krankheit. Da nur eine sehr kleine Stichprobe untersucht wurde (16 Patienten pro Gruppe), liefert diese Studie nur erste Hinweise auf die Wirksamkeit von Vitamin D vor einer Operation.

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	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 newly diagnosed head and neck squamous cell carcinoma who were being scheduled for surgery
Exclusion criteria	Had received immunotherapy or radiation treatment in the previous 3 weeks or concurrent malignancies
N randomized	32
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	NI
Countries of data collection	NI
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	NI

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	Head and Neck Cancers - Oral 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	The range of disease stages, based on pathologic evaluation, did not differ among patients enrolled in the two arms
Comorbidities	No
Current cancer therapies	Surgery
Specifications on cancer therapies	Surgical excision
Previous cancer therapies	Chemotherapy, No therapy, Radiation therapy
Gender	Mixed
Gender specifications	44% female, 56% male
Age groups	Adults (18+)
Age groups specification	Range: 45-92 Intervention arm: mean: 66 Control arm: mean: 63

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	16
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	1,25(OH)2 D
Dosage and regime	4 μg of 1,25(OH)2 D for each of 3 sequential days, followed by 4 days of no treatment
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	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	16
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	Untreated
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.	21
Side effects / Interactions	NA

Outcomes

DFS (Disease-Free Survival)

Outcome type As specificed by the authors	NI
Outcome specification	Time between surgical treatment and recurrence of detectable disease
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".	Longer time to recurrence in the intervention arm than in the control arm (p = 0.048), median time to recurrence for the control arm was 181 days, whereas the median time to recurrence for the intervention arm was 620 days
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".	NI

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	high risk
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	NA
Overall RoB judgment	high risk

Funding and Conflicts of Interest

Funding	Supported by the Clinical Science and Biomedical Laboratory Research and Development Services of the Department of Veterans Affairs and by grants R01CA85266 and R01CA128837 from the National Institutes of Health to MRIY
Conflicts of Interest	NI

Further points for assessing the study

Sample

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

Alternative Explanation

Other explanations for an effect besides the investigated intervention
- Possibility of attention effects	?
- Possibility of placebo effects	?
- Other reasons	?

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
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over
- Sufficient washout period	?
- Tested for carry-over effects	?
- Tested for sequence effects	?

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	?
Side effects systematically recorded	?
Side effects considered in result interpretation	?
Ethics votum	?

Additional Notes

PRO:

• No dropout

CONTRA:

• No blinding, control group receives nothing
• No information on vitamin D level, possible group differences
• Very small sample size
• Poor report quality, e.g. hardly any information on baseline characteristics