Akiba et al. (2018): Vitamin D Supplementation and Survival of Patients with Non–small Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial

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Title	Vitamin D Supplementation and Survival of Patients with Non–small Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial
Topic	Vitamin D
Author	Akiba, T, Morikawa, T, Odaka, M, Nakada, T, Kamiya, N, Yamashita, M, Yabe, M, Inagaki, T, Asano, H, Mori, S, Tsukamoto, Y, Urashima, M
Year	2018
Journal	Clinical Cancer Research
DOI	https://doi.org/10.1158/1078-0432.CCR-18-0483

Brief summary

FEHLT IN EVIDENZTABELLE

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	Histopathologically diagnosed as having NSCLC (adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, or large cell lung carcinoma); with stage IA to IIIA; aged 20 to 75 years at entry; diagnosed and operated at any one of four Jikei University Hospitals at Shimbashi, Kashiwa, Chofu, and Katsushika; with tumor totally resected; discharged without major complications; and could visit the Jikei University Hospitals (Tokyo, Japan) and be followed-up for as long as possible
Exclusion criteria	Already taking a vitamin D supplement or active vitamin D; had a history of urinary tract stones; and other difficulties as judged by the surgeon in charge
N randomized	155
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, ITT Analysis
Specifications on analyses	Kaplan–Meier survival curves were drawn and compared using the log-rank test in an intention-to-treat analysis
Countries of data collection	Japan
LoE Level of evidence	Level 2 Oxford 2011
Outcome timeline Data collection times	T0: Baseline

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	Lung Cancer - Non-Small Cell Lung 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	IA-IIIA
Comorbidities	NI
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	Oral or injection chemotherapy was administered to the patients according to the stage, except in stage IA and tumor size less than 2 cm
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	38 (25%) female
Age groups	Adults (18+)
Age groups specification	Mean (SD): 68 (9)

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	77
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	5
Drop-out reasons	Lost to follow-up
Intervention	Vitamin D
Dosage and regime	Two capsules of vitamin D3 (total 1,200 IU/day), for 12 months
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.	365
Side effects / Interactions	According to authors no side effects

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	78
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	6
Drop-out reasons	Lost to follow-up
Intervention	Placebo
Dosage and regime	Two capsule form and identical in appearance and taste, containing sesame oil, gelatin derived from swine, and glycerin, for 12 months
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.	365
Side effects / Interactions	According to authors no side effects

Outcomes

RFS (Recurrence-Free Survival)

Outcome type As specificed by the authors	Primary
Outcome specification	5-year recurrence-free survival: the time from the supplement start date to the earlier date of relapse of cancer or death from any cause
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 significant differences (p=0.64)

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	high risk
Bias in measurement of the outcome	low risk
Bias in selection of the reported result	low risk
Other sources of bias	NA
Overall RoB judgment	high risk

OS (Overall Survival)

Outcome type As specificed by the authors	Secondary
Outcome specification	5-year overall survival: the time from the supplement start date to the date of death from any cause
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 significant differences (p=0.63)

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	high risk
Bias in measurement of the outcome	low risk
Bias in selection of the reported result	low risk
Other sources of bias	NA
Overall RoB judgment	high risk

Vitamin D 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".	Intervention arm: mean levels of 25(OH)D increased significantly from 21 to 39 ng/mL (p=0.0001), placebo arm: no significant change (p=0.14)
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	NA
Bias due to deviation from intended intervention (assignment to intervention)	NA
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	NA
Bias in measurement of the outcome	NA
Bias in selection of the reported result	NA
Other sources of bias	NA
Overall RoB judgment	NA

Funding and Conflicts of Interest

Funding	Supported by the Ministry of Education, Culture, Sports, Science, and Technology in the Japan-Supported Program for the Strategic Research Foundation at Private Universities and by JSPH KAKENHI grant number: 22501060
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	No
- Reasons for insufficient sample size based on power analysis	At the midterm analysis in November 2014, 5-year RFS of the vitamin D and placebo groups was much closer than expected. As a result, the reestimated sample size was exploded from 300 to much more than 1,000. Thus, it was decided to stop new enrollment and terminate this trial after further 3-year follow-up. Consequently, a total of 155 patients with NSCLC were randomly assigned.
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	NA
Measurement of compliance	Yes
Consistent reporting in numbers (figures, flowchart, abstract, results)	No
Comprehensive and coherent reporting	No
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 vote
• Groups comparable to baseline
• Double blinding
• Power analysis with planned interim analysis
• Intention-to-treat analysis for overall survival

CONTRA:

• Flowchart: placebo arm n=78, where it was noted n=78 received intervention (placebo), but n=8 did not receive it
• Due to lack of efficacy on RSF at interim analysis, recruitment was stopped, so that neither the previously calculated nor recalculated number of subjects was reached
• No indication of the number of subjects per group for low or high 25(OH)D level
• Low number of subjects for subgroup analyses